PhosphataseWiki - User contributions [en]

Phosphatase Subfamily Auxilin

2025-03-14T00:55:42Z

Gerard: /* Domain Structure */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTEN|Family PTEN]]: [[Phosphatase_Subfamily_Auxilin|Subfamily Auxilin]]

Auxillins are pseudophosphatases and kinases that bind phospholipids and are involved in clathrin-coated vesicle function. Human forms are associated with Parkinson's disease.

===Evolution===
Auxilins are metazoan-specific. Human has two members: auxilin and DNAJC6, which emerged by gene duplication in jawed vertebrates. The DNAJ domain appears to be much older and has orthologs in Arabidopsis (JAC1) and yeast (Swa2) that are also involved in clathrin uncoating, but lack phosphatase and kinase domains.

===Domain Structure===
Most auxillins are 1000-1500 AA long, with an N-terminal GAK kinase domain, a PTEN-like phosphatase domain in the middle, and a DnaJ domain at the very C-terminus. One of the two human homologs, DNAJC6/Auxillin-1 has lost the kinase domain, and the C. elegans homolog has lost all but the kinase domain (though other nematodes have a more complete gene).

===Functions===
Human GAK is known as Cyclin G-Associated Kinase, and associated with Cyclin G and CDK5 <cite>Kanaoka</cite>. Both GAK and DNAJC6 are genetically implicated in Parkinson's disease and GAK physically associates with the Parkinson's kinase, LRRK2.
Human DNAJC6 is only expressed in neuronal tissues, but GAK is widespread, and generally expressed higher in non-neuronal tissue. GAK and DNAJC6 bind clathrin heavy chain and are found in and required for the function of clathrin-associated vesicles, particularly by interacting with Hsc70 in uncoating of the vesicles <cite>Scheele </cite>. GAK also binds AP1 and is required for endosomal sorting <cite>Kametaka </cite>. GAK can also localize to the nucleus and is required in a clathrin-dependent manner for mitosis <cite>Shimizu</cite>.

Little is known about the phosphatase or kinase activities of auxilins, though one report shows that GAK phosphorylates and activates the PP2A complex <cite>Naito</cite>. The phosphatase domains of both are predicted to be inactive (HCx5R changed to HCx5A in both), and both GAK and DNAJC6 phosphatase domains have been shown to bind phospholipids, which are also involved in clathrin-coated vesicles <cite>Lee, Kalli</cite>.

===References===
<biblio>
#Kanaoka pmid=9013862
#Kametaka pmid=17538018
#Shimizu pmid=19654208
#Naito pmid=22262175
#Scheele pmid=11470803
#Lee pmid=16895969
#Kalli pmid=23823232
</biblio>

Phosphatase Subfamily Auxilin

2025-03-14T00:55:03Z

Gerard: /* Evolution */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTEN|Family PTEN]]: [[Phosphatase_Subfamily_Auxilin|Subfamily Auxilin]]

Auxillins are pseudophosphatases and kinases that bind phospholipids and are involved in clathrin-coated vesicle function. Human forms are associated with Parkinson's disease.

===Evolution===
Auxilins are metazoan-specific. Human has two members: auxilin and DNAJC6, which emerged by gene duplication in jawed vertebrates. The DNAJ domain appears to be much older and has orthologs in Arabidopsis (JAC1) and yeast (Swa2) that are also involved in clathrin uncoating, but lack phosphatase and kinase domains.

===Domain Structure===
Most auxillins are 1000-1500 AA long, with an N-terminal GAK kinase domain, a PTEN-like phosphatase domain in the middle, and a DnaJ domain at the very C-terminus. One of the two human homologs, DNAJC6/Auxillin-1 has lost the kinase domain.

===Functions===
Human GAK is known as Cyclin G-Associated Kinase, and associated with Cyclin G and CDK5 <cite>Kanaoka</cite>. Both GAK and DNAJC6 are genetically implicated in Parkinson's disease and GAK physically associates with the Parkinson's kinase, LRRK2.
Human DNAJC6 is only expressed in neuronal tissues, but GAK is widespread, and generally expressed higher in non-neuronal tissue. GAK and DNAJC6 bind clathrin heavy chain and are found in and required for the function of clathrin-associated vesicles, particularly by interacting with Hsc70 in uncoating of the vesicles <cite>Scheele </cite>. GAK also binds AP1 and is required for endosomal sorting <cite>Kametaka </cite>. GAK can also localize to the nucleus and is required in a clathrin-dependent manner for mitosis <cite>Shimizu</cite>.

Little is known about the phosphatase or kinase activities of auxilins, though one report shows that GAK phosphorylates and activates the PP2A complex <cite>Naito</cite>. The phosphatase domains of both are predicted to be inactive (HCx5R changed to HCx5A in both), and both GAK and DNAJC6 phosphatase domains have been shown to bind phospholipids, which are also involved in clathrin-coated vesicles <cite>Lee, Kalli</cite>.

===References===
<biblio>
#Kanaoka pmid=9013862
#Kametaka pmid=17538018
#Shimizu pmid=19654208
#Naito pmid=22262175
#Scheele pmid=11470803
#Lee pmid=16895969
#Kalli pmid=23823232
</biblio>

Phosphatase Subfamily PPM1L

2024-05-21T04:45:33Z

Gerard: /* References */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]: [[Phosphatase_Subfamily_PPM1L|Subfamily PPM1L]] (PP2Cε, PP2Ce)

=== Evolution ===
PPM1L is found in most chordate and arthropod genomes, indicating that it emerged in [http://en.wikipedia.org/wiki/Bilateria bilateria] and was lost in nematodes. PPM1L is most closely related to [[Phosphatase_Subfamily_PPM1K|PPM1K]], a mitochondrial phosphatase.

=== Domain ===
PPM1L has an N-terminal transmembrane (TM) region, followed by PPM phosphatase domain. The TM (residues (26-45) of Human PPM1L has been experimentally validated, and the phosphatase domain shown to be on the cytoplasmic side of the endoplasmic reticulum membrane <cite>Saito08</cite>; the TMs of sea urchin and Drosophila PPM1Ls are predicted by sequence analysis [[http://www.cbs.dtu.dk/services/TMHMM/ TMHMM]].

=== Functions ===
Human PPM1L is widely expressed in different tissues. Although it is most abundant in heart, placenta, lung, liver, kidney and pancreas as shown by RT-PCR <cite>Jin04</cite>, RNA-seq data from [[http://www.gtexportal.org/home/gene/PPM1L GTEx]] showed different tissue distribution.

Human PPM1L has the following characterized substrates:
* TAK1. Human PPM1L associated with, dephosphorylated and inactivated TAK1 in vitro <cite>Li03</cite>. TAK1 can be also dephosphorylated by another PPM, [[Phosphatase_Subfamily_PPM1A#PPM1B_.28PP2C.CE.B2.29|PPM1B]], and associates with another PPM, the pseudophosphatase [[Phosphatase_Subfamily_TAB1|TAB1]]. [http://kinase.com/wiki/index.php/Kinase_Subfamily_TAK1 TAK1] emerged in holozoa.
* ASK1 (at Thr-845). Human PPM1L dephosphorylated ASK1 in vitro and associated with ASK1 in mouse brain extracts <cite>Saito07</cite>. ASK1 is also dephosphorylated by PP5, a member of the [[Phosphatase_Subfamily_PPP5C|PPP5C] subfamily of PPP phosphatases. The difference between PPM1L and PP5 is upon H2O2 exposure, PPM1L dissociated with ASK1, while PP5 associated with ASK1 <cite>Saito07</cite>. ASK1 also emerged in holozoa. TAK1 and ASK1 are both [http://kinase.com/wiki/index.php/Kinase_Family_STE11 STE11/MAP3K] kinases.
* [http://en.wikipedia.org/wiki/COL4A3BP Ceramide transport protein CERT] (official symbol COL4A3BP) <cite>Saito08</cite>. Human PPM1L dephosphorylates CERT in a manner depending on [http://en.wikipedia.org/wiki/VAPA vesicle-associated membrane protein-associated protein A (VAPA)], which is an ER resident integral membrane protein involved in recruiting lipid-binding proteins such as CERT to ER membrane. The dephosphorylation resulted in the redistribution of CERT from cytoplasm to Golgi apparatus. PPM1L also interacts with VAPA in vivo. Given that PPM1L is localized in ER, CERT is probably its physiological substrate. A model of PPM1L, VAPA, CERT and the fourth protein ACBD3 is proposed in <cite>Shinoda12</cite>. In comparison with PPM1L, CERT and VAPA emerged much earlier: CERT is found in almost all holozoa and VAPA in almost all eukaryotes.
* IRE1 in the Endoplasmic reticulum <cite>Lu</cite>

PPM1L is down-regulated in APC mutation-negative familial colorectal cancer patients <cite>Thean10</cite>.

=== References ===
<biblio>
#Jin04 pmid=15560375
#Li03 pmid=12556533
#Saito07 pmid=17456047
#Saito08 pmid=18165232
#Shinoda12 pmid=22796112
#Thean10 pmid=19847890
#Lu pmid=24327956
</biblio>

Phosphatase Subfamily PPM1L

2024-05-21T04:45:07Z

Gerard: /* Functions */

Phosphatase Subfamily PPM1L

2024-05-21T04:43:49Z

Gerard: /* Domain */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]: [[Phosphatase_Subfamily_PPM1L|Subfamily PPM1L]] (PP2Cε, PP2Ce)

=== Evolution ===
PPM1L is found in most chordate and arthropod genomes, indicating that it emerged in [http://en.wikipedia.org/wiki/Bilateria bilateria] and was lost in nematodes. PPM1L is most closely related to [[Phosphatase_Subfamily_PPM1K|PPM1K]], a mitochondrial phosphatase.

=== Domain ===
PPM1L has an N-terminal transmembrane (TM) region, followed by PPM phosphatase domain. The TM (residues (26-45) of Human PPM1L has been experimentally validated, and the phosphatase domain shown to be on the cytoplasmic side of the endoplasmic reticulum membrane <cite>Saito08</cite>; the TMs of sea urchin and Drosophila PPM1Ls are predicted by sequence analysis [[http://www.cbs.dtu.dk/services/TMHMM/ TMHMM]].

=== Functions ===
Human PPM1L is widely expressed in different tissues. Although it is most abundant in heart, placenta, lung, liver, kidney and pancreas as shown by RT-PCR <cite>Jin04</cite>, RNA-seq data from [[http://www.gtexportal.org/home/gene/PPM1L GTEx]] showed different tissue distribution.

Human PPM1L has the following characterized substrates:
* TAK1. Human PPM1L associated with, dephosphorylated and inactivated TAK1 in vitro <cite>Li03</cite>. TAK1 can be also dephosphorylated by another PPM, [[Phosphatase_Subfamily_PPM1A#PPM1B_.28PP2C.CE.B2.29|PPM1B]], and associates with another PPM, the pseudophosphatase [[Phosphatase_Subfamily_TAB1|TAB1]]. [http://kinase.com/wiki/index.php/Kinase_Subfamily_TAK1 TAK1] emerged in holozoa.
* ASK1 (at Thr-845). Human PPM1L dephosphorylated ASK1 in vitro and associated with ASK1 in mouse brain extracts <cite>Saito07</cite>. ASK1 is also dephosphorylated by PP5, a member of the [[Phosphatase_Subfamily_PPP5C|PPP5C] subfamily of PPP phosphatases. The difference between PPM1L and PP5 is upon H2O2 exposure, PPM1L dissociated with ASK1, while PP5 associated with ASK1 <cite>Saito07</cite>. ASK1 also emerged in holozoa. TAK1 and ASK1 are both [http://kinase.com/wiki/index.php/Kinase_Family_STE11 STE11/MAP3K] kinases.
* [http://en.wikipedia.org/wiki/COL4A3BP Ceramide transport protein CERT] (official symbol COL4A3BP) <cite>Saito08</cite>. Human PPM1L dephosphorylates CERT in a manner depending on [http://en.wikipedia.org/wiki/VAPA vesicle-associated membrane protein-associated protein A (VAPA)], which is an ER resident integral membrane protein involved in recruiting lipid-binding proteins such as CERT to ER membrane. The dephosphorylation resulted in the redistribution of CERT from cytoplasm to Golgi apparatus. PPM1L also interacts with VAPA in vivo. Given that PPM1L is localized in ER, CERT is probably its physiological substrate. A model of PPM1L, VAPA, CERT and the fourth protein ACBD3 is proposed in <cite>Shinoda12</cite>. In comparison with PPM1L, CERT and VAPA emerged much earlier: CERT is found in almost all holozoa and VAPA in almost all eukaryotes.

PPM1L is down-regulated in APC mutation-negative familial colorectal cancer patients <cite>Thean10</cite>.

=== References ===
<biblio>
#Jin04 pmid=15560375
#Li03 pmid=12556533
#Saito07 pmid=17456047
#Saito08 pmid=18165232
#Shinoda12 pmid=22796112
#Thean10 pmid=19847890
</biblio>

Phosphatase Subfamily DSP8

2024-04-02T13:10:54Z

Gerard:

__NOTOC__

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_DSP8|Subfamily DSP8]]

DSP8 is a metazoan subfamily that functions as an MKP (MAP Kinase Phosphatase) with preference towards JNK and p38. It is single copy in invertebrates but two copies in most vertebrates. The two human members DUSP8 and DUSP16 have different tissue expression patterns.

===Evolution===
DSP8 is found in metazoa but absent from most arthropods. It is typically single-copy in invertebrate, but expanded to two genes, DUSP8 and DUSP16 in vertebrates.

===Domain Structure===
The domain dissection is mainly based upon DUSP16 studies. But according to the sequence alignment and similarity, human DUSP8 has the same domain combination as DUSP16.

Human DUSP16 possesses a long C-terminal stretch containing a nuclear export signal (NES), two nuclear localization signal (NLS) and two PEST motifs, in addition to the rhodanese domain and the dual specificity phosphatase catalytic domain, both of which are conserved among MKP family members (see [http://www.jbc.org/content/278/34/32448/F9.large.jpg figure 9]). The rhodanese domain is required for interaction with ERK and p38, whereas phosphatase domain is required for interaction with JNK and p38, which is likely to be important for DUSP16 to suppress JNK and p38 activations. The COOH-terminal stretch of DUSP16 was shown to determine JNK preference for MKP-7 by masking MKP-7 activity toward p38 and is a domain bound by ERK. <cite>Masuda03</cite>.

DUSP16 also binds to JNK scaffolds, - JNK3 scaffold protein beta-arrestin 2 and JNK-interacting protein-1 (JIP-1), via 394-443 on C-terminal stretch <cite>Willoughby03, Willoughby05</cite>.

===Functions===
====== DUSP8 (hVH5) ======
Human DUSP8 is a protein tyrosine phosphatase abundant in brain that inactivates mitogen-activated protein kinase. It is expressed predominantly in the adult brain, heart, and skeletal muscle. In addition, in situ hybridization histochemistry of mouse embryo revealed high levels of expression and a wide distribution in the central and peripheral nervous system <cite>Martell95</cite> (tissue expression see [http://www.gtexportal.org/home/gene/DUSP8 GTEx]).

====== DUSP16 (MKP7) ======
DUSP16 mainly functions in MAPK pathways. It is expressed in many different tissues and is highest expressed in adrenal gland (see [http://www.gtexportal.org/home/gene/DUSP16 GTEx]).

DUSP16 is predominantly localized in the cytoplasm when expressed in cultured cells, whereas DUSP8 (hVH5) is both in the nucleus and the cytoplasm. Its localization became exclusively nuclear following leptomycin B treatment or introduction of a mutation in the nuclear export signal. DUSP16 binds to and inactivates p38 MAPK and JNK/SAPK, but not ERK. In particular, DUSP16 binds to and inactivates p38 alpha and -beta isoforms, but not gamma or delta. A mutant form DUSP16 functioned as a dominant negative particularly against the dephosphorylation of JNK, suggesting that DUSP16 works as a JNK-specific phosphatase in vivo <cite> Masuda01, Tanoue01, Willoughby03</cite>. Meanwhile, the structure of DUSP16 binding with p38alpha has been solved <cite>Kumar13</cite>.

Although DUSP16 does not dephoshorylate ERK, it has been reported to bind to ERK <cite>Masuda03</cite>. It is phosphorylated at serine 446 by ERK, which stabilize DUSP16 (longer half life) and therefore blocks JNK activation <cite>Masuda03, Katagiri05</cite>. On another hand, DUSP16 functions as ERK scaffold, which down-regulates ERK-dependent gene expression by blocking nuclear accumulation of phospho-ERK <cite> Masuda10</cite>.

DUSP16 can be nitrosylated and inactivated by chemokine stromal cell-derived factor-1alpha (SDF-1alpha), therefore inhibiting the activation of JNK and enhancing endothelial migration <cite>Pi09</cite>.

===References===
<biblio>
#Katagiri05 pmid=15689616
#Kumar13 pmid=23926106
#Martell95 pmid=7561881
#Masuda01 pmid=11489891
#Masuda03 pmid=12794087
#Masuda10 pmid=20122898
#Pi09 pmid=19307591
#Tanoue01 pmid=11359773
#Willoughby03 pmid=12524447
#Willoughby05 pmid=15888437
</biblio>

Phosphatase Subfamily PGAM

2024-04-02T13:08:39Z

Gerard: /* Catalytic activity */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_HP|Fold HP]]: [[Phosphatase_Superfamily_HP|Superfamily HP]]: [[Phosphatase_Family_HP1|HP, branch1 family]]: [[Phosphatase_Subfamily_PGAM|Subfamily PGAM]]

PGAMs mainly function as glycolytic enzymes regulating intracellular levels of its substrate [[Phosphatase_Glossary#3-phosphoglycerate|3-phosphoglycerate]] and product [[Phosphatase_Glossary#2-phosphoglycerate|2-phosphoglycerate]]. Human BPGM is a 2,3-bisphosphoglycerate mutase.

=== Evolution ===
PGAM is found in most eukaryotic genomes with duplication in individual lineages. For instance, human has four PGAMs and yeast has three. They emerged by independent duplication events.

=== Domain ===
PGAM has single domain, a HP1-family phosphatase domain.

=== Catalytic activity ===
Human has four members:
* [[Phosphatase_Gene_PGAM1|PGAM1]]: phosphoglycerate mutase 1 (brain). Glycolytic enzyme PGAM1 regulates anabolic biosynthesis by controlling intracellular levels of its substrate [[Phosphatase_Glossary#3-phosphoglycerate|3-phosphoglycerate]] and product [[Phosphatase_Glossary#2-phosphoglycerate|2-phosphoglycerate]]. Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. Y26 phosphorylation of PGAM1 is common in human cancer cells, promoting cancer cell proliferation and tumor growth. This is the mechanism behind oncogenic signalling to coordinate glycolysis and anabolic biosynthesis in cancer cells <cite>hitosugi12,hitosugi13</cite>. NAD+-dependent deacetylase Sirt1 deacetylates PGAM1 and attenuates catalytic activity <cite>hallows12</cite>.
* [[Phosphatase_Gene_PGAM2|PGAM2]]: phosphoglycerate mutase 2 (muscle). A muscle-specific form of PGAM <cite>tsujino93</cite>.
* [[Phosphatase_Gene_PGAM4|PGAM4]] (aka PGAM3): phosphoglycerate mutase family member 4.
* [[Phosphatase_Gene_BPGM|BPGM]]: 2,3-bisphosphoglycerate mutase. Bisphosphoglycerate mutase is an erythrocyte-specific enzyme catalyzing a series of intermolecular phosphoryl group transfer reactions. Its main function is to synthesize 2,3- bisphosphoglycerate <cite>wang04, wang06</cite>.

=== References ===
<biblio>
#wang04 pmid=15258155
#wang06 pmid=23653202
#hitosugi12 pmid=23153533
#hitosugi13 pmid=23653202
#hallows12 pmid=22157007
#tsujino93 pmid=8447317
</biblio>

Phosphatase Subfamily PGAM

2024-04-02T13:05:22Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_HP|Fold HP]]: [[Phosphatase_Superfamily_HP|Superfamily HP]]: [[Phosphatase_Family_HP1|HP, branch1 family]]: [[Phosphatase_Subfamily_PGAM|Subfamily PGAM]]

PGAMs mainly function as glycolytic enzymes regulating intracellular levels of its substrate [[Phosphatase_Glossary#3-phosphoglycerate|3-phosphoglycerate]] and product [[Phosphatase_Glossary#2-phosphoglycerate|2-phosphoglycerate]]. Human BPGM is a 2,3-bisphosphoglycerate mutase.

=== Evolution ===
PGAM is found in most eukaryotic genomes with duplication in individual lineages. For instance, human has four PGAMs and yeast has three. They emerged by independent duplication events.

=== Domain ===
PGAM has single domain, a HP1-family phosphatase domain.

=== Catalytic activity ===
Human has four members:
* [[Phosphatase_Gene_BPGM|BPGM]]: 2,3-bisphosphoglycerate mutase. Bisphosphoglycerate mutase is an erythrocyte-specific en- zyme catalyzing a series of intermolecular phosphoryl group transfer reactions. Its main function is to synthesize 2,3- bisphosphoglycerate <cite>wang04, wang06</cite>.
* [[Phosphatase_Gene_PGAM1|PGAM1]]: phosphoglycerate mutase 1 (brain). Glycolytic enzyme PGAM1 regulates anabolic biosynthesis by controlling intracellular levels of its substrate [[Phosphatase_Glossary#3-phosphoglycerate|3-phosphoglycerate]] and product [[Phosphatase_Glossary#2-phosphoglycerate|2-phosphoglycerate]]. Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting cancer cell proliferation and tumour growth. This is the mechanism behind oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells <cite>hitosugi12,hitosugi13</cite>. NAD+-dependent deacetylase Sirt1 deacetylates phosphoglycerate mutase-1 (PGAM1) and attenuates catalytic activity <cite>hallows12</cite>.
* [[Phosphatase_Gene_PGAM2|PGAM2]]: phosphoglycerate mutase 2 (muscle). Glycolytic enzyme PGAM expressed in muscle <cite>tsujino93</cite>.
* [[Phosphatase_Gene_PGAM4|PGAM4]] (aka PGAM3): phosphoglycerate mutase family member 4.

=== References ===
<biblio>
#wang04 pmid=15258155
#wang06 pmid=23653202
#hitosugi12 pmid=23153533
#hitosugi13 pmid=23653202
#hallows12 pmid=22157007
#tsujino93 pmid=8447317
</biblio>

Phosphatase Fold CC1

2024-04-02T13:03:53Z

Gerard: /* Structure */

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]

Fold CC1 has a single superfamily [[Phosphatase_Superfamily_CC1|CC1]].

=== Structure ===
A structural alignment analysis of the crystal structures of five phosphatases of different families, including human DUSP3 (DSP), PTEN (PTEN), PTPN1 (PTP), MTMR2 (myotubularin) and yeast Sac1p (Sac) (family names in parentheses; Paladin and OCA have no structure). showed that all five phosphatases share the same secondary structure (SS) combination of E2, E3, H2, E4, E11, H3, E12, H4, H5, H6 (E denotes beta strand, H denotes helix, SS numbered by PTP <cite> Andersen01</cite>).

=== References ===
<biblio>
#Andersen01 pmid=11585896
</biblio>

Phosphatase Family PPP

2020-02-18T19:02:12Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPPL|Fold PPPL]]: [[Phosphatase_Superfamily_PPPL|Superfamily PPPL]]: [[Phosphatase_Family_PPP|Family PPP]]

PPPs are found in both eukaryotes and prokaryotes. PPPs share the highest sequence similarity compared to other phosphatase superfamilies. PPP are enzymatically active as part of a complex, consisting of one catalytic subunit and one or two regulatory subunits, of which there are a wide variety. Here, we focus on the catalytic subunit only.

== Subfamilies ==
Note: PPP2C, PPP4C, PPP6C are grouped as PP2A in some literature.

======[[Phosphatase_Subfamily_PPP1C|PPP1C]] (PP1, catalytic subunit)======
PPP1C, catalytic subunit of holoenzyme PP1, is a ubiquitous serine/threonine phosphatase found throughout eukaryotes and even in some prokaryotes. Holoenzyme PP1 is involved in many various processes.

======[[Phosphatase_Subfamily_PPP2C|PPP2C]] (PP2A, catalytic subunit)======
PPP2C, catalytic subunit of holoenzyme PP2A, is found throughout eukaryotes with various number in different lineages. PP2A accounts for the majority of phospho-serine/threonine phosphatase activity in most cells and is involved in the regulation of nearly every cellular process.

======[[Phosphatase_Subfamily_PPP4C|PPP4C]] (PP4, catalytic subunit) ======
PPP4C, the catalytic subunit of Protein Phosphatase 4 (PP4) holoenzyme, is found widely in eukaryotes including animals, plants and fungi. Like other members in this family, PP4 has many different substrates and is involved in a wide variety of processes.

======[[Phosphatase_Subfamily_PPP6C|PPP6C]] (PP6, catalytic subunit) ======
PPP6C, the catalytic subunit of holoenzyme PP6, is found throughout eukaryotes.

======[[Phosphatase_Subfamily_PPP3C|PPP3C]] (PP2B/calcineurin, catalytic subunit) ======
PPP3C (PP2B, calcineurin) is a calcium-dependent serine/threonine phosphatase conserved in eukaryotes. It is involved in various biological processes and has significantly clinical relevance. PPP3C (PP2B, calcineurin) is an attractive antifungal drug target.

======[[Phosphatase_Subfamily_PPP5C|PPP5C]]======
PPP5C also known as Protein Phosphatase 5 (PP5) is unique among PPP family members in that its catalytic and regulatory domains are contained in the same polypeptide chain. It has a tetratricopeptide repeat (TPR) domain which maintains the phosphatase in an auto-inhibited conformation that is neutralized when the heat shock protein Hsp90, or fatty acids, bind to this region.

The phosphatase interacts with various proteins and participate in multiple signaling pathways. The phosphatase interacts with ATM, ATR, 53BP1, and DNA-depdent protein kianse catalytic subunits (DNA-PKc) following DNA damage. While enchance the activity of ATM and ATR, the phosphatase negatively regulates 53BP1 and DNA-PKc by dephosphorylating them. It regulates Raf-MEK-ERK pathway via inhibiting Raf-1 by dephosphorylating Serine 338. PPP5 is involved in mammalian circadian clock by activating the major clock kinae casein kinase I (CKI) ε. In addition, the elevated levels of this phosphatase may be associated with breast cancer development.

======[[Phosphatase_Subfamily_PPP7C|PPP7C]] (PPEF) subfamily functions in sensory neurons ======
PPEFs contain calmodulin-binding motif IQ and calcium-binding domains EF hand to the N- and C-terminal side of phosphatase domain, respectively, which suggests its involvement in calcium signaling. This would be a reminiscent of another PPP subfamily, PPP3C (calcineurin/PP2B), which are regulated by calmodulin and another EF-hand protein, calcineurin B.

In C. elegans, Drosophila and mammals, PPEF expression was mainly detected in various sensory neurons. The Drosophila PPEF phosphatase, rdgC, is essential for dephosphorylation of rhodopsin. However, mice lacking both PPEF1 and PPEF2 showed no signs of photoreceptor synases. PPEF is present not only in animals but unicellular eukaryotes, indicating its ancient origin and basic functions of eukaryotes. The function and evolution of this phosphatase is reviewed in paper PMID: 19662497.

======[[Phosphatase_Subfamily_YNL217W|YNL217W]] (yeast) subfamily======
Function unknown. It is found in most fungi, and some basal eukaryotes (Chromalveolata and Excavata), but not in plants or amoebazoa. It is found in some basal metazoans but absent from vertebrates, nematodes, and insects.

======[[Phosphatase_Subfamily_PPG1|PPG1]] (yeast) subfamily======
The gene PPG encodes a novel yeast protein phosphatase involved in glycogen accumulation (see SGD database). It is found in all fungi, and absent from holozoan. It is not found in plants, but is found in Dictyostellium and some basal eukaryotes. (Note: the evolutionary history is from gOrtholog.)

====== [[Phosphatase_Subfamily_PPPLV|PPPLV]] subfamily ======
PPPLV stands for PPP lost in vertebrates.

======Nematode-specific PPP subfamilies======
At least 36 PPPs are only found in C. elegans. Taking account the total number of PPPs in most eukaryotes is less than 20, this expansion is very unusual. However, almost nothing is known about these phosphatases.
* [[Phosphatase_Subfamily_CelePPP-sf4|CelePPP-sf4]]

Phosphatase Superfamily PPPL

2020-02-18T18:28:23Z

Gerard:

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPPL|Fold PPPL]]: [[Phosphatase_Superfamily_PPPL|Superfamily PPPL]]

PPPL (PPP-Like) is a phosphatase superfamily found in both eukaryotes and prokaryotes. It contains a variety of phosphoesterases, including phosphodisterases, nucleotidases and nucleases. It is defined as a [http://scop.berkeley.edu/sunid=56300 superfamily] in SCOP, and by profile HMMs from [http://pfam.xfam.org/family/PF00149 Pfam] and [http://supfam.cs.bris.ac.uk/SUPERFAMILY/cgi-bin/scop.cgi?sunid=56300 SUPERFAMILY]. PPPL contains many families, some of which are non-protein phosphatases, or non-phosphatases. Two families include protein phosphatases:

* [[Phosphatase_Family_PPP|PPP]]: serine/threonine-specific phosphatases.
* [[Phosphatase_Family_PAP|PAP]] (Purple Acid Phosphatase) member have a wide variety of substrates, including proteins.

Phosphatase Family EYA

2018-09-27T22:33:15Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_HAD|Fold HAD]]: [[Phosphatase_Superfamily_HAD|Superfamily HAD]]: [[Phosphatase_Family_EYA|Family EYA]]

EYA (EYes Absent) was first identified in Drosophila as a gene required for eye development. There are four members in human, and a single copy in most invetebrates. This family contains a single subfamily, also named [[Phosphatase_Subfamily_EYA|EYA]].

=== Evolution ===
EYA is found in animals and choanoflagellates, and also plants and Phytophthora. The N-terminal transcription factor domain is absent or short and degraded in both plants and Phytophthora, suggesting it may have distinct functions. EYA is only found in Phytophthora genus rather than other genera in heterokonts.

The catalytic motif sequences varies. From Monosiga to human, most EYAs have the canonical catalytic motif sequence DLDET, except Hydra (DLDDV) and nematodes. In particular, all nematodes except Trichinella spiralis have neither conserved nor canonical sequence motif (DIDDI, DLEDV, EMEDV). In plants, the catalytic motif sequence is conserved as DMDET, and in Phytophora, that is DLDET again.

Human, and most vertebrates, have four copies of EYAs; Sea urchin has three copies; Most invertebrates such as fruit fly and ''C elegans'' have a single copy.

=== Domain Structure===
EYA has two regions corresponding to its two main function. The N-terminal region, in animals and choanoflagellates, is transcriptional factor domain, and the C-terminal region is a HAD-fold phosphatase domain (known as ED) <cite>tootle04</cite>.

=== Function ===
Putative substrates are myelin basic protein, RNA pol II, MAPK, and EYA itself (see Review <cite>Jmec07</cite>).

EYA is involved in apoptosis by dephosphorylating Y142 of the histone variant H2AX in mouse <cite>Cook09</cite>, and through direct transcriptional activation of egl-1 in C. elegans <cite>Hirose10</cite>. The existence of H2AX in C. elegans is uncertain - some have suggested CENP-A to be the functional analog, but it does not have an equivalent to Y142.

Eya1 cooperates with the DNA-binding protein Six1 to promote gene expression in response to Shh. Eya1/Six1 together regulate Gli transcriptional activators in normal hindbrain and Shh-dependent hindbrain tumors <cite>Eisner15</cite>.

=== Related kinase ===
WSTF phosphorylates H2AX on Y142 <cite>Xiao09</cite>.

=== Correlated presence/absence of EYA and Y142 ===
The presence/absence of EYA well correlates that of Y142. The Y142 is conserved from Nematostella to human with the exception of nematodes. Surprisingly, Phytophthora also has Y142, though most of the bikonts (plants + heterokonts + alveolates + excavates) do not. The co-ordinated loss of Y142 and Eya function suggests that H2AX dephosphorylation is a major function of Eya

=== Reference ===
<biblio>
#Eisner15 pmid=25816987
#tootle04 pmid=14628053
#Jmec07 pmid=17341163
#Cook09 pmid=19234442
#Hirose10 pmid=20713707
#Xiao09 pmid=19092802
</biblio>

Phosphatase Subfamily DSP10

2018-09-12T19:32:04Z

Gerard:

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_ DSP10 |Subfamily DSP10]] (MKP5)
__NOTOC__

DSP10 selectively dephosphorylates p38 and JNK. It is conserved across holozoa but lost in nematodes.

=== Evolution ===
The DSP10 (MKP5) subfamily is found in most [[holozoa]]. DSP10 is usually one copy per genome, e.g. DUSP10 (MKP5) in human. DSP10 is lost from nematodes, and dipteran insects have lost the rhodanese domain.

=== Domain ===
The DSP10 (MKP5) has two domains: rhodanese domain and phosphatase domain. The rhodanese domain can bind to kinases <cite>Tao07</cite>. Drosophila has lost the whole rhodanese domain.

=== Function ===
Human DUSP10 is a phosphatase specific for p38 and JNK. It binds to and inactivates p38 and JNK, but not ERK. p38 is a preferred substrate. It is present evenly in both the cytoplasm and the nucleus. DUSP10 is widely expressed in various tissues, and its expression in cultured cells is elevated by stress stimuli <cite>Tanoue99, Theodosiou99, Jeong06</cite>.

On the other hand, it has been reported that human DUSP10 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription <cite>Nomura12</cite>.

Human DUSP10 is frequently upregulated in colorectal cancer (CRC). Certain mutations in DUSP10 correlate with the incidence of CRC. DUSP10/MKP5 also negatively regulates intestinal epithelial cell growth <cite>Png15</cite>.

Human DUSP10 (MKP5) also has an immune role. It functions in the type I interferon system responding to viral infection. It interacts with, dephosphorylates and inactivates [http://en.wikipedia.org/wiki/IRF3 Interferon regulatory factor 3 (IRF3)], an interferon regulatory factor which plays an important role in the type I interferon system. Increased type I interferon responses were observed in DUSP10/MKP5-deficient cells and animals upon various RNA virus infection, including H1N1 influenza virus, vesicular stomatitis virus and sendai virus <cite>James15</cite>. DUSP10/MKP5 also regulates adipose tissue inflammation and insulin resistance <cite>Zhang15</cite>.

=== References ===
<biblio>
#James15 pmid=25772359
#Jeong06 pmid=16806267
#Nomura12 pmid=22711061
#Png15 pmid=25772234
#Tanoue99 pmid=10391943
#Tao07 pmid=17400920
#Theodosiou99 pmid=10597297
#Zhang15 pmid=25922079
</biblio>

Phosphatase Subfamily DSP10

2018-09-12T19:31:32Z

Gerard: /* Technical notes */

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_ DSP10 |Subfamily DSP10]] (MKP5)
__NOTOC__

Human DSP10 selectively dephosphorylates p38 and JNK. It is conserved across holozoa but lost in nematodes.

=== Evolution ===
The DSP10 (MKP5) subfamily is found in most [[holozoa]]. DSP10 is usually one copy per genome, e.g. DUSP10 (MKP5) in human. DSP10 is lost from nematodes, and dipteran insects have lost the rhodanese domain.

=== Domain ===
The DSP10 (MKP5) has two domains: rhodanese domain and phosphatase domain. The rhodanese domain can bind to kinases <cite>Tao07</cite>. Drosophila has lost the whole rhodanese domain.

=== Function ===
Human DUSP10 is a phosphatase specific for p38 and JNK. It binds to and inactivates p38 and JNK, but not ERK. p38 is a preferred substrate. It is present evenly in both the cytoplasm and the nucleus. DUSP10 is widely expressed in various tissues, and its expression in cultured cells is elevated by stress stimuli <cite>Tanoue99, Theodosiou99, Jeong06</cite>.

On the other hand, it has been reported that human DUSP10 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription <cite>Nomura12</cite>.

Human DUSP10 is frequently upregulated in colorectal cancer (CRC). Certain mutations in DUSP10 correlate with the incidence of CRC. DUSP10/MKP5 also negatively regulates intestinal epithelial cell growth <cite>Png15</cite>.

Human DUSP10 (MKP5) also has an immune role. It functions in the type I interferon system responding to viral infection. It interacts with, dephosphorylates and inactivates [http://en.wikipedia.org/wiki/IRF3 Interferon regulatory factor 3 (IRF3)], an interferon regulatory factor which plays an important role in the type I interferon system. Increased type I interferon responses were observed in DUSP10/MKP5-deficient cells and animals upon various RNA virus infection, including H1N1 influenza virus, vesicular stomatitis virus and sendai virus <cite>James15</cite>. DUSP10/MKP5 also regulates adipose tissue inflammation and insulin resistance <cite>Zhang15</cite>.

=== References ===
<biblio>
#James15 pmid=25772359
#Jeong06 pmid=16806267
#Nomura12 pmid=22711061
#Png15 pmid=25772234
#Tanoue99 pmid=10391943
#Tao07 pmid=17400920
#Theodosiou99 pmid=10597297
#Zhang15 pmid=25922079
</biblio>

Phosphatase Subfamily DSP10

2018-09-12T19:31:11Z

Gerard: /* Function */

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_ DSP10 |Subfamily DSP10]] (MKP5)
__NOTOC__

Human DSP10 selectively dephosphorylates p38 and JNK. It is conserved across holozoa but lost in nematodes.

=== Evolution ===
The DSP10 (MKP5) subfamily is found in most [[holozoa]]. DSP10 is usually one copy per genome, e.g. DUSP10 (MKP5) in human. DSP10 is lost from nematodes, and dipteran insects have lost the rhodanese domain.

=== Domain ===
The DSP10 (MKP5) has two domains: rhodanese domain and phosphatase domain. The rhodanese domain can bind to kinases <cite>Tao07</cite>. Drosophila has lost the whole rhodanese domain.

=== Function ===
Human DUSP10 is a phosphatase specific for p38 and JNK. It binds to and inactivates p38 and JNK, but not ERK. p38 is a preferred substrate. It is present evenly in both the cytoplasm and the nucleus. DUSP10 is widely expressed in various tissues, and its expression in cultured cells is elevated by stress stimuli <cite>Tanoue99, Theodosiou99, Jeong06</cite>.

On the other hand, it has been reported that human DUSP10 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription <cite>Nomura12</cite>.

Human DUSP10 is frequently upregulated in colorectal cancer (CRC). Certain mutations in DUSP10 correlate with the incidence of CRC. DUSP10/MKP5 also negatively regulates intestinal epithelial cell growth <cite>Png15</cite>.

Human DUSP10 (MKP5) also has an immune role. It functions in the type I interferon system responding to viral infection. It interacts with, dephosphorylates and inactivates [http://en.wikipedia.org/wiki/IRF3 Interferon regulatory factor 3 (IRF3)], an interferon regulatory factor which plays an important role in the type I interferon system. Increased type I interferon responses were observed in DUSP10/MKP5-deficient cells and animals upon various RNA virus infection, including H1N1 influenza virus, vesicular stomatitis virus and sendai virus <cite>James15</cite>. DUSP10/MKP5 also regulates adipose tissue inflammation and insulin resistance <cite>Zhang15</cite>.

=== Technical notes ===
===== Rhodanese domain lost in diptera =====
We observed the lost of rhodanese domain in Drosophila melanogaster. We then asked when the lose happened, it was lost in D. melanogaster only, or in all arthropods, or somewhere in between. We obtained all the DSP10s from our internal orthology database, searched the Pfam domains using Pfam web server (E-value cutoff 1.0), and eyeballed the presence and absence of rhodanese domain in 31 arthropods. We found the rhodanese domain was lost in diptera and is generally present in other arthropods.

=== References ===
<biblio>
#James15 pmid=25772359
#Jeong06 pmid=16806267
#Nomura12 pmid=22711061
#Png15 pmid=25772234
#Tanoue99 pmid=10391943
#Tao07 pmid=17400920
#Theodosiou99 pmid=10597297
#Zhang15 pmid=25922079
</biblio>

Phosphatase Subfamily DSP10

2018-09-12T19:28:51Z

Gerard: /* Evolution */

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_ DSP10 |Subfamily DSP10]] (MKP5)
__NOTOC__

Human DSP10 selectively dephosphorylates p38 and JNK. It is conserved across holozoa but lost in nematodes.

=== Evolution ===
The DSP10 (MKP5) subfamily is found in most [[holozoa]]. DSP10 is usually one copy per genome, e.g. DUSP10 (MKP5) in human. DSP10 is lost from nematodes, and dipteran insects have lost the rhodanese domain.

=== Domain ===
The DSP10 (MKP5) has two domains: rhodanese domain and phosphatase domain. The rhodanese domain can bind to kinases <cite>Tao07</cite>. Drosophila has lost the whole rhodanese domain.

=== Function ===
Human DUSP10 is a phosphatase specific for p38 and SAPK/JNK. It binds to p38 and SAPK/JNK, but not to MAPK/ERK, and inactivates p38 and SAPK/JNK, but not MAPK/ERK. p38 is a preferred substrate. It is present evenly in both the cytoplasm and the nucleus. DUSP10 is widely expressed in various tissues and organs, and its expression in cultured cells is elevated by stress stimuli <cite>Tanoue99, Theodosiou99, Jeong06</cite>.

On the other hand, it has been reported that human DUSP10 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription <cite>Nomura12</cite>.

Human DUSP10 is frequently upregulated in colorectal cancer (CRC). Certain mutations in DUSP10 correlate with the incidence of CRC. DUSP10/MKP5 also negatively regulates intestinal epithelial cell growth <cite>Png15</cite>.

Human DUSP10 (MKP5) is implicated in immune system. It functions in the type I interferon system responding to viral infection. It interacts with, dephosphorylates and inactivates [http://en.wikipedia.org/wiki/IRF3 Interferon regulatory factor 3 (IRF3)], an interferon regulatory factor which plays an important role in the type I interferon system. Increased type I interferon responses were observed in DUSP10/MKP5-deficient cells and animals upon various RNA virus infection, including H1N1 influenza virus, vesicular stomatitis virus and sendai virus <cite>James15</cite>. DUSP10/MKP5 also regulates adipose tissue inflammation and insulin resistance <cite>Zhang15</cite>.

=== Technical notes ===
===== Rhodanese domain lost in diptera =====
We observed the lost of rhodanese domain in Drosophila melanogaster. We then asked when the lose happened, it was lost in D. melanogaster only, or in all arthropods, or somewhere in between. We obtained all the DSP10s from our internal orthology database, searched the Pfam domains using Pfam web server (E-value cutoff 1.0), and eyeballed the presence and absence of rhodanese domain in 31 arthropods. We found the rhodanese domain was lost in diptera and is generally present in other arthropods.

=== References ===
<biblio>
#James15 pmid=25772359
#Jeong06 pmid=16806267
#Nomura12 pmid=22711061
#Png15 pmid=25772234
#Tanoue99 pmid=10391943
#Tao07 pmid=17400920
#Theodosiou99 pmid=10597297
#Zhang15 pmid=25922079
</biblio>

Phosphatase Subfamily DSP10

2018-09-12T19:27:49Z

Gerard:

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_ DSP10 |Subfamily DSP10]] (MKP5)
__NOTOC__

Human DSP10 selectively dephosphorylates p38 and JNK. It is conserved across holozoa but lost in nematodes.

=== Evolution ===
The DSP10 (MKP5) subfamily is found in most [[holozoa]] except nematodes. DSP10 is usually one copy per genome, e.g. DUSP10 (MKP5) in human. Diptera lost rhodanese domain as inferred by BLASTing human against protein NR database of arthropods.

=== Domain ===
The DSP10 (MKP5) has two domains: rhodanese domain and phosphatase domain. The rhodanese domain can bind to kinases <cite>Tao07</cite>. Drosophila has lost the whole rhodanese domain.

=== Function ===
Human DUSP10 is a phosphatase specific for p38 and SAPK/JNK. It binds to p38 and SAPK/JNK, but not to MAPK/ERK, and inactivates p38 and SAPK/JNK, but not MAPK/ERK. p38 is a preferred substrate. It is present evenly in both the cytoplasm and the nucleus. DUSP10 is widely expressed in various tissues and organs, and its expression in cultured cells is elevated by stress stimuli <cite>Tanoue99, Theodosiou99, Jeong06</cite>.

On the other hand, it has been reported that human DUSP10 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription <cite>Nomura12</cite>.

Human DUSP10 is frequently upregulated in colorectal cancer (CRC). Certain mutations in DUSP10 correlate with the incidence of CRC. DUSP10/MKP5 also negatively regulates intestinal epithelial cell growth <cite>Png15</cite>.

Human DUSP10 (MKP5) is implicated in immune system. It functions in the type I interferon system responding to viral infection. It interacts with, dephosphorylates and inactivates [http://en.wikipedia.org/wiki/IRF3 Interferon regulatory factor 3 (IRF3)], an interferon regulatory factor which plays an important role in the type I interferon system. Increased type I interferon responses were observed in DUSP10/MKP5-deficient cells and animals upon various RNA virus infection, including H1N1 influenza virus, vesicular stomatitis virus and sendai virus <cite>James15</cite>. DUSP10/MKP5 also regulates adipose tissue inflammation and insulin resistance <cite>Zhang15</cite>.

=== Technical notes ===
===== Rhodanese domain lost in diptera =====
We observed the lost of rhodanese domain in Drosophila melanogaster. We then asked when the lose happened, it was lost in D. melanogaster only, or in all arthropods, or somewhere in between. We obtained all the DSP10s from our internal orthology database, searched the Pfam domains using Pfam web server (E-value cutoff 1.0), and eyeballed the presence and absence of rhodanese domain in 31 arthropods. We found the rhodanese domain was lost in diptera and is generally present in other arthropods.

=== References ===
<biblio>
#James15 pmid=25772359
#Jeong06 pmid=16806267
#Nomura12 pmid=22711061
#Png15 pmid=25772234
#Tanoue99 pmid=10391943
#Tao07 pmid=17400920
#Theodosiou99 pmid=10597297
#Zhang15 pmid=25922079
</biblio>

Phosphatase Subfamily DSP10

2018-09-12T19:27:14Z

Gerard:

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_ DSP10 |Subfamily DSP10]] (MKP5)
_NOTOC_
Human DSP10 selectively dephosphorylates p38 and JNK. It is conserved across holozoan but lost in nematodes.

=== Evolution ===
The DSP10 (MKP5) subfamily is found in most [[holozoa]] except nematodes. DSP10 is usually one copy per genome, e.g. DUSP10 (MKP5) in human. Diptera lost rhodanese domain as inferred by BLASTing human against protein NR database of arthropods.

=== Domain ===
The DSP10 (MKP5) has two domains: rhodanese domain and phosphatase domain. The rhodanese domain can bind to kinases <cite>Tao07</cite>. Drosophila has lost the whole rhodanese domain.

=== Function ===
Human DUSP10 is a phosphatase specific for p38 and SAPK/JNK. It binds to p38 and SAPK/JNK, but not to MAPK/ERK, and inactivates p38 and SAPK/JNK, but not MAPK/ERK. p38 is a preferred substrate. It is present evenly in both the cytoplasm and the nucleus. DUSP10 is widely expressed in various tissues and organs, and its expression in cultured cells is elevated by stress stimuli <cite>Tanoue99, Theodosiou99, Jeong06</cite>.

On the other hand, it has been reported that human DUSP10 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription <cite>Nomura12</cite>.

Human DUSP10 is frequently upregulated in colorectal cancer (CRC). Certain mutations in DUSP10 correlate with the incidence of CRC. DUSP10/MKP5 also negatively regulates intestinal epithelial cell growth <cite>Png15</cite>.

Human DUSP10 (MKP5) is implicated in immune system. It functions in the type I interferon system responding to viral infection. It interacts with, dephosphorylates and inactivates [http://en.wikipedia.org/wiki/IRF3 Interferon regulatory factor 3 (IRF3)], an interferon regulatory factor which plays an important role in the type I interferon system. Increased type I interferon responses were observed in DUSP10/MKP5-deficient cells and animals upon various RNA virus infection, including H1N1 influenza virus, vesicular stomatitis virus and sendai virus <cite>James15</cite>. DUSP10/MKP5 also regulates adipose tissue inflammation and insulin resistance <cite>Zhang15</cite>.

=== Technical notes ===
===== Rhodanese domain lost in diptera =====
We observed the lost of rhodanese domain in Drosophila melanogaster. We then asked when the lose happened, it was lost in D. melanogaster only, or in all arthropods, or somewhere in between. We obtained all the DSP10s from our internal orthology database, searched the Pfam domains using Pfam web server (E-value cutoff 1.0), and eyeballed the presence and absence of rhodanese domain in 31 arthropods. We found the rhodanese domain was lost in diptera and is generally present in other arthropods.

=== References ===
<biblio>
#James15 pmid=25772359
#Jeong06 pmid=16806267
#Nomura12 pmid=22711061
#Png15 pmid=25772234
#Tanoue99 pmid=10391943
#Tao07 pmid=17400920
#Theodosiou99 pmid=10597297
#Zhang15 pmid=25922079
</biblio>

Phosphatase Family DSP

2018-09-12T19:26:43Z

Gerard: /* DSP6 */

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]
__NOTOC__
This family consists of the dual-specific protein phosphatases (DSPs) that dephosphorylate both tyrosine and serine/threonine, as well as related non-protein phosphatases.

== Subfamilies ==

=== MKP: MAP Kinase Phosphatases with a Rhodanese Domain ===

Several related subfamilies of DSP that dephosphorylate [http://kinase.com/wiki/index.php/Kinase_Family_MAPK MAPK Kinases] and share an N-terminal non-catalytic rhodanese domain. These are named MKP, ('''M'''AP '''K'''inase '''P'''hosphatase). They are regulators of MAPK activity, and can mediate crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules (see reviews <cite>Dickinson06, Caunt13</cite>). The rhodanese domains usually contain kinase-interacting motifs (KIMs) for MAPK binding <cite>Dickinson06</cite>.

===== [[Phosphatase_Subfamily_DSP1|DSP1]] =====
DSP1 is an inducible nuclear MKP found throughout eukaryotes. As a key player in MAPK pathway, it is implicated in immune regulation and cancer. Human has four members, DUSP1 (MKP1), DUSP2, DUSP4 (MKP2) and DUSP5.

===== [[Phosphatase_Subfamily_DSP6|DSP6]] =====
DSP6 is a cytoplasmic MKP subfamily that selectively dephosphorylates ERK. It is found throughout [[metazoa]] and duplicated in vertebrates, including 3 human members: DUSP6 (MKP3/PYST1), DUSP7 (MKPX/PYST2) and DUSP9 (MKP4/PYST3).

===== [[Phosphatase_Subfamily_DSP8|DSP8]] =====
The DSP8 subfamily is a metazoan subfamily that functions as an MKP with preference towards JNK and p38. It is single copy in invertebrate but two copies in most vertebrates. The two human members DUSP8 and DUSP16 (MKP7) have different tissue expression patterns.

===== [[Phosphatase_Subfamily_DSP10|DSP10]] =====
Human DUSP10 (MKP5) selectively dephosphorylates p38 and JNK. It is conserved across [[holozoa]] but lost in nematodes. Human DUSP10 is frequently dysregulated in colorectal cancer.

===== [[Phosphatase_Subfamily_STYXL1|STYXL1]] =====
The STYXL1 subfamily is a pseudophosphatase (catalytically inactive) conserved in metazoa but lost in ecdysozoa. It is also known as MK-STYX, named after the catalytically inactive phosphatase subfamily [[Phosphatase_Subfamily_STYX|STYX]]. In comparison with STYX, it has an N-terminal rhodanese domain, which is a common feature between MKPs. Two binding partners have been known so far: phosphatase PTPMT1 and a Ras signaling regulator G3BP1.

===Likely MKPs without a Rhondanese Domain===

===== [[Phosphatase_Subfamily_DSP3|DSP3]]=====
Human DSP3s are abundantly expressed in skeletal muscle and heart. It emerged in eumetazoa, lost in nematodes and duplicated in deuterostomes. Human has five members: DUSP3 (VHR), DUSP13 (BEDP/TMDP/MDSP/SKRP4), DUSP26 (MKP8), DUSP27, DUPD1.

===== [[Phosphatase_Subfamily_DSP14|DSP14]] =====
The DSP14 subfamily emerged in eumetazoa and duplicated in vertebrates. Human has four members, DUSP14 (MKP6), DUSP18, DUSP21 and DUSP28 (VHP). Little is known about their functions.

===== [[Phosphatase_Subfamily_DSP15|DSP15]] =====
The DSP15 subfamily emerged in metazoa and duplicated in vertebrates. It has a N-terminal myristoylation site which targets it to plasma membrane. Little is known about its molecular function.

===== [[Phosphatase_Subfamily_DSP19|DSP19]] =====
DSP19 is found across eukaryotes but absent from fungi. Human DUSP19 (SKRP1) regulates JNK signaling but the mechanism is unclear.

===== [[Phosphatase_Subfamily_STYX|STYX]] =====
The STYX subfamily of catalytically inactive phosphatases found in most opisthokonts but lost in nematodes.

===== [[Phosphatase_Subfamily_DSP23|DSP23]] =====
Human DUSP23 is a nuclear phosphatase found in metazoa but lost in ecdysozoa.

===Cyclin-dependent kinase phosphatases===

===== [[Phosphatase_Subfamily_CDC14|CDC14]] =====
CDC14 is a cell cycle phosphatase found in most eukaryotes other than higher plants.

===== [[Phosphatase_Subfamily_CDKN3|CDKN3]] =====
CDKN3 (KAP) is a chordate-specific phosphatase targeting Cyclin-dependent kinases (CDKs) CDK1 and CDK2.

===DSPs with non-protein substrates===

===== [[Phosphatase_Subfamily_DSP12|DSP12]] =====
The DSP12 subfamily is found throughout unikonts, with suggested roles in fat and glucose metabolism, MAPK regulation, ribosome biogenesis and cell cycle progression.

===== [[Phosphatase_Subfamily_RNGTT|RNGTT]] =====
The RNGTT subfamily is an mRNA capping enzyme found in [[holozoa]]. It has a phosphatase domain and guanylyltransferase.

===== [[Phosphatase_Subfamily_DSP11|DSP11]] =====
The DSP11 subfamily is a metazoan-specific subfamily. Its physiological substrate is unknown, but several lines of evidence link this phosphatase to RNA splicing. Human has a single copy DUSP11 (PIR1).

===== [[Phosphatase_Subfamily_Laforin|Laforin]] =====
The laforin subfamily is a glucan phosphatase, found in vertebrates and scattered other species. Mutations in the human member, EPM2A, are associated with myoclonic epilepsy of [http://en.wikipedia.org/wiki/Lafora_disease Lafora].

===== [[Phosphatase_Subfamily_PTPMT1|PTPMT1]] =====
PTPMT1 is a mitochondrial non-protein phosphatase that converts phosphatidylglycerolphosphate (PGP) to phosphatidylglycerol, during biosynthesis of cardiolipin. It is found in most or all animals and higher plants, and most protists but is absent from fungi, ''Monosiga'', and some lower plants.

===Other subfamilies found in human===

===== [[Phosphatase_Subfamily_PTPDC1|PTPDC1]] =====
PTPDC1 is found in [[holozoa]] and some protists, but lost from most insects. It may function in centriole and cilium biology.

===== [[Phosphatase_Subfamily_PRL|PRL]] =====
The PRL (PTP4A) subfamily is present in animals, amoeba, and many basal eukaryotes, but is absent from fungi and plants ([http://resdev.gene.com/gOrtholog/view/cluster/MC0001030/overview unpublished data from gOrtholog]). The three human members, PRL1, PRL2, PRL3, have all been linked to cancer metastasis.

===== [[Phosphatase_Subfamily_Slingshot|Slingshot]] =====
The slingshot subfamily is conserved in holozoa but lost in nematodes, regulates [http://en.wikipedia.org/wiki/Cofilin cofilin] phosphorylation in opposition to LIMK and TESK kinases.

=== Non-human subfamilies and unclassified DSPs ===

===== ''Dictyostelium [[Phosphatase_Gene_dupA|dupA]]'' =====
''Dictyostelium DupA'' has an active kinase domain and an inactive phosphatase domain. The cysteine at CX5R motif of phosphatase domain is substituted by serine, so its phosphatase domain is probably catalytically inactive. The kinase domain is pretty divergent but has the key catalytic residues. It is also found in other ''Dictyosteliida'', but not other amoebazoa, by BLASTing against NR - eukaryotes data set and amoebazoa data set. It may regulate a MAP kinase response to bacteria Legionella pneumophila <cite>Li09</cite>.

===== ''Dictyostelium'' LRR-DSP =====
The LRR-DSP subfamily has LRR repeats at N-terminal. It is found in most amoebozoa by BLASTing against NR database through NCBI BLAST server.

== Phosphatase domain structures ==
Almost all DSP phosphatase domains (PDs) have a secondary structure (SS) combination of E2, E3, H2, E4, E11, H3, E12, H4, H5, H6 (E denotes beta strand, H denotes helix, SS numbered by PTPN1. The combination is exactly same as the common SS combination in [[Phosphatase_Fold_CC1#Structure|CC1 fold]]), except that some DSPs have the helix H2 split into two helices separated by single amino acid.

DSPs have dramatic diversity in structure, although they generally share the same SS combination, especially at the following two regions:
* E3-H2-E4 region. As mentioned above, some but not all DSPs have the helix split into two helices. CDKN3 has a 2-stranded beta sheet inserted between E3 and H2.
* E4-E11 region. The region contains the so-called WPD loop. Some DSPs have one or two helices inserted, even DUSP6 has an inserted beta strand interacting with E11.

Some DSPs have additional SS element(s) at the termini:
* N-terminal helix. The DSP3 and laforin families, as well as vaccinia virus DSP (PDB code: 2P4D) have an additional N-terminal helix different in structure and evolutionary origins. The additional helix are involved in substrate recognition in both DUSP3 and laforin.
* DUSP14 and DUSP18 of the DSP14 subfamily have a 2-stranded beta sheet followed by a helix at C terminus.
* C-terminal helix. DUSP10 and DUSP12 of two different subfamilies have an additional C-terminal helix, but they occupy distinct spaces.

Three PDs do not all the SS elements as mentioned above:
* First PD of CDC14. CDC14s have two tandem DSP PDs. The first PD is inactive and lacks H2, H3, E11.
* RNGTT. RNTGG lacks E2 according the SS annotations of the PDB files of three RNGTTs (human, mouse and a virus). However, in the papers of mouse RNGTT and virus RNGTT (human RNGTT is not in publication), the authors presented E2, which was annotated through visualization (personal correspondences).
* DUSP11. DUSP11 lacks E2 according to the SS annotations of the multiple PDB files of human DUSP11. However, the authors presented E2. It worthy pointing out that DUSP11 and RNGTT can be well aligned at the region in structure. Given the fact that both of them are involved in RNA processing or editing, it is interesting to find out the functional impact of the absence of E2.

Technical notes: the SS elements were annotated by using the program Stride to infer SS from PDB files.

== Accessory domains ==
* Most MKPs have an N-terminal domain of rhodanese fold.
* Laforin has an N-terminal carbohydrate binding domain.
* RNGTT has a C-terminal guanylyltransferase (GTase) domain.

=== References ===
<biblio>
#Caunt13 pmid=22812510
#Dickinson06 pmid=17093265
#Li09 pmid=19748467
</biblio>

Phosphatase Family DSP

2018-09-12T19:25:38Z

Gerard: /* DSP1 */

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]
__NOTOC__
This family consists of the dual-specific protein phosphatases (DSPs) that dephosphorylate both tyrosine and serine/threonine, as well as related non-protein phosphatases.

== Subfamilies ==

=== MKP: MAP Kinase Phosphatases with a Rhodanese Domain ===

Several related subfamilies of DSP that dephosphorylate [http://kinase.com/wiki/index.php/Kinase_Family_MAPK MAPK Kinases] and share an N-terminal non-catalytic rhodanese domain. These are named MKP, ('''M'''AP '''K'''inase '''P'''hosphatase). They are regulators of MAPK activity, and can mediate crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules (see reviews <cite>Dickinson06, Caunt13</cite>). The rhodanese domains usually contain kinase-interacting motifs (KIMs) for MAPK binding <cite>Dickinson06</cite>.

===== [[Phosphatase_Subfamily_DSP1|DSP1]] =====
DSP1 is an inducible nuclear MKP found throughout eukaryotes. As a key player in MAPK pathway, it is implicated in immune regulation and cancer. Human has four members, DUSP1 (MKP1), DUSP2, DUSP4 (MKP2) and DUSP5.

===== [[Phosphatase_Subfamily_DSP6|DSP6]] =====
The DSP6 subfamily is a cytoplasmic MKP subfamily selectively dephosphorylating ERK. It is found throughout [[metazoa]] and duplicated in vertebrates. Human genome has three members: DUSP6 (MKP3/PYST1), DUSP7 (MKPX/PYST2) and DUSP9 (MKP4/PYST3).

===== [[Phosphatase_Subfamily_DSP8|DSP8]] =====
The DSP8 subfamily is a metazoan subfamily that functions as an MKP with preference towards JNK and p38. It is single copy in invertebrate but two copies in most vertebrates. The two human members DUSP8 and DUSP16 (MKP7) have different tissue expression patterns.

===== [[Phosphatase_Subfamily_DSP10|DSP10]] =====
Human DUSP10 (MKP5) selectively dephosphorylates p38 and JNK. It is conserved across [[holozoa]] but lost in nematodes. Human DUSP10 is frequently dysregulated in colorectal cancer.

===== [[Phosphatase_Subfamily_STYXL1|STYXL1]] =====
The STYXL1 subfamily is a pseudophosphatase (catalytically inactive) conserved in metazoa but lost in ecdysozoa. It is also known as MK-STYX, named after the catalytically inactive phosphatase subfamily [[Phosphatase_Subfamily_STYX|STYX]]. In comparison with STYX, it has an N-terminal rhodanese domain, which is a common feature between MKPs. Two binding partners have been known so far: phosphatase PTPMT1 and a Ras signaling regulator G3BP1.

===Likely MKPs without a Rhondanese Domain===

===== [[Phosphatase_Subfamily_DSP3|DSP3]]=====
Human DSP3s are abundantly expressed in skeletal muscle and heart. It emerged in eumetazoa, lost in nematodes and duplicated in deuterostomes. Human has five members: DUSP3 (VHR), DUSP13 (BEDP/TMDP/MDSP/SKRP4), DUSP26 (MKP8), DUSP27, DUPD1.

===== [[Phosphatase_Subfamily_DSP14|DSP14]] =====
The DSP14 subfamily emerged in eumetazoa and duplicated in vertebrates. Human has four members, DUSP14 (MKP6), DUSP18, DUSP21 and DUSP28 (VHP). Little is known about their functions.

===== [[Phosphatase_Subfamily_DSP15|DSP15]] =====
The DSP15 subfamily emerged in metazoa and duplicated in vertebrates. It has a N-terminal myristoylation site which targets it to plasma membrane. Little is known about its molecular function.

===== [[Phosphatase_Subfamily_DSP19|DSP19]] =====
DSP19 is found across eukaryotes but absent from fungi. Human DUSP19 (SKRP1) regulates JNK signaling but the mechanism is unclear.

===== [[Phosphatase_Subfamily_STYX|STYX]] =====
The STYX subfamily of catalytically inactive phosphatases found in most opisthokonts but lost in nematodes.

===== [[Phosphatase_Subfamily_DSP23|DSP23]] =====
Human DUSP23 is a nuclear phosphatase found in metazoa but lost in ecdysozoa.

===Cyclin-dependent kinase phosphatases===

===== [[Phosphatase_Subfamily_CDC14|CDC14]] =====
CDC14 is a cell cycle phosphatase found in most eukaryotes other than higher plants.

===== [[Phosphatase_Subfamily_CDKN3|CDKN3]] =====
CDKN3 (KAP) is a chordate-specific phosphatase targeting Cyclin-dependent kinases (CDKs) CDK1 and CDK2.

===DSPs with non-protein substrates===

===== [[Phosphatase_Subfamily_DSP12|DSP12]] =====
The DSP12 subfamily is found throughout unikonts, with suggested roles in fat and glucose metabolism, MAPK regulation, ribosome biogenesis and cell cycle progression.

===== [[Phosphatase_Subfamily_RNGTT|RNGTT]] =====
The RNGTT subfamily is an mRNA capping enzyme found in [[holozoa]]. It has a phosphatase domain and guanylyltransferase.

===== [[Phosphatase_Subfamily_DSP11|DSP11]] =====
The DSP11 subfamily is a metazoan-specific subfamily. Its physiological substrate is unknown, but several lines of evidence link this phosphatase to RNA splicing. Human has a single copy DUSP11 (PIR1).

===== [[Phosphatase_Subfamily_Laforin|Laforin]] =====
The laforin subfamily is a glucan phosphatase, found in vertebrates and scattered other species. Mutations in the human member, EPM2A, are associated with myoclonic epilepsy of [http://en.wikipedia.org/wiki/Lafora_disease Lafora].

===== [[Phosphatase_Subfamily_PTPMT1|PTPMT1]] =====
PTPMT1 is a mitochondrial non-protein phosphatase that converts phosphatidylglycerolphosphate (PGP) to phosphatidylglycerol, during biosynthesis of cardiolipin. It is found in most or all animals and higher plants, and most protists but is absent from fungi, ''Monosiga'', and some lower plants.

===Other subfamilies found in human===

===== [[Phosphatase_Subfamily_PTPDC1|PTPDC1]] =====
PTPDC1 is found in [[holozoa]] and some protists, but lost from most insects. It may function in centriole and cilium biology.

===== [[Phosphatase_Subfamily_PRL|PRL]] =====
The PRL (PTP4A) subfamily is present in animals, amoeba, and many basal eukaryotes, but is absent from fungi and plants ([http://resdev.gene.com/gOrtholog/view/cluster/MC0001030/overview unpublished data from gOrtholog]). The three human members, PRL1, PRL2, PRL3, have all been linked to cancer metastasis.

===== [[Phosphatase_Subfamily_Slingshot|Slingshot]] =====
The slingshot subfamily is conserved in holozoa but lost in nematodes, regulates [http://en.wikipedia.org/wiki/Cofilin cofilin] phosphorylation in opposition to LIMK and TESK kinases.

=== Non-human subfamilies and unclassified DSPs ===

===== ''Dictyostelium [[Phosphatase_Gene_dupA|dupA]]'' =====
''Dictyostelium DupA'' has an active kinase domain and an inactive phosphatase domain. The cysteine at CX5R motif of phosphatase domain is substituted by serine, so its phosphatase domain is probably catalytically inactive. The kinase domain is pretty divergent but has the key catalytic residues. It is also found in other ''Dictyosteliida'', but not other amoebazoa, by BLASTing against NR - eukaryotes data set and amoebazoa data set. It may regulate a MAP kinase response to bacteria Legionella pneumophila <cite>Li09</cite>.

===== ''Dictyostelium'' LRR-DSP =====
The LRR-DSP subfamily has LRR repeats at N-terminal. It is found in most amoebozoa by BLASTing against NR database through NCBI BLAST server.

== Phosphatase domain structures ==
Almost all DSP phosphatase domains (PDs) have a secondary structure (SS) combination of E2, E3, H2, E4, E11, H3, E12, H4, H5, H6 (E denotes beta strand, H denotes helix, SS numbered by PTPN1. The combination is exactly same as the common SS combination in [[Phosphatase_Fold_CC1#Structure|CC1 fold]]), except that some DSPs have the helix H2 split into two helices separated by single amino acid.

DSPs have dramatic diversity in structure, although they generally share the same SS combination, especially at the following two regions:
* E3-H2-E4 region. As mentioned above, some but not all DSPs have the helix split into two helices. CDKN3 has a 2-stranded beta sheet inserted between E3 and H2.
* E4-E11 region. The region contains the so-called WPD loop. Some DSPs have one or two helices inserted, even DUSP6 has an inserted beta strand interacting with E11.

Some DSPs have additional SS element(s) at the termini:
* N-terminal helix. The DSP3 and laforin families, as well as vaccinia virus DSP (PDB code: 2P4D) have an additional N-terminal helix different in structure and evolutionary origins. The additional helix are involved in substrate recognition in both DUSP3 and laforin.
* DUSP14 and DUSP18 of the DSP14 subfamily have a 2-stranded beta sheet followed by a helix at C terminus.
* C-terminal helix. DUSP10 and DUSP12 of two different subfamilies have an additional C-terminal helix, but they occupy distinct spaces.

Three PDs do not all the SS elements as mentioned above:
* First PD of CDC14. CDC14s have two tandem DSP PDs. The first PD is inactive and lacks H2, H3, E11.
* RNGTT. RNTGG lacks E2 according the SS annotations of the PDB files of three RNGTTs (human, mouse and a virus). However, in the papers of mouse RNGTT and virus RNGTT (human RNGTT is not in publication), the authors presented E2, which was annotated through visualization (personal correspondences).
* DUSP11. DUSP11 lacks E2 according to the SS annotations of the multiple PDB files of human DUSP11. However, the authors presented E2. It worthy pointing out that DUSP11 and RNGTT can be well aligned at the region in structure. Given the fact that both of them are involved in RNA processing or editing, it is interesting to find out the functional impact of the absence of E2.

Technical notes: the SS elements were annotated by using the program Stride to infer SS from PDB files.

== Accessory domains ==
* Most MKPs have an N-terminal domain of rhodanese fold.
* Laforin has an N-terminal carbohydrate binding domain.
* RNGTT has a C-terminal guanylyltransferase (GTase) domain.

=== References ===
<biblio>
#Caunt13 pmid=22812510
#Dickinson06 pmid=17093265
#Li09 pmid=19748467
</biblio>

Phosphatase Family DSP

2018-09-12T19:24:27Z

Gerard:

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]
__NOTOC__
This family consists of the dual-specific protein phosphatases (DSPs) that dephosphorylate both tyrosine and serine/threonine, as well as related non-protein phosphatases.

== Subfamilies ==

=== MKP: MAP Kinase Phosphatases with a Rhodanese Domain ===

Several related subfamilies of DSP that dephosphorylate [http://kinase.com/wiki/index.php/Kinase_Family_MAPK MAPK Kinases] and share an N-terminal non-catalytic rhodanese domain. These are named MKP, ('''M'''AP '''K'''inase '''P'''hosphatase). They are regulators of MAPK activity, and can mediate crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules (see reviews <cite>Dickinson06, Caunt13</cite>). The rhodanese domains usually contain kinase-interacting motifs (KIMs) for MAPK binding <cite>Dickinson06</cite>.

===== [[Phosphatase_Subfamily_DSP1|DSP1]] =====
The DSP1 subfamily is an inducible nuclear MKP subfamily found throughout eukaryotes. As a key player in MAPK pathway, it is implicated in immune regulation and cancer. Human has four members, DUSP1 (MKP1), DUSP2, DUSP4 (MKP2) and DUSP5.

===== [[Phosphatase_Subfamily_DSP6|DSP6]] =====
The DSP6 subfamily is a cytoplasmic MKP subfamily selectively dephosphorylating ERK. It is found throughout [[metazoa]] and duplicated in vertebrates. Human genome has three members: DUSP6 (MKP3/PYST1), DUSP7 (MKPX/PYST2) and DUSP9 (MKP4/PYST3).

===== [[Phosphatase_Subfamily_DSP8|DSP8]] =====
The DSP8 subfamily is a metazoan subfamily that functions as an MKP with preference towards JNK and p38. It is single copy in invertebrate but two copies in most vertebrates. The two human members DUSP8 and DUSP16 (MKP7) have different tissue expression patterns.

===== [[Phosphatase_Subfamily_DSP10|DSP10]] =====
Human DUSP10 (MKP5) selectively dephosphorylates p38 and JNK. It is conserved across [[holozoa]] but lost in nematodes. Human DUSP10 is frequently dysregulated in colorectal cancer.

===== [[Phosphatase_Subfamily_STYXL1|STYXL1]] =====
The STYXL1 subfamily is a pseudophosphatase (catalytically inactive) conserved in metazoa but lost in ecdysozoa. It is also known as MK-STYX, named after the catalytically inactive phosphatase subfamily [[Phosphatase_Subfamily_STYX|STYX]]. In comparison with STYX, it has an N-terminal rhodanese domain, which is a common feature between MKPs. Two binding partners have been known so far: phosphatase PTPMT1 and a Ras signaling regulator G3BP1.

===Likely MKPs without a Rhondanese Domain===

===== [[Phosphatase_Subfamily_DSP3|DSP3]]=====
Human DSP3s are abundantly expressed in skeletal muscle and heart. It emerged in eumetazoa, lost in nematodes and duplicated in deuterostomes. Human has five members: DUSP3 (VHR), DUSP13 (BEDP/TMDP/MDSP/SKRP4), DUSP26 (MKP8), DUSP27, DUPD1.

===== [[Phosphatase_Subfamily_DSP14|DSP14]] =====
The DSP14 subfamily emerged in eumetazoa and duplicated in vertebrates. Human has four members, DUSP14 (MKP6), DUSP18, DUSP21 and DUSP28 (VHP). Little is known about their functions.

===== [[Phosphatase_Subfamily_DSP15|DSP15]] =====
The DSP15 subfamily emerged in metazoa and duplicated in vertebrates. It has a N-terminal myristoylation site which targets it to plasma membrane. Little is known about its molecular function.

===== [[Phosphatase_Subfamily_DSP19|DSP19]] =====
DSP19 is found across eukaryotes but absent from fungi. Human DUSP19 (SKRP1) regulates JNK signaling but the mechanism is unclear.

===== [[Phosphatase_Subfamily_STYX|STYX]] =====
The STYX subfamily of catalytically inactive phosphatases found in most opisthokonts but lost in nematodes.

===== [[Phosphatase_Subfamily_DSP23|DSP23]] =====
Human DUSP23 is a nuclear phosphatase found in metazoa but lost in ecdysozoa.

===Cyclin-dependent kinase phosphatases===

===== [[Phosphatase_Subfamily_CDC14|CDC14]] =====
CDC14 is a cell cycle phosphatase found in most eukaryotes other than higher plants.

===== [[Phosphatase_Subfamily_CDKN3|CDKN3]] =====
CDKN3 (KAP) is a chordate-specific phosphatase targeting Cyclin-dependent kinases (CDKs) CDK1 and CDK2.

===DSPs with non-protein substrates===

===== [[Phosphatase_Subfamily_DSP12|DSP12]] =====
The DSP12 subfamily is found throughout unikonts, with suggested roles in fat and glucose metabolism, MAPK regulation, ribosome biogenesis and cell cycle progression.

===== [[Phosphatase_Subfamily_RNGTT|RNGTT]] =====
The RNGTT subfamily is an mRNA capping enzyme found in [[holozoa]]. It has a phosphatase domain and guanylyltransferase.

===== [[Phosphatase_Subfamily_DSP11|DSP11]] =====
The DSP11 subfamily is a metazoan-specific subfamily. Its physiological substrate is unknown, but several lines of evidence link this phosphatase to RNA splicing. Human has a single copy DUSP11 (PIR1).

===== [[Phosphatase_Subfamily_Laforin|Laforin]] =====
The laforin subfamily is a glucan phosphatase, found in vertebrates and scattered other species. Mutations in the human member, EPM2A, are associated with myoclonic epilepsy of [http://en.wikipedia.org/wiki/Lafora_disease Lafora].

===== [[Phosphatase_Subfamily_PTPMT1|PTPMT1]] =====
PTPMT1 is a mitochondrial non-protein phosphatase that converts phosphatidylglycerolphosphate (PGP) to phosphatidylglycerol, during biosynthesis of cardiolipin. It is found in most or all animals and higher plants, and most protists but is absent from fungi, ''Monosiga'', and some lower plants.

===Other subfamilies found in human===

===== [[Phosphatase_Subfamily_PTPDC1|PTPDC1]] =====
PTPDC1 is found in [[holozoa]] and some protists, but lost from most insects. It may function in centriole and cilium biology.

===== [[Phosphatase_Subfamily_PRL|PRL]] =====
The PRL (PTP4A) subfamily is present in animals, amoeba, and many basal eukaryotes, but is absent from fungi and plants ([http://resdev.gene.com/gOrtholog/view/cluster/MC0001030/overview unpublished data from gOrtholog]). The three human members, PRL1, PRL2, PRL3, have all been linked to cancer metastasis.

===== [[Phosphatase_Subfamily_Slingshot|Slingshot]] =====
The slingshot subfamily is conserved in holozoa but lost in nematodes, regulates [http://en.wikipedia.org/wiki/Cofilin cofilin] phosphorylation in opposition to LIMK and TESK kinases.

=== Non-human subfamilies and unclassified DSPs ===

===== ''Dictyostelium [[Phosphatase_Gene_dupA|dupA]]'' =====
''Dictyostelium DupA'' has an active kinase domain and an inactive phosphatase domain. The cysteine at CX5R motif of phosphatase domain is substituted by serine, so its phosphatase domain is probably catalytically inactive. The kinase domain is pretty divergent but has the key catalytic residues. It is also found in other ''Dictyosteliida'', but not other amoebazoa, by BLASTing against NR - eukaryotes data set and amoebazoa data set. It may regulate a MAP kinase response to bacteria Legionella pneumophila <cite>Li09</cite>.

===== ''Dictyostelium'' LRR-DSP =====
The LRR-DSP subfamily has LRR repeats at N-terminal. It is found in most amoebozoa by BLASTing against NR database through NCBI BLAST server.

== Phosphatase domain structures ==
Almost all DSP phosphatase domains (PDs) have a secondary structure (SS) combination of E2, E3, H2, E4, E11, H3, E12, H4, H5, H6 (E denotes beta strand, H denotes helix, SS numbered by PTPN1. The combination is exactly same as the common SS combination in [[Phosphatase_Fold_CC1#Structure|CC1 fold]]), except that some DSPs have the helix H2 split into two helices separated by single amino acid.

DSPs have dramatic diversity in structure, although they generally share the same SS combination, especially at the following two regions:
* E3-H2-E4 region. As mentioned above, some but not all DSPs have the helix split into two helices. CDKN3 has a 2-stranded beta sheet inserted between E3 and H2.
* E4-E11 region. The region contains the so-called WPD loop. Some DSPs have one or two helices inserted, even DUSP6 has an inserted beta strand interacting with E11.

Some DSPs have additional SS element(s) at the termini:
* N-terminal helix. The DSP3 and laforin families, as well as vaccinia virus DSP (PDB code: 2P4D) have an additional N-terminal helix different in structure and evolutionary origins. The additional helix are involved in substrate recognition in both DUSP3 and laforin.
* DUSP14 and DUSP18 of the DSP14 subfamily have a 2-stranded beta sheet followed by a helix at C terminus.
* C-terminal helix. DUSP10 and DUSP12 of two different subfamilies have an additional C-terminal helix, but they occupy distinct spaces.

Three PDs do not all the SS elements as mentioned above:
* First PD of CDC14. CDC14s have two tandem DSP PDs. The first PD is inactive and lacks H2, H3, E11.
* RNGTT. RNTGG lacks E2 according the SS annotations of the PDB files of three RNGTTs (human, mouse and a virus). However, in the papers of mouse RNGTT and virus RNGTT (human RNGTT is not in publication), the authors presented E2, which was annotated through visualization (personal correspondences).
* DUSP11. DUSP11 lacks E2 according to the SS annotations of the multiple PDB files of human DUSP11. However, the authors presented E2. It worthy pointing out that DUSP11 and RNGTT can be well aligned at the region in structure. Given the fact that both of them are involved in RNA processing or editing, it is interesting to find out the functional impact of the absence of E2.

Technical notes: the SS elements were annotated by using the program Stride to infer SS from PDB files.

== Accessory domains ==
* Most MKPs have an N-terminal domain of rhodanese fold.
* Laforin has an N-terminal carbohydrate binding domain.
* RNGTT has a C-terminal guanylyltransferase (GTase) domain.

=== References ===
<biblio>
#Caunt13 pmid=22812510
#Dickinson06 pmid=17093265
#Li09 pmid=19748467
</biblio>

Phosphatase Family DSP

2018-09-12T19:24:00Z

Gerard:

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]

__NOTOC__

This family consists of the dual-specific protein phosphatases (DSPs) that dephosphorylate both tyrosine and serine/threonine, as well as related non-protein phosphatases.

== Subfamilies ==

=== MKP: MAP Kinase Phosphatases with a Rhodanese Domain ===

Several related subfamilies of DSP that dephosphorylate [http://kinase.com/wiki/index.php/Kinase_Family_MAPK MAPK Kinases] and share an N-terminal non-catalytic rhodanese domain. These are named MKP, ('''M'''AP '''K'''inase '''P'''hosphatase). They are regulators of MAPK activity, and can mediate crosstalk between distinct MAPK pathways and between MAPK signalling and other intracellular signalling modules (see reviews <cite>Dickinson06, Caunt13</cite>). The rhodanese domains usually contain kinase-interacting motifs (KIMs) for MAPK binding <cite>Dickinson06</cite>.

===== [[Phosphatase_Subfamily_DSP1|DSP1]] =====
The DSP1 subfamily is an inducible nuclear MKP subfamily found throughout eukaryotes. As a key player in MAPK pathway, it is implicated in immune regulation and cancer. Human has four members, DUSP1 (MKP1), DUSP2, DUSP4 (MKP2) and DUSP5.

===== [[Phosphatase_Subfamily_DSP6|DSP6]] =====
The DSP6 subfamily is a cytoplasmic MKP subfamily selectively dephosphorylating ERK. It is found throughout [[metazoa]] and duplicated in vertebrates. Human genome has three members: DUSP6 (MKP3/PYST1), DUSP7 (MKPX/PYST2) and DUSP9 (MKP4/PYST3).

===== [[Phosphatase_Subfamily_DSP8|DSP8]] =====
The DSP8 subfamily is a metazoan subfamily that functions as an MKP with preference towards JNK and p38. It is single copy in invertebrate but two copies in most vertebrates. The two human members DUSP8 and DUSP16 (MKP7) have different tissue expression patterns.

===== [[Phosphatase_Subfamily_DSP10|DSP10]] =====
Human DUSP10 (MKP5) selectively dephosphorylates p38 and JNK. It is conserved across [[holozoa]] but lost in nematodes. Human DUSP10 is frequently dysregulated in colorectal cancer.

===== [[Phosphatase_Subfamily_STYXL1|STYXL1]] =====
The STYXL1 subfamily is a pseudophosphatase (catalytically inactive) conserved in metazoa but lost in ecdysozoa. It is also known as MK-STYX, named after the catalytically inactive phosphatase subfamily [[Phosphatase_Subfamily_STYX|STYX]]. In comparison with STYX, it has an N-terminal rhodanese domain, which is a common feature between MKPs. Two binding partners have been known so far: phosphatase PTPMT1 and a Ras signaling regulator G3BP1.

===Likely MKPs without a Rhondanese Domain===

===== [[Phosphatase_Subfamily_DSP3|DSP3]]=====
Human DSP3s are abundantly expressed in skeletal muscle and heart. It emerged in eumetazoa, lost in nematodes and duplicated in deuterostomes. Human has five members: DUSP3 (VHR), DUSP13 (BEDP/TMDP/MDSP/SKRP4), DUSP26 (MKP8), DUSP27, DUPD1.

===== [[Phosphatase_Subfamily_DSP14|DSP14]] =====
The DSP14 subfamily emerged in eumetazoa and duplicated in vertebrates. Human has four members, DUSP14 (MKP6), DUSP18, DUSP21 and DUSP28 (VHP). Little is known about their functions.

===== [[Phosphatase_Subfamily_DSP15|DSP15]] =====
The DSP15 subfamily emerged in metazoa and duplicated in vertebrates. It has a N-terminal myristoylation site which targets it to plasma membrane. Little is known about its molecular function.

===== [[Phosphatase_Subfamily_DSP19|DSP19]] =====
DSP19 is found across eukaryotes but absent from fungi. Human DUSP19 (SKRP1) regulates JNK signaling but the mechanism is unclear.

===== [[Phosphatase_Subfamily_STYX|STYX]] =====
The STYX subfamily of catalytically inactive phosphatases found in most opisthokonts but lost in nematodes.

===== [[Phosphatase_Subfamily_DSP23|DSP23]] =====
Human DUSP23 is a nuclear phosphatase found in metazoa but lost in ecdysozoa.

===Cyclin-dependent kinase phosphatases===

===== [[Phosphatase_Subfamily_CDC14|CDC14]] =====
CDC14 is a cell cycle phosphatase found in most eukaryotes other than higher plants.

===== [[Phosphatase_Subfamily_CDKN3|CDKN3]] =====
CDKN3 (KAP) is a chordate-specific phosphatase targeting Cyclin-dependent kinases (CDKs) CDK1 and CDK2.

===DSPs with non-protein substrates===

===== [[Phosphatase_Subfamily_DSP12|DSP12]] =====
The DSP12 subfamily is found throughout unikonts, with suggested roles in fat and glucose metabolism, MAPK regulation, ribosome biogenesis and cell cycle progression.

===== [[Phosphatase_Subfamily_RNGTT|RNGTT]] =====
The RNGTT subfamily is an mRNA capping enzyme found in [[holozoa]]. It has a phosphatase domain and guanylyltransferase.

===== [[Phosphatase_Subfamily_DSP11|DSP11]] =====
The DSP11 subfamily is a metazoan-specific subfamily. Its physiological substrate is unknown, but several lines of evidence link this phosphatase to RNA splicing. Human has a single copy DUSP11 (PIR1).

===== [[Phosphatase_Subfamily_Laforin|Laforin]] =====
The laforin subfamily is a glucan phosphatase, found in vertebrates and scattered other species. Mutations in the human member, EPM2A, are associated with myoclonic epilepsy of [http://en.wikipedia.org/wiki/Lafora_disease Lafora].

===== [[Phosphatase_Subfamily_PTPMT1|PTPMT1]] =====
PTPMT1 is a mitochondrial non-protein phosphatase that converts phosphatidylglycerolphosphate (PGP) to phosphatidylglycerol, during biosynthesis of cardiolipin. It is found in most or all animals and higher plants, and most protists but is absent from fungi, ''Monosiga'', and some lower plants.

===Other subfamilies found in human===

===== [[Phosphatase_Subfamily_PTPDC1|PTPDC1]] =====
PTPDC1 is found in [[holozoa]] and some protists, but lost from most insects. It may function in centriole and cilium biology.

===== [[Phosphatase_Subfamily_PRL|PRL]] =====
The PRL (PTP4A) subfamily is present in animals, amoeba, and many basal eukaryotes, but is absent from fungi and plants ([http://resdev.gene.com/gOrtholog/view/cluster/MC0001030/overview unpublished data from gOrtholog]). The three human members, PRL1, PRL2, PRL3, have all been linked to cancer metastasis.

===== [[Phosphatase_Subfamily_Slingshot|Slingshot]] =====
The slingshot subfamily is conserved in holozoa but lost in nematodes, regulates [http://en.wikipedia.org/wiki/Cofilin cofilin] phosphorylation in opposition to LIMK and TESK kinases.

=== Non-human subfamilies and unclassified DSPs ===

===== ''Dictyostelium [[Phosphatase_Gene_dupA|dupA]]'' =====
''Dictyostelium DupA'' has an active kinase domain and an inactive phosphatase domain. The cysteine at CX5R motif of phosphatase domain is substituted by serine, so its phosphatase domain is probably catalytically inactive. The kinase domain is pretty divergent but has the key catalytic residues. It is also found in other ''Dictyosteliida'', but not other amoebazoa, by BLASTing against NR - eukaryotes data set and amoebazoa data set. It may regulate a MAP kinase response to bacteria Legionella pneumophila <cite>Li09</cite>.

===== ''Dictyostelium'' LRR-DSP =====
The LRR-DSP subfamily has LRR repeats at N-terminal. It is found in most amoebozoa by BLASTing against NR database through NCBI BLAST server.

== Phosphatase domain structures ==
Almost all DSP phosphatase domains (PDs) have a secondary structure (SS) combination of E2, E3, H2, E4, E11, H3, E12, H4, H5, H6 (E denotes beta strand, H denotes helix, SS numbered by PTPN1. The combination is exactly same as the common SS combination in [[Phosphatase_Fold_CC1#Structure|CC1 fold]]), except that some DSPs have the helix H2 split into two helices separated by single amino acid.

DSPs have dramatic diversity in structure, although they generally share the same SS combination, especially at the following two regions:
* E3-H2-E4 region. As mentioned above, some but not all DSPs have the helix split into two helices. CDKN3 has a 2-stranded beta sheet inserted between E3 and H2.
* E4-E11 region. The region contains the so-called WPD loop. Some DSPs have one or two helices inserted, even DUSP6 has an inserted beta strand interacting with E11.

Some DSPs have additional SS element(s) at the termini:
* N-terminal helix. The DSP3 and laforin families, as well as vaccinia virus DSP (PDB code: 2P4D) have an additional N-terminal helix different in structure and evolutionary origins. The additional helix are involved in substrate recognition in both DUSP3 and laforin.
* DUSP14 and DUSP18 of the DSP14 subfamily have a 2-stranded beta sheet followed by a helix at C terminus.
* C-terminal helix. DUSP10 and DUSP12 of two different subfamilies have an additional C-terminal helix, but they occupy distinct spaces.

Three PDs do not all the SS elements as mentioned above:
* First PD of CDC14. CDC14s have two tandem DSP PDs. The first PD is inactive and lacks H2, H3, E11.
* RNGTT. RNTGG lacks E2 according the SS annotations of the PDB files of three RNGTTs (human, mouse and a virus). However, in the papers of mouse RNGTT and virus RNGTT (human RNGTT is not in publication), the authors presented E2, which was annotated through visualization (personal correspondences).
* DUSP11. DUSP11 lacks E2 according to the SS annotations of the multiple PDB files of human DUSP11. However, the authors presented E2. It worthy pointing out that DUSP11 and RNGTT can be well aligned at the region in structure. Given the fact that both of them are involved in RNA processing or editing, it is interesting to find out the functional impact of the absence of E2.

Technical notes: the SS elements were annotated by using the program Stride to infer SS from PDB files.

== Accessory domains ==
* Most MKPs have an N-terminal domain of rhodanese fold.
* Laforin has an N-terminal carbohydrate binding domain.
* RNGTT has a C-terminal guanylyltransferase (GTase) domain.

=== References ===
<biblio>
#Caunt13 pmid=22812510
#Dickinson06 pmid=17093265
#Li09 pmid=19748467
</biblio>

Phosphatase Subfamily Tensin

2018-05-04T19:00:42Z

Gerard: /* Domain Structure */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTEN|Family PTEN]]: [[Phosphatase_Subfamily_Tensin|Subfamily Tensin]]

Tensins are PTEN-related phosphatases involved in integrin signaling.

===Evolution===
Tensins are found throughout [[holozoa]]. The domain combination is under dramatic changes during evolution. Drosophilids have a truncated ortholog ([http://www.sdbonline.org/sites/fly/cytoskel/blistery1.htm ''blistery'']) which lacks the phosphatase domain, though the full-length form is seen in mosquitoes. One of the four human members, TNS4, is also truncated.

===Domain Structure===
Tensins are long proteins, with an N-terminal phosphatase domain followed immediately by a PTEN_C2 domain, which acts as a lipid-binding domain. They have a poorly conserved middle region, SH2 and usually PTB domains at the C-terminus. Many Tensins also have an N-terminal C1 domain. Humans also have a homologous TNS4 protein which is N-terminally truncated and has lost the phosphatase domain. The phosphatase domain is quite divergent and often can not be picked by Pfam or SMART.

TNS1 and TNS2 are predicted to be catalytically inactive, given the arginine residue is replaced by asparagine and lysine at CX5R motif, respectively, though catalytic activity of TNS2 has been reported. These may function as binding domains for phosphatidyl inositols. The single orthologs in most invertebrates are predicted to be catalytically active.

The functions of the phosphatase domain are not well understood:
* TNS1. The phosphatase domain can bind to PPP1CA in focal adhesions <cite>Eto07</cite>.
* TNS2. TNS2 induced in vivo dephosporylation of phosphatidylinositol 3,4,5-trisphosphate, though the activity could not be replicated in vitro <cite>Hafizi</cite>. Another report <cite>Koh</cite> showed TNS2 protein tyrosine phosphatase activity on IRS-1.

===Functions===
Tensins are localized to integrin-mediated focal adhesions. The PTB domain binds to the cytoplasmic region of integrins, and N-terminal regions bind actin. The SH2 domain interacts with a variety of tyrosine-phosphorylated proteins, including PI3K, FAK, and p130Cas. Several tensins are linked to cell migration and metastasis suppression and to signaling downstream of receptor tyrosine kinases.

===References===
<biblio>
#Hafizi pmid=20678486
#Koh pmid=23401856
#Eto07 pmid=17435217
</biblio>

Phosphatase Family PTEN

2018-05-04T18:56:24Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTEN|Family PTEN]]

PTEN is a family of lipid phosphatases and lipid-binding proteins that is closely related to the [[Phosphatase_Family_DSP|DSP]] family. PTEN itself is found in all eukaryotes and is a negative regulator of PI3K signaling. Other defined subfamilies are largely [[holozoa]]n-specific and frequently appear to be catalytically inactive and to function as lipid-binding domains of larger proteins. All subfamilies have a specialized C2 domain (C2_PTEN) immediately following the phosphatase domain.

===== [[Phosphatase_Subfamily_PTEN|PTEN subfamily]] =====
PTEN subfamily is named after its single member in human, PTEN, which acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3). PTEN is one of the most commonly lost tumor suppressors in human cancer. It is found throughout eukaryotes ([http://resdev.gene.com/gOrtholog/view/cluster/MC0001193/overview unpublished data from gOrtholog]).

===== [[Phosphatase_Subfamily_VSP|VSP subfamily]] =====
The Voltage Sensitive Phosphatase (VSP) members consist of a voltage sensor consisting of four transmembrane segments <cite>Iwasaki08</cite>, in addition to phosphatase domain and C2 domain. It has two members in human, TPTE and TPTE2 (TPIP), but TPTE is a pseudophosphatase. The subfamily is conserved in [[holozoa]] but absent from nematodes and most arthropods. It usually has a single copy in each species, and the two human copies appear to be a primate duplication.

===== [[Phosphatase_Subfamily_Tensin|Tensin subfamily]] =====
Tensin are adaptor proteins that link integrins to the actin cytoskeleton and are involved in a variety of signal transduction cascades.

===== [[Phosphatase_Subfamily_Auxilin|Auxilin subfamily]] =====
Inactive phosphatases that bind phospholipids during clathrin-coated vesicle formation and uncoating. Most also have a kinase domain.

=== References ===
<biblio>
#Iwasaki08 pmid=18524949
</biblio>

Phosphatase Family PTEN

2018-05-04T18:52:02Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTEN|Family PTEN]]

PTEN is a family of lipid phosphatases and lipid-binding proteins that is closely related to the [[Phosphatase_Family_DSP|DSP]] family. PTEN itself is found in all eukaryotes and is a negative regulator of PI3K signaling. Other defined subfamilies are largely [[holozoa]]n-specific and frequently appear to be catalytically inactive and to function as lipid-binding domains of larger proteins.

===== [[Phosphatase_Subfamily_PTEN|PTEN subfamily]] =====
PTEN subfamily is named after its single member in human, PTEN, which acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3). PTEN is one of the most commonly lost tumor suppressors in human cancer. It is found throughout eukaryotes ([http://resdev.gene.com/gOrtholog/view/cluster/MC0001193/overview unpublished data from gOrtholog]).

===== [[Phosphatase_Subfamily_VSP|VSP subfamily]] =====
The Voltage Sensitive Phosphatase (VSP) members consist of a voltage sensor consisting of four transmembrane segments <cite>Iwasaki08</cite>, in addition to phosphatase domain and C2 domain. It has two members in human, TPTE and TPTE2 (TPIP), but TPTE is a pseudophosphatase. The subfamily is conserved in [[holozoa]] but absent from nematodes and most arthropods. It usually has a single copy in each species, and the two human copies appear to be a primate duplication.

===== [[Phosphatase_Subfamily_Tensin|Tensin subfamily]] =====
Tensin are adaptor proteins that link integrins to the actin cytoskeleton and are involved in a variety of signal transduction cascades.

===== [[Phosphatase_Subfamily_Auxilin|Auxilin subfamily]] =====
Inactive phosphatases that bind phospholipids during clathrin-coated vesicle formation and uncoating. Most also have a kinase domain.

=== References ===
<biblio>
#Iwasaki08 pmid=18524949
</biblio>

Phosphatase Subfamily Tensin

2018-05-04T18:28:13Z

Gerard: /* Evolution */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTEN|Family PTEN]]: [[Phosphatase_Subfamily_Tensin|Subfamily Tensin]]

Tensins are PTEN-related phosphatases involved in integrin signaling.

===Evolution===
Tensins are found throughout [[holozoa]]. The domain combination is under dramatic changes during evolution. Drosophilids have a truncated ortholog ([http://www.sdbonline.org/sites/fly/cytoskel/blistery1.htm ''blistery'']) which lacks the phosphatase domain, though the full-length form is seen in mosquitoes. One of the four human members, TNS4, is also truncated.

===Domain Structure===
Tensins are long proteins, with an N-terminal phosphatase domain followed immediately by a PTEN_C2 domain, which acts as a lipid-binding domain. They have a poorly conserved middle region, SH2 and usually PTB domains at the C-terminus. Many Tensins also have an N-terminal C1 domain. Humans also have a homologous TNS4 protein which is N-terminally truncated and has lost the phosphatase domain. The phosphatase domain is quite divergent and often can not be picked by Pfam or SMART.

TNS1 and TNS2 are predicted to be catalytically inactive, given the arginine residue is replaced by asparagine and lysine at CX5R motif, respectively. But, the catalytic activity of TNS2 has been reported. These may function as binding domains for phosphatidyl inositols.

The functions of the phosphatase domain are not well understood:
* TNS1. The phosphatase domain can bind to PPP1CA in focal adhesions <cite>Eto07</cite>.
* TNS2. TNS2 induced in vivo dephosporylation of phosphatidylinositol 3,4,5-trisphosphate, though the activity could not be replicated in vitro <cite>Hafizi</cite>. Another report <cite>Koh</cite> showed TNS2 protein tyrosine phosphatase activity on IRS-1.

===Functions===
Tensins are localized to integrin-mediated focal adhesions. The PTB domain binds to the cytoplasmic region of integrins, and N-terminal regions bind actin. The SH2 domain interacts with a variety of tyrosine-phosphorylated proteins, including PI3K, FAK, and p130Cas. Several tensins are linked to cell migration and metastasis suppression and to signaling downstream of receptor tyrosine kinases.

===References===
<biblio>
#Hafizi pmid=20678486
#Koh pmid=23401856
#Eto07 pmid=17435217
</biblio>

Phosphatase Family PTP

2018-05-04T17:35:24Z

Gerard: /* Non-receptor PTPs */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTP|Family PTP]]

The Protein Tyrosine Phosphatase Family (PTP) is the major tyrosine-specific family of phosphatases, present throughout animals and consisting of both transmembrane receptors (rPTPs) and non-receptor phosphatases (nrPTP), in several distinct subfamilies. This subfamily is known as High Molecular Weight Protein Tyrosine Phosphatase (HMWPTP) in the [http://scop.berkeley.edu/sunid=52805 SCOP database]. Compared to the related [[Phosphatase_Family_DSP|DSP]] and [[Phosphatase_Family_PTEN|PTEN]] families, it has an extension to the beta-sheet of 3 antiparallel strands before strand 4.

=== Evolution ===
PTPs first emerged in holozoa. Among the 17 subfamilies present in human, 6 emerged in holozoa, 5 in metazoa, 3 in eumetazoa, and 3 in chordates or vertebrates. The relationship between the subfamilies is not well understood. The relationships between non-receptor PTPs and those between PTPRN and PTPRR/N5 and other subfamilies, as depicted by tree, are not significantly supported by statistical tests, and the branching order varies in published studies <cite>Andersen01, Andersen04, Barr09</cite> (as well as [http://ptp.cshl.edu/proteinclass.shtml PTP website at CSHL]).

=== Subfamilies ===
The PTPs can be grouped into two classes: receptor PTPs and non-receptor PTPs.

==== Receptor PTPs ====
Receptor PTPs usually have an extracellular region, a single transmembrane region, and one or two intracytoplasmic catalytic phosphatase domains. Some receptor PTPs encode isoforms without extracellular or transmembrane regions, which function as non-receptor PTPs.

* [[Phosphatase_Subfamily_PTPRA|PTPRA]] is a deuterostome-specific subfamily. Human members are PTPRA (HEPTP/R-PTP-alpha) and PTPRE (R-PTP-EPSILON).

* [[Phosphatase_Subfamily_PTPRC|PTPRC]] (CD45) is a vertebrate-specific subfamily involved in lymphocyte activation. In particular, it dephosphorylates and activates Src kinases.

* [[Phosphatase_Subfamily_PTPRD|PTPRD]] (LAR) functions in the nervous system. The three human members, PTPRF (LAR), PTPRD (RPTPdelta) and PTPRS (RPTPsigma) dephosphorylate different proteins mostly involved in cell signaling. PTPRD is found in animals and choanoflagellates.

* [[Phosphatase_Subfamily_PTPRG|PTPRG]] is an eumetazoan subfamily that functions in nervous system and maybe cancer. Humans have two members, PTPRG (R-PTP-GAMMA) and PTPRZ1 (RPTPbeta/R-PTP-zeta-2/Rptpζ), which can interact with other PTPs, such as PTPRD.

* [[Phosphatase_Subfamily_PTPRK|PTPRK]] (R2B) is a chordate subfamily that regulates cell-cell adhesion, implicated in human cancer and the nervous system. The four human members are PTPRK (R-PTP-kappa), PTPRM (PTP mu), PTPRT (RPTPrho), and PTPRU (PTP-RO/hPTP-J/PTP pi/PTP lambda).

* [[Phosphatase_Subfamily_PTPRB|PTPRB]] (R3) is a metazoan-specific subfamily with functions in the nervous and immune systems. Human has five members: PTPRB (VE-PTP), PTPRH (SAP-1), PTPRJ (CD148/DEP1/RPTP eta), PTPRO (GLEPP1/PTP phi), and PTPRQ. They have distinct substrates. PTPRQ is lipid phosphatase rather than tyrosine phosphatase.

* [[Phosphatase_Subfamily_PTPRN|PTPRN]] (IA-2) is a metazoan family involved in neuronal and endocrine vesicle trafficking. No members have shown protein phosphatase activity, but at least one is reported to be a phospholipid phosphatase.

* [[Phosphatase_Subfamily_PTPN5_RR|PTPRR]] (STEP) is a eumetazoan subfamily duplicated in vertebrates but absent from nematodes. . It is characterized by a kinase interaction motif (KIM), which is regulated by the phosphorylation state of a serine within the motif. Human has three members: PTPN5/STEP, PTPN7/HePTP, PTPRR/PTP-SL. Two of the three members have predicted transmembrane regions. They all regulate ERK pathway, but may have their specific substrates. They are expressed in different tissues, particularly, abundant in spleen, thymus, and different parts of brain.

* [[Phosphatase_Subfamily_Ptp69D|Ptp69D]] is a subfamily similar to PTPRD. It is involved in neuronal pathfinding. It emerged in metazoa but is absent from vertebrates.

* [[Phosphatase_Subfamily_CG42327|CG42327]] is found in arthropods and probably other invertebrates. Its function is unclear.

* [[Phosphatase_Subfamily_NvecPTP-sf2|NvecPTP-sf2]] is found in cnidarians, and is of unknown function.

* [[Phosphatase_Subfamily_NvecPTP-sf6|NvecPTP-sf6]] is a Cnidarian-specific family most similar to PTPRD.

* [[Phosphatase_Subfamily_SpurPTP-sf1|SpurPTP-sf1]], [[Phosphatase_Subfamily_SpurPTP-sf3|SpurPTP-sf3]], [[Phosphatase_Subfamily_SpurPTP-sf4|SpurPTP-sf4]] are found in the sea urchin and have no known functions.

==== Non-receptor PTPs ====
* [[Phosphatase_Subfamily_PTPN1|PTPN1]] dephosphorylates various families of kinases. It emerged in animals and duplicated in vertebrates. Human has two members, PTPN1 (PTP1B) and PTPN2 (TCPTP).

* [[Phosphatase_Subfamily_PTPN3|PTPN3]] emerged in holozoa and duplicated in vertebrates. It has a domain combination of FERM domain, PEST sequence, PDZ domain and phosphatase domain. Human has two members of this subfamily, PTPN3 (PTPH1) and PTPN4 (PTPMEG). The expression pattern, substrates and interacting partners of PTPN3 and PTPN4 have limited overlap.

* [[Phosphatase_Subfamily_PTPN6|PTPN6]] (SHP) is implicated in cancer and diabetes. It emerged in holozoa and duplicated in vertebrates. It is characterized by tandem SH2 domains.

* [[Phosphatase_Subfamily_PTPN9|PTPN9]] is a metazoan subfamily functions in regulated secretory pathway. It has a characteristic accessory domain, a N-terminal Sec14p homology domain, which localizes it to secretory vesicles.

* [[Phosphatase_Subfamily_PTPN12|PTPN12]] is a cytosolic PTP subfamily emerged in holozoan, duplicated in vertebrates and lost in ecdysozoa. It has a N-terminal phosphatase domain and a C-terminal region containing several proline-rich sequences. Human has three members, PTPN12/PTP-PEST, PTPN18/BDP and PTPN22/LYP. PTPN22/LYP variant R620W is associated with various autoimmune diseases, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D).

* [[Phosphatase_Subfamily_PTPN13|PTPN13]] is a cytosolic PTP subfamily that has diverse functions. It has various substrates and interacting partners. PTPN13 has a FERM domain localizing it to plasma membrane, five PDZ domains interacting with different proteins, and a phosphatase domain. PTPN13 probably emerged in holozoan, but lost in various metazoan lineages such as ecdysozoa. PTPN13 has two human members: PTPN13/FAP-1/PTP1E/PTPL1/PTP-BAS, and PTPN20

* [[Phosphatase_Subfamily_PTPN14|PTPN14]] (PEZ) is a cytoskeletal-associated phosphatase with roles in cell migration and adhesion, EGFR signaling and regulation of the Hippo pathway. PTPRN14 emerged in metazoa; it is lost in all nematodes and duplicated in vertebrates.

* [[Phosphatase_Subfamily_PTPN23|PTPN23]] (HD-PTP) functions in endosomal protein sorting. It has a signature BRO1 domain that distinguishes it from other protein phosphatases. It is under debate whether PTPN23 is catalytically inactive. PTPN23 emerged in holozoan but absent from some individual lineages, such as sponge and nematode.

* [[Phosphatase_Subfamily_Ptp36E|Ptp36E]] (CG7180) is a ecdysozoan-specific subfamily found in both nematodes and arthropods. Its function is unclear. Interestingly, it has two tandem PTP domains, which is a signature of receptor PTPs, and is similar to PTPRK, but lacks a transmembrane region or signal peptide.

* [[Phosphatase_Subfamily_eak|Eak]] is a nematode-specific subfamily. ''C. elegans'' has two members eak-6 and sdf-9/eak-5 which potentiate AKT-1/PKB signaling. The function seems independent of phosphatase activity, because sdf-9 is predicted to be catalytically inactive given the replacement of cysteine by serine at the Cx5R motif.

* [[Phosphatase_Subfamily_egg|Egg]] is a nematode-specific subfamily of pseudophosphatases. ''C. elegans'' has three members egg-3, egg-4, egg-5. Egg-4/egg-5 binds to the substrate-binding site of the kinase MBK-2 and inhibits the kinase to bind and phoshorylate its substrate, thereby inhibiting downstream signaling.

* [[Phosphatase_Subfamily_ptpB|PtpB]] (a.k.a. [http://dictybase.org/gene/DDB_G0277865 PTP2 in Dictyostelium discoideum]) is a subfamily found in most species in the order of Dictyosteliida (protein domain sequence identify >40%). In the species of Dictyostelium, it regulates MAP kinase ERK1 <cite>Sun11</cite>.

* [[Phosphatase_Subfamily_ptpC|PtpC]] (a.k.a. [http://dictybase.org/gene/DDB_G0282145 PTP3 in Dictyostelium discoideum]) is a subfamily found in some species in the order of Dictyosteliida (protein domain sequence identify >70%). In the species of Dictyostelium, it is involved in STAT signaling pathway, downstream of [http://kinase.com/web/current/kinbase/genes/Family/DPYK/ Dictyostelium protein tyrosine kinase] (DPYK) <cite>Sun11</cite>.

* [[Phosphatase_Subfamily_MbrePTP-sf1|MbrePTP-sf1]] is one of several clade-specific subfamilies that have no known functions.

=== Phosphatase Domain ===
The PTP phosphatase domain (PD) has ten motifs <cite>Andersen01</cite>. The motif 1 (nxxKNRY) is proposed to be pTr-recognition loop. The Y is substituted in i) D2 domain of human receptor PTPs, ii) catalytically inactive PTPs, including PTPRN, PTPN14, and PTPN23, iii) lipid phosphatases PTPRQ and PTPRN2.

==== Second phosphatase domain (D2) ====
'''PTPRC'''. D2 is necessary for PTPRC (CD45). The loss of D1 PTP activity after the deletion of all or even small portions of the D2 PTP domain <cite> Ng95, Wang00 </cite>. PTPRC (CD45) has a 19-aa acidic region in D2 domain, which serves as a regulatory module in lymphocyte activation <cite> Wang00 </cite>.

'''PTPRA'''. The D2 of PTPRA demonstrated higher susceptibility to oxidation <cite>Persson04</cite>. The oxidation at the cysteine of Cx5R catalytic motif led to inactivation in PTPN1 (PTP1B).

==== Minor subfamilies ====
Several species-specific subfamilies are seen:
* [[Phosphatase_Subfamily_CelePTP-sf11|CelePTP-sf11]]

=== References ===
<biblio>
#Andersen01 pmid=11585896
#Andersen04 pmid=14718383
#Barr09 pmid=19167335
#Ng95 pmid=7818534
#Persson04 pmid=14762163
#Sun11 pmid=21776390
#Wang00 pmid=10679094
</biblio>

Phosphatase Subfamily DSP6

2018-02-20T19:02:48Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_DSP6|Subfamily DSP6]]

DSP6 is a metazoan cytoplasmic MKP subfamily that selectively dephosphorylates ERK.

=== Evolution ===
DSP6 is found throughout metazoa. It duplicated in vertebrates. The three human members are DUSP6 (MKP3), DUSP7 (MKPX) and DUSP9 (MKP4).

=== Domain ===
DSP6 has two domains: rhodanese domain and phosphatase domain.

The rhodanese domain inhibit phosphatase domain activity in DUSP6 <cite>Camps98</cite>, which is achieved by the binding of rhodanese domain and phosphatase domain. The binding stabilizes the inactive conformation of the phosphatase catalytic site <cite>Mark08</cite>. The rhodanese domain also mediates interaction with MAP kinases (often ERK) ('''via kinase interaction motif?'''). Its binding to MAP kinases induces conformation change in phosphatase domain, which can increase the phosphatase activity <cite>Stewart99</cite>.

Rhodanese domain of DSP6 also has two conserved Leu-rich nuclear export signals <cite>Karlsson04</cite> (particular Figure 5 and Figure 11).

The rhodanese domain was lost in many nematodes (see technical notes).

=== Function ===

====== DUSP6 (MKP3/PYST1) ======
DUSP6 preferentially dephosphorylates ERK <cite>Muda96, Groom96, Kim03</cite>, due to ability of DUSP6 to bind ERK but not p38 or JNK. The interaction is mediated by rhodanese domain (or kinase interaction motif embedded in rhodanese domain?) <cite>Muda98</cite>. Later study has shown DUSP6 is ERK1/2-specific, as it does not inactive ERK5 <cite>Arkell08</cite>.

Furthermore, DUSP6, ERK2, and phosphorylated p38alpha can form a stable ternary complex in solution, and the phosphatase activity of DUSP6 toward p38alpha substrate is allosterically regulated by ERK2-DUSP6 interaction. This suggests that DUSP6 may mediate cross-talk between ERK and p38 pathways <cite>Zhang11</cite>. ('''note: this is perhaps the mechanism behind DUSP6 modules DNA damage response <cite>Bagnyukova13</cite>.''')

As a negative regulator of ERK <cite>Muda96, Camps98, Jurek09, Zhang10</cite>, DUSP6 is proposed to be tumor suppressor via feedback mechanisms <cite>Zeliadt08</cite>:
* Significant loss of DUSP6 was observed in 100% of 11 esophageal squamous cell carcinoma cell lines and 71% of seven nasopharyngeal carcinoma cell lines <cite>Wong12</cite>.
* DUSP6 plays tumor suppressive role in non-small-cell lung cancers <cite>Zhang10</cite>.
* DUSP6 expression was correlated with lower histological grade and lower [http://en.wikipedia.org/wiki/Ki-67_%28protein%29 Ki-67 index] in the lung adenocarcinomas <cite>Lee11</cite>.
* DUSP6 expression was down-regulated through hypermethylation at enhancer in some pancreatic cell lines and pancreatic cancer tissues <cite>Furukawa98, Xu05</cite>.
* Degradation of DUSP6 caused by reactive oxygen species (ROS) leads to aberrant ERK1/2 activation and contributes to tumorigenicity and chemoresistance of human ovarian cancer cells <cite>Chan08</cite>.
* DUSP6 upregulation induced by angiotensin II mediates endothelial cell apoptosis <cite>Rossig02</cite>.

But, DUSP6 is up-regulated or not associated with cancers in some cases:
* DUSP6 was up-regulated in endometrial adenocarcinomas <cite>Zhang13</cite>, thyroid carcinoma <cite>Lee12, DeglInnocenti13</cite>, and glioblastomas <cite>Messina11</cite>, MCF-7 breast cancer cells <cite>Nunes-Xavier10</cite>.
* DUSP6 methylation is a rare event in endometrial cancer. Thus, silencing of the DUSP6 phosphatase is unlikely to contribute to constitutive activation of the ERK kinase cascade in endometrial cancer <cite>Chiappinelli10</cite>.
* DUSP6 expression was not correlated with [http://en.wikipedia.org/wiki/Ki-67_%28protein%29 Ki-67 index] lung squamous cell carcinomas <cite>Lee11</cite>.

('''note: DUSP6 upregulation in cancer could be explained by feedback mechanisms?''')

DUSP6 (MKP3) inhibits brown adipocyte differentiation perhaps via regulation of Erk phosphorylation <cite>Kim15</cite>.

Like DUSP2, DUSP4 and DUSP4 of DSP1 subfamily, DUSP6 is phosphorylated by ERK <cite>Marchetti05</cite>. However, the phosphorylation sites are different. DUSP6 is phosphorylated at serines 159 and 197 <cite>Marchetti05</cite>, which are found in DUSP6 and DUSP7, but not DUSP9 or other DSPs.

DUSP6 expression is regulated by:
* p53. There are two p53 binding sites in DUSP6 promoter <cite>Piya12</cite>. p53 binds to promoter of DUSP2 and DUSP5 of DSP1 subfamily.
* [http://en.wikipedia.org/wiki/ETS1 ETS1], a transcription factor that can be activated by Erk2 and Ras at Thr38 <cite>Zhang10</cite> ('''note: a feedback of ERK2, DUSP6, ETS1''').
* [http://en.wikipedia.org/wiki/WT1 Wilms tumor protein (WT1)], a transcription factor as tumor suppressor, up-regulates DUSP6 expression <cite>Morrison08</cite>.
* Nitric oxide down-regulates DUSP6 mRNA levels <cite>Rossig00</cite> (note: which pathway?). Read [http://en.wikipedia.org/wiki/Nitric_oxide#Biological_functions here for NO's biological function].

====== DUSP7 (MKPX/PYST2) ======
DUSP7 is constitutively expressed in a wide variety of human cell lines. DUSP7 is predominantly cytosolic when expressed in COS-1 cells. In common with other members of DSP6 subfamily, DUSP7 shows substrate selectivity ERK > p38 = JNK. DUSP7 binds ERK in vivo. Both ERK and JNK activate DUSP7 phosphatase activity in vitro <cite>Dowd98</cite>.

DUSP7 has at least two isoforms. The longer isoform is constitutively highly expressed in myeloid leukemia and other malignant cells <cite>Levy-Nissenbaum03a, Levy-Nissenbaum03b, Levy-Nissenbaum04</cite>.

====== DUSP9 (MKP4) ======
DUSP6 blocks activation of MAP kinases with the selectivity ERK > p38 = JNK. Same as other members in the subfamily, it locates in cytosol <cite>Muda97, Liu07</cite>. DUSP9 is unique among these cytoplasmic MKPs in containing a conserved PKA consensus phosphorylation site (55)RRXSer-58 immediately adjacent to the kinase interaction motif. DUSP9 is phosphorylated on Ser-58 by PKA in vitro, and phosphorylation abrogates the binding of DUSP9 to both ERK2 and p38alpha MAP kinases <cite>Dickinson11</cite>.

Decreased expression of DUSP-9 is associated with poor prognosis in clear cell renal cell carcinomas <cite>Wu11</cite>.

=== Technical notes ===
===== Nematodes lost rhodanese domain =====
We observed the absence of rhodanese domain in C. elegans. We then asked whether the loss is conserved, which can be use to measure the reliability of the loss. We obtained DSP6s from our internal orthology database, which has 203 eukaryotic genomes and 9 nematode genomes. We then searched Pfam domain in the DSP6s using Pfam web server (E-value cutoff 1.0). We found none of the 10 nematode DSPs from 7 nematode genomes has rhodanese domain. The DSP6 subfamily is not found in another 2 nematode genomes: Pristionchus pacificus and Loa loa.

We also BLASTed human DUSP6 against nematode NR protein data set. We found rhodanese-containing DSP6 in most Trichocephalida, which suggest the lost in happened posterior to Trichocephalida diverged from other nematodes.

=== References ===
<biblio>
#Arkell08 pmid=18280112
#Bagnyukova13 pmid=23839489
#Camps98 pmid=9596579
#Chan08 pmid=18632752
#Chiappinelli10 pmid=20638106
#DeglInnocenti13 pmid=23132790
#Dickinson11 pmid=21908610
#Dowd98 pmid=9788880
#Furukawa98 pmid=9858808
#Groom96 pmid=8670865
#Jurek09 pmid=19106095
#Karlsson04 pmid=15269220
#Kim03 pmid=14690430
#Kim15 pmid=26325440
#Lee11 pmid=21680106
#Lee12 pmid=22535643
#Levy-Nissenbaum03a pmid=14576828
#Levy-Nissenbaum03b pmid=14674243
#Levy-Nissenbaum04 pmid=14603440
#Liu07 pmid=18006813
#Marchetti05 pmid=15632084
#Mark08 pmid=18694935
#Messina11 pmid=21499306
#Morrison08 pmid=18644985
#Muda96 pmid=8626780
#Muda97 pmid=9030581
#Muda98 pmid=9535927
#Nunes-Xavier10 pmid=20554528
#Piya12 pmid=23108049
#Rossig00 pmid=10846176
#Rossig02 pmid=11998972
#Stewart99 pmid=10048930
#Wong12 pmid=21387288
#Wu11 pmid=21943117
#Xu05 pmid=15824892
#Zeliadt08 pmid=18771677
#Zhang10 pmid=20097731
#Zhang11 pmid=21454500
#Zhang13 pmid=23419500
</biblio>

Phosphatase Subfamily DSP6

2018-02-20T19:02:36Z

Gerard:

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_DSP6|Subfamily DSP6]]

DSP6 is a metazoan cytoplasmic MKP subfamily that selectively dephosphorylates ERK.

=== Evolution ===
DSP6 is found throughout metazoa. It duplicated in vertebrates. The three human members are DUSP6 (MKP3), DUSP7 (MKPX) and DUSP9 (MKP4).

=== Domain ===
DSP6 has two domains: rhodanese domain and phosphatase domain.

The rhodanese domain inhibit phosphatase domain activity in DUSP6 <cite>Camps98</cite>, which is achieved by the binding of rhodanese domain and phosphatase domain. The binding stabilizes the inactive conformation of the phosphatase catalytic site <cite>Mark08</cite>. The rhodanese domain also mediates interaction with MAP kinases (often ERK) ('''via kinase interaction motif?'''). Its binding to MAP kinases induces conformation change in phosphatase domain, which can increase the phosphatase activity <cite>Stewart99</cite>.

Rhodanese domain of DSP6 also has two conserved Leu-rich nuclear export signals <cite>Karlsson04</cite> (particular Figure 5 and Figure 11).

The rhodanese domain was lost in many nematodes (see technical notes).

=== Function ===

====== DUSP6 (MKP3/PYST1) ======
DUSP6 preferentially dephosphorylates ERK <cite>Muda96, Groom96, Kim03</cite>, due to ability of DUSP6 to bind ERK but not p38 or JNK. The interaction is mediated by rhodanese domain (or kinase interaction motif embedded in rhodanese domain?) <cite>Muda98</cite>. Later study has shown DUSP6 is ERK1/2-specific, as it does not inactive ERK5 <cite>Arkell08</cite>.

Furthermore, DUSP6, ERK2, and phosphorylated p38alpha can form a stable ternary complex in solution, and the phosphatase activity of DUSP6 toward p38alpha substrate is allosterically regulated by ERK2-DUSP6 interaction. This suggests that DUSP6 may mediate cross-talk between ERK and p38 pathways <cite>Zhang11</cite>. ('''note: this is perhaps the mechanism behind DUSP6 modules DNA damage response <cite>Bagnyukova13</cite>.''')

As a negative regulator of ERK <cite>Muda96, Camps98, Jurek09, Zhang10</cite>, DUSP6 is proposed to be tumor suppressor via feedback mechanisms <cite>Zeliadt08</cite>:
* Significant loss of DUSP6 was observed in 100% of 11 esophageal squamous cell carcinoma cell lines and 71% of seven nasopharyngeal carcinoma cell lines <cite>Wong12</cite>.
* DUSP6 plays tumor suppressive role in non-small-cell lung cancers <cite>Zhang10</cite>.
* DUSP6 expression was correlated with lower histological grade and lower [http://en.wikipedia.org/wiki/Ki-67_%28protein%29 Ki-67 index] in the lung adenocarcinomas <cite>Lee11</cite>.
* DUSP6 expression was down-regulated through hypermethylation at enhancer in some pancreatic cell lines and pancreatic cancer tissues <cite>Furukawa98, Xu05</cite>.
* Degradation of DUSP6 caused by reactive oxygen species (ROS) leads to aberrant ERK1/2 activation and contributes to tumorigenicity and chemoresistance of human ovarian cancer cells <cite>Chan08</cite>.
* DUSP6 upregulation induced by angiotensin II mediates endothelial cell apoptosis <cite>Rossig02</cite>.

But, DUSP6 is up-regulated or not associated with cancers in some cases:
* DUSP6 was up-regulated in endometrial adenocarcinomas <cite>Zhang13</cite>, thyroid carcinoma <cite>Lee12, DeglInnocenti13</cite>, and glioblastomas <cite>Messina11</cite>, MCF-7 breast cancer cells <cite>Nunes-Xavier10</cite>.
* DUSP6 methylation is a rare event in endometrial cancer. Thus, silencing of the DUSP6 phosphatase is unlikely to contribute to constitutive activation of the ERK kinase cascade in endometrial cancer <cite>Chiappinelli10</cite>.
* DUSP6 expression was not correlated with [http://en.wikipedia.org/wiki/Ki-67_%28protein%29 Ki-67 index] lung squamous cell carcinomas <cite>Lee11</cite>.

('''note: DUSP6 upregulation in cancer could be explained by feedback mechanisms?''')

DUSP6 (MKP3) inhibits brown adipocyte differentiation perhaps via regulation of Erk phosphorylation <cite>Kim15</cite>.

Like DUSP2, DUSP4 and DUSP4 of DSP1 subfamily, DUSP6 is phosphorylated by ERK <cite>Marchetti05</cite>. However, the phosphorylation sites are different. DUSP6 is phosphorylated at serines 159 and 197 <cite>Marchetti05</cite>, which are found in DUSP6 and DUSP7, but not DUSP9 or other DSPs.

DUSP6 expression is regulated by:
* p53. There are two p53 binding sites in DUSP6 promoter <cite>Piya12</cite>. p53 binds to promoter of DUSP2 and DUSP5 of DSP1 subfamily.
* [http://en.wikipedia.org/wiki/ETS1 ETS1], a transcription factor that can be activated by Erk2 and Ras at Thr38 <cite>Zhang10</cite> ('''note: a feedback of ERK2, DUSP6, ETS1''').
* [http://en.wikipedia.org/wiki/WT1 Wilms tumor protein (WT1)], a transcription factor as tumor suppressor, up-regulates DUSP6 expression <cite>Morrison08</cite>.
* Nitric oxide down-regulates DUSP6 mRNA levels <cite>Rossig00</cite> (note: which pathway?). Read [http://en.wikipedia.org/wiki/Nitric_oxide#Biological_functions here for NO's biological function].

====== DUSP7 (MKPX/PYST2) ======
DUSP7 is constitutively expressed in a wide variety of human cell lines. DUSP7 is predominantly cytosolic when expressed in COS-1 cells. In common with other members of DSP6 subfamily, DUSP7 shows substrate selectivity ERK > p38 = JNK. DUSP7 binds ERK in vivo. Both ERK and JNK activate DUSP7 phosphatase activity in vitro <cite>Dowd98</cite>.

DUSP7 has at least two isoforms. The longer isoform is constitutively highly expressed in myeloid leukemia and other malignant cells <cite>Levy-Nissenbaum03a, Levy-Nissenbaum03b, Levy-Nissenbaum04</cite>.

====== DUSP9 (MKP4) ======
DUSP6 blocks activation of MAP kinases with the selectivity ERK > p38 = JNK. Same as other members in the subfamily, it locates in cytosol <cite>Muda97, Liu07</cite>. DUSP9 is unique among these cytoplasmic MKPs in containing a conserved PKA consensus phosphorylation site (55)RRXSer-58 immediately adjacent to the kinase interaction motif. DUSP9 is phosphorylated on Ser-58 by PKA in vitro, and phosphorylation abrogates the binding of DUSP9 to both ERK2 and p38alpha MAP kinases <cite>Dickinson11</cite>.

Decreased expression of DUSP-9 is associated with poor prognosis in clear cell renal cell carcinomas <cite>Wu11</cite>.

=== Technical notes ===
===== Nematodes lost rhodanese domain =====
We observed the absence of rhodanese domain in C. elegans. We then asked whether the loss is conserved, which can be use to measure the reliability of the loss. We obtained DSP6s from our internal orthology database, which has 203 eukaryotic genomes and 9 nematode genomes. We then searched Pfam domain in the DSP6s using Pfam web server (E-value cutoff 1.0). We found none of the 10 nematode DSPs from 7 nematode genomes has rhodanese domain. The DSP6 subfamily is not found in another 2 nematode genomes: Pristionchus pacificus and Loa loa.

We also BLASTed human DUSP6 against nematode NR protein data set. We found rhodanese-containing DSP6 in most Trichocephalida, which suggest the lost in happened posterior to Trichocephalida diverged from other nematodes.

=== References ===
<biblio>
#Arkell08 pmid=18280112
#Bagnyukova13 pmid=23839489
#Camps98 pmid=9596579
#Chan08 pmid=18632752
#Chiappinelli10 pmid=20638106
#DeglInnocenti13 pmid=23132790
#Dickinson11 pmid=21908610
#Dowd98 pmid=9788880
#Furukawa98 pmid=9858808
#Groom96 pmid=8670865
#Jurek09 pmid=19106095
#Karlsson04 pmid=15269220
#Kim03 pmid=14690430
#Kim15 pmid=26325440
#Lee11 pmid=21680106
#Lee12 pmid=22535643
#Levy-Nissenbaum03a pmid=14576828
#Levy-Nissenbaum03b pmid=14674243
#Levy-Nissenbaum04 pmid=14603440
#Liu07 pmid=18006813
#Marchetti05 pmid=15632084
#Mark08 pmid=18694935
#Messina11 pmid=21499306
#Morrison08 pmid=18644985
#Muda96 pmid=8626780
#Muda97 pmid=9030581
#Muda98 pmid=9535927
#Nunes-Xavier10 pmid=20554528
#Piya12 pmid=23108049
#Rossig00 pmid=10846176
#Rossig02 pmid=11998972
#Stewart99 pmid=10048930
#Wong12 pmid=21387288
#Wu11 pmid=21943117
#Xu05 pmid=15824892
#Zeliadt08 pmid=18771677
#Zhang10 pmid=20097731
#Zhang11 pmid=21454500
#Zhang13 pmid=23419500
</biblio>

Phosphatase Subfamily PPP2C

2017-11-15T05:22:02Z

Gerard: /* Evolution */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPPL|Fold PPPL]]: [[Phosphatase_Superfamily_PPPL|Superfamily PPPL]]: [[Phosphatase_Family_PPP|Family PPP]]: [[Phosphatase_Subfamily_PPP2C|Subfamily PPP2C]] (PP2A, catalytic subunit)

PPP2C is the catalytic subunit of the holoenzyme PP2A. PP2A is heterotrimer consisting of a core dimer of two catalytic (C) subunits and an A regulatory subunit, along with one (C) and regulatory subunit A (PR65), and a third regulatory subunit B-type <cite>janssens08</cite>. Multiple genes encode each subunits, which resulting in a total of about 75 different holoenzyme compositions <cite>janssens05</cite>.

===Evolution===
PPP2C is found throughout eukaryotes. Human has two PPP2C: [[Phosphatase_Gene_PPP2CA|PPP2CA]] and [[Phosphatase_Gene_PPP2CB|PPP2CB]], along with two A subunits (PPP2R1A, PPP2R1B) and at least 12 B regulatory subunits. Most invertebrates have a single copy of the catalytic subunit, and yeast has two [[Phosphatase_Gene_PPH21|PPH21]] and [[Phosphatase_Gene_PPH22|PPH22]].

=== Domain ===
PPP1C has a single domain - phosphatase domain. The activity of phosphatase is inhibited by binding to Zinc2+ in vitro <cite>Xiong15</cite>.

===Functions===
PP2A accounts for the majority of phospho-serine/threonine phosphatase activity in most cells and is involved in the regulation of nearly every cellular process, including multiple inflammatory signaling pathways <cite>Rahman15</cite>, cell cycle progression, autophagy <cite>Wong15</cite>, DNA replication, gene transcription and protein translation <cite>janssens01 sontag01</cite>. It is considered to be a principal guardian against tumorigenic transformation <cite>westermarck08</cite>. Some viruses target this protein to hijack the host cell <cite>janssens08</cite>.

PP2A controls the activity of at least 50 different kinases by directly interaction or linked via a anchoring protein. PP2A not only integrate signals within phoshorylation cascades but also to be the focal point of a distinct post-translational modification, reversible protein methylation <cite>janssens05</cite>. Here are some examples of PP2A functions:

* Hedgehog signaling. PP2A functions with PPFIA1 to promote the dephosphorylation of Kif7, triggering Kif7 localization to the tips of primary cilia and promoting Gli transcriptional activity. Both Kif7 and Gli are components in Hedgehog signaling <cite>liu14</cite>. (PS: Interestingly, [http://www.ncbi.nlm.nih.gov/gene/8500 PPFIA1] is known as interacting partner with tyrosine phosphatase PTPRF.)

* PP2A/B55 complex dephosphorylates heat shock factor 1. The regulatory subunit B55 directly binds to HSF1 <cite>Ishikawa15</cite>.

* PP2A-B56ϵ complex is involved in dephosphorylation of γ-H2AX in the repair process of topoisomerase I inhibitor camptothecin-induced DNA double-strand breaks <cite>Li15</cite>.

PP2A is regulated by Lyn, a Src kinase, through phosphorylation at Tyr-307 <cite>Zonta15</cite>.

===References===
<biblio>
#Ishikawa15 pmid=25816751
#janssens08 pmid=18291659
#janssens05 pmid=15661531
#janssens01 pmid=11171037
#Li15 pmid=25772433
#liu14 pmid=25492966
#Rahman15 pmid=25985190
#sontag01 pmid=11257442
#westermarck08 pmid=18329957
#Wong15 pmid=26310906
#Xiong15 pmid=25854679
#Zonta15 pmid=25931585
</biblio>

Phosphatase Family PPP

2017-11-15T05:18:04Z

Gerard: /* YNL217W (yeast) subfamily */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPPL|Fold PPPL]]: [[Phosphatase_Superfamily_PPPL|Superfamily PPPL]]: [[Phosphatase_Family_PPP|Family PPP]]

PPPs can be found in both eukaryotes and prokaryotes. PPPs share the highest sequence similarity compared to other phosphatase superfamilies. PPP carries out phosphatase activity through complex (aka holoenzyme) rather than in monoenzyme. The PPP holoenzyme consists of one catalytic subunit and one or two regulatory subunits. Here, we focus on the catalytic subunit only. (PS: PPP has a large number of regulatory subunits. Perhaps, it is better to study and document their evolution and function by complex.)

== Subfamilies ==
Note: PPP2C, PPP4C, PPP6C are grouped as PP2A in some literature.

======[[Phosphatase_Subfamily_PPP1C|PPP1C]] (PP1, catalytic subunit)======
PPP1C, catalytic subunit of holoenzyme PP1, is a ubiquitous serine/threonine phosphatase found throughout eukaryotes and even in some prokaryotes. Holoenzyme PP1 is involved in many various processes.

======[[Phosphatase_Subfamily_PPP2C|PPP2C]] (PP2A, catalytic subunit)======
PPP2C, catalytic subunit of holoenzyme PP2A, is found throughout eukaryotes with various number in different lineages. PP2A accounts for the majority of phospho-serine/threonine phosphatase activity in most cells and is involved in the regulation of nearly every cellular process.

======[[Phosphatase_Subfamily_PPP4C|PPP4C]] (PP4, catalytic subunit) ======
PPP4C, the catalytic subunit of Protein Phosphatase 4 (PP4) holoenzyme, is found widely in eukaryotes including animals, plants and fungi. Like other members in this family, PP4 has many different substrates and is involved in a wide variety of processes.

======[[Phosphatase_Subfamily_PPP6C|PPP6C]] (PP6, catalytic subunit) ======
PPP6C, the catalytic subunit of holoenzyme PP6, is found throughout eukaryotes.

======[[Phosphatase_Subfamily_PPP3C|PPP3C]] (PP2B/calcineurin, catalytic subunit) ======
PPP3C (PP2B, calcineurin) is a calcium-dependent serine/threonine phosphatase conserved in eukaryotes. It is involved in various biological processes and has significantly clinical relevance. PPP3C (PP2B, calcineurin) is an attractive antifungal drug target.

======[[Phosphatase_Subfamily_PPP5C|PPP5C]]======
PPP5C also known as Protein Phospahtase 5 (PP5) is unique among PPP family members in that its catalytic and regulatory domains are contained in the same polypeptide chain. It has a tetratricopeptide repeat (TPR) domain which maintains the phosphatase in an auto-inhibited conformation that is neutralized when the heat shock protein Hsp90, or fatty acids, bind to this region. ε.

The phosphatase interacts with various proteins and participate in multiple signaling pathways. The phosphatase interacts with ATM, ATR, 53BP1, and DNA-depdent protein kianse catalytic subunits (DNA-PKc) following DNA damage. While enchance the activity of ATM and ATR, the phosphatase negatively regulates 53BP1 and DNA-PKc by dephosphorylating them. It regulates Raf-MEK-ERK pathway via inhibiting Raf-1 by dephosphorylating Serine 338. PPP5 is involved in mammalian circadian clock by activating the major clock kinae casein kinase I (CKI) ε. In addition, the elevated levels of this phosphatase may be associated with breast cancer development.

======[[Phosphatase_Subfamily_PPP7C|PPP7C]] (PPEF) subfamily functions in sensory neurons ======
PPEFs contain calmodulin-binding motif IQ and calcium-binding domains EF hand to the N- and C-terminal side of phosphatase domain, respectively, which suggests its involvement in calcium signaling. This would be a reminiscent of another PPP subfamily, PPP3C (calcineurin/PP2B), which are regulated by calmodulin and another EF-hand protein, calcineurin B.

In C. elegans, Drosophila and mammals, PPEF expression was mainly detected in various sensory neurons. The Drosophila PPEF phosphatase, rdgC, is essential for dephosphorylation of rhodopsin. However, mice lacking both PPEF1 and PPEF2 showed no signs of photoreceptor synases. PPEF is present not only in animals but unicellular eukaryotes, indicating its ancient origin and basic functions of eukaryotes. The function and evolution of this phosphatase is reviewed in paper PMID: 19662497.

======[[Phosphatase_Subfamily_YNL217W|YNL217W]] (yeast) subfamily======
Function unknown. It is found in most fungi, and some basal eukaryotes (Chromalveolata and Excavata), but not in plants or amoebazoa. It is found in some basal metazoans but absent from vertebrates, nematodes, and insects.

======[[Phosphatase_Subfamily_PPG1|PPG1]] (yeast) subfamily======
The gene PPG encodes a novel yeast protein phosphatase involved in glycogen accumulation (see SGD database). It is found in all fungi, and absent from holozoan. It is not found in plants, but is found in Dictyostellium and some basal eukaryotes. (Note: the evolutionary history is from gOrtholog.)

====== [[Phosphatase_Subfamily_PPPLV|PPPLV]] subfamily ======
PPPLV stands for PPP lost in vertebrates.

======Nematode-specific PPP subfamilies======
At least 36 PPPs are only found in C. elegans. Taking account the total number of PPPs in most eukaryotes is less than 20, this expansion is very unusual. However, almost nothing is known about these phosphatases.
* [[Phosphatase_Subfamily_CelePPP-sf4|CelePPP-sf4]]

Phosphatase Family PPP

2017-11-15T05:17:16Z

Gerard: /* YNL217W (yeast) subfamily */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPPL|Fold PPPL]]: [[Phosphatase_Superfamily_PPPL|Superfamily PPPL]]: [[Phosphatase_Family_PPP|Family PPP]]

PPPs can be found in both eukaryotes and prokaryotes. PPPs share the highest sequence similarity compared to other phosphatase superfamilies. PPP carries out phosphatase activity through complex (aka holoenzyme) rather than in monoenzyme. The PPP holoenzyme consists of one catalytic subunit and one or two regulatory subunits. Here, we focus on the catalytic subunit only. (PS: PPP has a large number of regulatory subunits. Perhaps, it is better to study and document their evolution and function by complex.)

== Subfamilies ==
Note: PPP2C, PPP4C, PPP6C are grouped as PP2A in some literature.

======[[Phosphatase_Subfamily_PPP1C|PPP1C]] (PP1, catalytic subunit)======
PPP1C, catalytic subunit of holoenzyme PP1, is a ubiquitous serine/threonine phosphatase found throughout eukaryotes and even in some prokaryotes. Holoenzyme PP1 is involved in many various processes.

======[[Phosphatase_Subfamily_PPP2C|PPP2C]] (PP2A, catalytic subunit)======
PPP2C, catalytic subunit of holoenzyme PP2A, is found throughout eukaryotes with various number in different lineages. PP2A accounts for the majority of phospho-serine/threonine phosphatase activity in most cells and is involved in the regulation of nearly every cellular process.

======[[Phosphatase_Subfamily_PPP4C|PPP4C]] (PP4, catalytic subunit) ======
PPP4C, the catalytic subunit of Protein Phosphatase 4 (PP4) holoenzyme, is found widely in eukaryotes including animals, plants and fungi. Like other members in this family, PP4 has many different substrates and is involved in a wide variety of processes.

======[[Phosphatase_Subfamily_PPP6C|PPP6C]] (PP6, catalytic subunit) ======
PPP6C, the catalytic subunit of holoenzyme PP6, is found throughout eukaryotes.

======[[Phosphatase_Subfamily_PPP3C|PPP3C]] (PP2B/calcineurin, catalytic subunit) ======
PPP3C (PP2B, calcineurin) is a calcium-dependent serine/threonine phosphatase conserved in eukaryotes. It is involved in various biological processes and has significantly clinical relevance. PPP3C (PP2B, calcineurin) is an attractive antifungal drug target.

======[[Phosphatase_Subfamily_PPP5C|PPP5C]]======
PPP5C also known as Protein Phospahtase 5 (PP5) is unique among PPP family members in that its catalytic and regulatory domains are contained in the same polypeptide chain. It has a tetratricopeptide repeat (TPR) domain which maintains the phosphatase in an auto-inhibited conformation that is neutralized when the heat shock protein Hsp90, or fatty acids, bind to this region. ε.

The phosphatase interacts with various proteins and participate in multiple signaling pathways. The phosphatase interacts with ATM, ATR, 53BP1, and DNA-depdent protein kianse catalytic subunits (DNA-PKc) following DNA damage. While enchance the activity of ATM and ATR, the phosphatase negatively regulates 53BP1 and DNA-PKc by dephosphorylating them. It regulates Raf-MEK-ERK pathway via inhibiting Raf-1 by dephosphorylating Serine 338. PPP5 is involved in mammalian circadian clock by activating the major clock kinae casein kinase I (CKI) ε. In addition, the elevated levels of this phosphatase may be associated with breast cancer development.

======[[Phosphatase_Subfamily_PPP7C|PPP7C]] (PPEF) subfamily functions in sensory neurons ======
PPEFs contain calmodulin-binding motif IQ and calcium-binding domains EF hand to the N- and C-terminal side of phosphatase domain, respectively, which suggests its involvement in calcium signaling. This would be a reminiscent of another PPP subfamily, PPP3C (calcineurin/PP2B), which are regulated by calmodulin and another EF-hand protein, calcineurin B.

In C. elegans, Drosophila and mammals, PPEF expression was mainly detected in various sensory neurons. The Drosophila PPEF phosphatase, rdgC, is essential for dephosphorylation of rhodopsin. However, mice lacking both PPEF1 and PPEF2 showed no signs of photoreceptor synases. PPEF is present not only in animals but unicellular eukaryotes, indicating its ancient origin and basic functions of eukaryotes. The function and evolution of this phosphatase is reviewed in paper PMID: 19662497.

======[[Phosphatase_Subfamily_YNL217W|YNL217W]] (yeast) subfamily======
Function unknown. It is found in most fungi, and some basal eukaryotes (Chromalveolata and Excavata), but not in plants or amoebazoa. It is found in some basal metazoans but absent from almost all deuterostomes.

======[[Phosphatase_Subfamily_PPG1|PPG1]] (yeast) subfamily======
The gene PPG encodes a novel yeast protein phosphatase involved in glycogen accumulation (see SGD database). It is found in all fungi, and absent from holozoan. It is not found in plants, but is found in Dictyostellium and some basal eukaryotes. (Note: the evolutionary history is from gOrtholog.)

====== [[Phosphatase_Subfamily_PPPLV|PPPLV]] subfamily ======
PPPLV stands for PPP lost in vertebrates.

======Nematode-specific PPP subfamilies======
At least 36 PPPs are only found in C. elegans. Taking account the total number of PPPs in most eukaryotes is less than 20, this expansion is very unusual. However, almost nothing is known about these phosphatases.
* [[Phosphatase_Subfamily_CelePPP-sf4|CelePPP-sf4]]

Phosphatase Subfamily PPP2C

2017-11-15T05:14:45Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPPL|Fold PPPL]]: [[Phosphatase_Superfamily_PPPL|Superfamily PPPL]]: [[Phosphatase_Family_PPP|Family PPP]]: [[Phosphatase_Subfamily_PPP2C|Subfamily PPP2C]] (PP2A, catalytic subunit)

PPP2C is the catalytic subunit of the holoenzyme PP2A. PP2A is heterotrimer consisting of a core dimer of two catalytic (C) subunits and an A regulatory subunit, along with one (C) and regulatory subunit A (PR65), and a third regulatory subunit B-type <cite>janssens08</cite>. Multiple genes encode each subunits, which resulting in a total of about 75 different holoenzyme compositions <cite>janssens05</cite>.

===Evolution===
PPP2C is found throughout eukaryotes. Human has two PPP2C: [[Phosphatase_Gene_PPP2CA|PPP2CA]] and [[Phosphatase_Gene_PPP2CB|PPP2CB]], along with two A subunits (PPP2R1A, PPP2R1B) and at least 8 B regulatory subunits. Most invertebrates have a single copy of the catalytic subunit, and yeast has two [[Phosphatase_Gene_PPH21|PPH21]] and [[Phosphatase_Gene_PPH22|PPH22]].

=== Domain ===
PPP1C has a single domain - phosphatase domain. The activity of phosphatase is inhibited by binding to Zinc2+ in vitro <cite>Xiong15</cite>.

===Functions===
PP2A accounts for the majority of phospho-serine/threonine phosphatase activity in most cells and is involved in the regulation of nearly every cellular process, including multiple inflammatory signaling pathways <cite>Rahman15</cite>, cell cycle progression, autophagy <cite>Wong15</cite>, DNA replication, gene transcription and protein translation <cite>janssens01 sontag01</cite>. It is considered to be a principal guardian against tumorigenic transformation <cite>westermarck08</cite>. Some viruses target this protein to hijack the host cell <cite>janssens08</cite>.

PP2A controls the activity of at least 50 different kinases by directly interaction or linked via a anchoring protein. PP2A not only integrate signals within phoshorylation cascades but also to be the focal point of a distinct post-translational modification, reversible protein methylation <cite>janssens05</cite>. Here are some examples of PP2A functions:

* Hedgehog signaling. PP2A functions with PPFIA1 to promote the dephosphorylation of Kif7, triggering Kif7 localization to the tips of primary cilia and promoting Gli transcriptional activity. Both Kif7 and Gli are components in Hedgehog signaling <cite>liu14</cite>. (PS: Interestingly, [http://www.ncbi.nlm.nih.gov/gene/8500 PPFIA1] is known as interacting partner with tyrosine phosphatase PTPRF.)

* PP2A/B55 complex dephosphorylates heat shock factor 1. The regulatory subunit B55 directly binds to HSF1 <cite>Ishikawa15</cite>.

* PP2A-B56ϵ complex is involved in dephosphorylation of γ-H2AX in the repair process of topoisomerase I inhibitor camptothecin-induced DNA double-strand breaks <cite>Li15</cite>.

PP2A is regulated by Lyn, a Src kinase, through phosphorylation at Tyr-307 <cite>Zonta15</cite>.

===References===
<biblio>
#Ishikawa15 pmid=25816751
#janssens08 pmid=18291659
#janssens05 pmid=15661531
#janssens01 pmid=11171037
#Li15 pmid=25772433
#liu14 pmid=25492966
#Rahman15 pmid=25985190
#sontag01 pmid=11257442
#westermarck08 pmid=18329957
#Wong15 pmid=26310906
#Xiong15 pmid=25854679
#Zonta15 pmid=25931585
</biblio>

Phosphatase Subfamily PTPN3

2017-07-26T08:12:14Z

Gerard: /* PTPN3 (PTPH1) */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]:[[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTP|Family PTP]]: [[Phosphatase_Subfamily_PTPN3|Subfamily PTPN3]]

===Evolution===
The PTPN3 subfamily emerged in holozoa and duplicated in vertebrates. Human has two members, PTPN3 (PTPH1) and PTPN4 (PTP-MEG).

===Domain ===
The PTPN3 subfamily has a domain combination of FERM domain, PEST sequence, PDZ domain and phosphatase domain <cite>Yang91, Itoh93, Gu96b</cite>. PDZ domain can bind to other proteins and modulate the phosphatase domain <cite>Maisonneuve14</cite>.

===Functions===
The expression pattern, substrates and interacting partners of PTPN3/PTPH1 and PTPN4 have limited overlap.

===== PTPN3 (PTPH1) =====
PTPN3/PTPH1 is widely expressed in different tissues; it is expressed at a relatively higher level in skin and skeletal muscle according to [http://www.gtexportal.org/home/gene/PTPN3 GTEx].
Substrates include:
* Cell cycle regulator VCP (p97/CDC48) <cite>Zhang99</cite>.
* T cell receptor zeta subunit <cite>Sozio04</cite>.
* Estrogen receptor at Tyr-537 <cite>Suresh14</cite>.
* Epidermal growth factor receptor (EGFR) pathway substrate 15 (Eps15) at Tyr-849<cite>Chen15</cite>.
* EGFR <cite>Ma15</cite>.
* p38γ mitogen-activated protein kinase (MAPK). The interaction is mediated through PDZ binding <cite>Hou10</cite>, and vice versa, p38γ is also a kinase of PTPN3 <cite>Hou11</cite>.

PTPN3 interacts with and regulates Cardiac sodium channel Na(v)1.5. The interaction is mediated by the PDZ domain of PTPN3 and the PDZ-domain binding motif of Na(v)1.5 <cite>Jespersen06</cite>. PTPN3 is a negative regulator of Tumor necrosis factor alpha-convertase (TACE), a metalloprotease-disintegrin involved in the ectodomain shedding of several proteins and is critical for proper murine development. The interaction is mediated via binding of the PDZ domain of PTPN2 to the COOH terminus of TACE <cite>Zheng02</cite>. PTPN3 interacts with adaptor protein 14-3-3beta in a manner dependent on the phosphorylation state of PTPN3 <cite>Zhang97</cite>. PTPN3 binds to vitamin D receptor (VDR) and increases VDR's cytoplasmic accumulation, leading to their mutual stabilization and stimulating breast cancer growth <cite>Zhi11</cite>. PTPN3 controls growth hormone receptor (GHR) signaling <cite>Pilecka07</cite>.

PTPN3 is implicated in breast cancer <cite>Suresh14, Zhi11</cite>, intrahepatic cholangiocarcinoma <cite>Gao14</cite>, and human hepatocellular carcinomas <cite>Ikuta94</cite>.

===== PTPN4 (PTPMEG) =====
PTPN4/PTPMEG primarily locates in the membrane and cytoskeleton <cite>Gu91, Gu96a</cite>. PTPN4/PTPMEG has been shown to be specifically expressed in testis <cite>Park00</cite>. However, RNA-seq data in [http://www.gtexportal.org/home/gene/PTPN4 GTEx] shows it is widely expressed in different tissues, most abundantly in cerebellum and the expression level in testis is close to the average.

PTPN4 dephosphorylates T cell receptor (TCR) at ITAM motifs, a conserved signaling motif and are present in one or more copies in the cytoplasmic tails of the CD3 γ, δ, ε and TCR ζ subunits <cite>Young08</cite>.

PTPN4 dephosphorylates TRIF-related adaptor molecule (TRAM, also known as TICAM2), therefore inhibiting TRIF-dependent [http://en.wikipedia.org/wiki/TLR4 TLR4 pathway] <cite>Huai15</cite>.

PTPN4/PTPMEG interacts with but does not directly phosphorylates glutamate receptor delta 2 and epsilon subunits <cite>Hironaka00</cite>.

===References===
<biblio>
#Chen15 pmid=25728925
#Gao14 pmid=24503127
#Gu91 pmid=1648233
#Gu96a pmid=8910369
#Gu96b pmid=8917530
#Hironaka00 pmid=10748123
#Hou10 pmid=20332238
#Hou11 pmid=22730326
#Huai15 pmid=25825441
#Ikuta94 pmid=7874267
#Itoh93 pmid=8253532
#Jespersen06 pmid=16930557
#Maisonneuve14 pmid=25158884
#Ma15 pmid=26079946
#Park00 pmid=11054567
#Pilecka07 pmid=17921143
#Sozio04 pmid=14672952
#Suresh14 pmid=24227889
#Yang91 pmid=1648725
#Young08 pmid=18614237
#Zhang97 pmid=9341175
#Zhang99 pmid=10364224
#Zheng02 pmid=12207026
#Zhi11 pmid=21119599
</biblio>

Phosphatase Subfamily PTPN3

2017-07-26T08:10:35Z

Gerard: /* Evolution */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]:[[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTP|Family PTP]]: [[Phosphatase_Subfamily_PTPN3|Subfamily PTPN3]]

===Evolution===
The PTPN3 subfamily emerged in holozoa and duplicated in vertebrates. Human has two members, PTPN3 (PTPH1) and PTPN4 (PTP-MEG).

===Domain ===
The PTPN3 subfamily has a domain combination of FERM domain, PEST sequence, PDZ domain and phosphatase domain <cite>Yang91, Itoh93, Gu96b</cite>. PDZ domain can bind to other proteins and modulate the phosphatase domain <cite>Maisonneuve14</cite>.

===Functions===
The expression pattern, substrates and interacting partners of PTPN3/PTPH1 and PTPN4 have limited overlap.

===== PTPN3 (PTPH1) =====
PTPN3/PTPH1 is widely expressed in different tissues; it is expressed at a relatively higher level in skin and skeletal muscle according to [http://www.gtexportal.org/home/gene/PTPN3 GTEx].

PTPN3/PTPH1 substrates:
* Cell cycle regulator VCP (p97/CDC48) <cite>Zhang99</cite>.
* T cell receptor zeta subunit <cite>Sozio04</cite>.
* Estrogen receptor at Tyr-537 <cite>Suresh14</cite>.
* Epidermal growth factor receptor (EGFR) pathway substrate 15 (Eps15) at Tyr-849<cite>Chen15</cite>.
* EGFR <cite>Ma15</cite>.
* p38γ mitogen-activated protein kinase (MAPK). The interaction is mediated through PDZ binding <cite>Hou10</cite>, and vice versa, p38γ is also a kinase of PTPN3 <cite>Hou11</cite>.

PTPN3/PTPH1 interacts with and regulates Cardiac sodium channel Na(v)1.5. The interaction is mediated by the PDZ domain of PTPN3 and the PDZ-domain binding motif of Na(v)1.5 <cite>Jespersen06</cite>. PTPN3/PTPH1 is a negative regulator of Tumor necrosis factor alpha-convertase (TACE), a metalloprotease-disintegrin involved in the ectodomain shedding of several proteins and is critical for proper murine development. The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE <cite>Zheng02</cite>. PTPN3/PTPH1 interacts with adaptor protein 14-3-3beta in a manner dependent on the phosphorylation state of PTPN3 <cite>Zhang97</cite>. PTPN3/PTPH1 binds to vitamin D receptor (VDR) and increases VDR's cytoplasmic accumulation, leading to their mutual stabilization and stimulating breast cancer growth <cite>Zhi11</cite>. PTPN3/PTPH1 controls growth hormone receptor (GHR) signaling <cite>Pilecka07</cite>.

PTPN3/PTPH1 is implicated in breast cancer <cite>Suresh14, Zhi11</cite>, intrahepatic cholangiocarcinoma <cite>Gao14</cite>, and human hepatocellular carcinomas <cite>Ikuta94</cite>.

===== PTPN4 (PTPMEG) =====
PTPN4/PTPMEG primarily locates in the membrane and cytoskeleton <cite>Gu91, Gu96a</cite>. PTPN4/PTPMEG has been shown to be specifically expressed in testis <cite>Park00</cite>. However, RNA-seq data in [http://www.gtexportal.org/home/gene/PTPN4 GTEx] shows it is widely expressed in different tissues, most abundantly in cerebellum and the expression level in testis is close to the average.

PTPN4 dephosphorylates T cell receptor (TCR) at ITAM motifs, a conserved signaling motif and are present in one or more copies in the cytoplasmic tails of the CD3 γ, δ, ε and TCR ζ subunits <cite>Young08</cite>.

PTPN4 dephosphorylates TRIF-related adaptor molecule (TRAM, also known as TICAM2), therefore inhibiting TRIF-dependent [http://en.wikipedia.org/wiki/TLR4 TLR4 pathway] <cite>Huai15</cite>.

PTPN4/PTPMEG interacts with but does not directly phosphorylates glutamate receptor delta 2 and epsilon subunits <cite>Hironaka00</cite>.

===References===
<biblio>
#Chen15 pmid=25728925
#Gao14 pmid=24503127
#Gu91 pmid=1648233
#Gu96a pmid=8910369
#Gu96b pmid=8917530
#Hironaka00 pmid=10748123
#Hou10 pmid=20332238
#Hou11 pmid=22730326
#Huai15 pmid=25825441
#Ikuta94 pmid=7874267
#Itoh93 pmid=8253532
#Jespersen06 pmid=16930557
#Maisonneuve14 pmid=25158884
#Ma15 pmid=26079946
#Park00 pmid=11054567
#Pilecka07 pmid=17921143
#Sozio04 pmid=14672952
#Suresh14 pmid=24227889
#Yang91 pmid=1648725
#Young08 pmid=18614237
#Zhang97 pmid=9341175
#Zhang99 pmid=10364224
#Zheng02 pmid=12207026
#Zhi11 pmid=21119599
</biblio>

Phosphatase Subfamily PTPN3

2017-07-26T08:09:44Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]:[[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_PTP|Family PTP]]: [[Phosphatase_Subfamily_PTPN3|Subfamily PTPN3]]

===Evolution===
The PTPN3 subfamily emerged in holozoa and duplicated in vertebrates. Human has two members of this subfamily, PTPN3/PTPH1 and PTPN4/PTPMEG.

===Domain ===
The PTPN3 subfamily has a domain combination of FERM domain, PEST sequence, PDZ domain and phosphatase domain <cite>Yang91, Itoh93, Gu96b</cite>. PDZ domain can bind to other proteins and modulate the phosphatase domain <cite>Maisonneuve14</cite>.

===Functions===
The expression pattern, substrates and interacting partners of PTPN3/PTPH1 and PTPN4 have limited overlap.

===== PTPN3 (PTPH1) =====
PTPN3/PTPH1 is widely expressed in different tissues; it is expressed at a relatively higher level in skin and skeletal muscle according to [http://www.gtexportal.org/home/gene/PTPN3 GTEx].

PTPN3/PTPH1 substrates:
* Cell cycle regulator VCP (p97/CDC48) <cite>Zhang99</cite>.
* T cell receptor zeta subunit <cite>Sozio04</cite>.
* Estrogen receptor at Tyr-537 <cite>Suresh14</cite>.
* Epidermal growth factor receptor (EGFR) pathway substrate 15 (Eps15) at Tyr-849<cite>Chen15</cite>.
* EGFR <cite>Ma15</cite>.
* p38γ mitogen-activated protein kinase (MAPK). The interaction is mediated through PDZ binding <cite>Hou10</cite>, and vice versa, p38γ is also a kinase of PTPN3 <cite>Hou11</cite>.

PTPN3/PTPH1 interacts with and regulates Cardiac sodium channel Na(v)1.5. The interaction is mediated by the PDZ domain of PTPN3 and the PDZ-domain binding motif of Na(v)1.5 <cite>Jespersen06</cite>. PTPN3/PTPH1 is a negative regulator of Tumor necrosis factor alpha-convertase (TACE), a metalloprotease-disintegrin involved in the ectodomain shedding of several proteins and is critical for proper murine development. The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE <cite>Zheng02</cite>. PTPN3/PTPH1 interacts with adaptor protein 14-3-3beta in a manner dependent on the phosphorylation state of PTPN3 <cite>Zhang97</cite>. PTPN3/PTPH1 binds to vitamin D receptor (VDR) and increases VDR's cytoplasmic accumulation, leading to their mutual stabilization and stimulating breast cancer growth <cite>Zhi11</cite>. PTPN3/PTPH1 controls growth hormone receptor (GHR) signaling <cite>Pilecka07</cite>.

PTPN3/PTPH1 is implicated in breast cancer <cite>Suresh14, Zhi11</cite>, intrahepatic cholangiocarcinoma <cite>Gao14</cite>, and human hepatocellular carcinomas <cite>Ikuta94</cite>.

===== PTPN4 (PTPMEG) =====
PTPN4/PTPMEG primarily locates in the membrane and cytoskeleton <cite>Gu91, Gu96a</cite>. PTPN4/PTPMEG has been shown to be specifically expressed in testis <cite>Park00</cite>. However, RNA-seq data in [http://www.gtexportal.org/home/gene/PTPN4 GTEx] shows it is widely expressed in different tissues, most abundantly in cerebellum and the expression level in testis is close to the average.

PTPN4 dephosphorylates T cell receptor (TCR) at ITAM motifs, a conserved signaling motif and are present in one or more copies in the cytoplasmic tails of the CD3 γ, δ, ε and TCR ζ subunits <cite>Young08</cite>.

PTPN4 dephosphorylates TRIF-related adaptor molecule (TRAM, also known as TICAM2), therefore inhibiting TRIF-dependent [http://en.wikipedia.org/wiki/TLR4 TLR4 pathway] <cite>Huai15</cite>.

PTPN4/PTPMEG interacts with but does not directly phosphorylates glutamate receptor delta 2 and epsilon subunits <cite>Hironaka00</cite>.

===References===
<biblio>
#Chen15 pmid=25728925
#Gao14 pmid=24503127
#Gu91 pmid=1648233
#Gu96a pmid=8910369
#Gu96b pmid=8917530
#Hironaka00 pmid=10748123
#Hou10 pmid=20332238
#Hou11 pmid=22730326
#Huai15 pmid=25825441
#Ikuta94 pmid=7874267
#Itoh93 pmid=8253532
#Jespersen06 pmid=16930557
#Maisonneuve14 pmid=25158884
#Ma15 pmid=26079946
#Park00 pmid=11054567
#Pilecka07 pmid=17921143
#Sozio04 pmid=14672952
#Suresh14 pmid=24227889
#Yang91 pmid=1648725
#Young08 pmid=18614237
#Zhang97 pmid=9341175
#Zhang99 pmid=10364224
#Zheng02 pmid=12207026
#Zhi11 pmid=21119599
</biblio>

Phosphatase Subfamily STYXL1

2017-07-26T08:05:47Z

Gerard: /* Domain */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_ STYXL1 |Subfamily STYXL1]]

STYXL1 (MK-STYX) is a pseudophosphatase (catalytically inactive) conserved in metazoa but lost in ecdysozoa. Two binding partners have been known so far: phosphatase PTPMT1 and a Ras signaling regulator G3BP1.

=== Evolution ===
STYXL1 is found in [[metazoa]] but lost in [[ecdysozoa]] (arthropods and nematodes) <cite>Chen</cite>. It is usually found in one copy per genome.

=== Domain ===
STYXL1 has an N-terminal rhodanese domain and C-terminal phosphatase domain.

=== Functions ===
STYXL1 is expressed in most tissues (see [http://www.gtexportal.org/home/gene/STYXL1 GTEx data]).

STYXL1 physically and genetically interacts with the mitochondrial phosphatase PTPMT1, and suppresses PTPMT1 catalytic activity. STYXL1 knockdown induces robust chemoresistance to multiple cytotoxic death-inducing agents. Loss of STYXL1 blocks cytochrome c release, a critical and rate-limiting step in apoptosis. knockdown of PTPMT1 resensitizes STYXL1 knockdown cells to chemotherapeutics and restores the ability to release cytochrome c. This suggests that STYXL1 controls apoptosis by negatively regulating PTPMT1 <cite> Niemi11, Niemi14</cite>.

STYXL1 also interacts with G3BP-1 (Ras-GTPase activating protein SH3 domain binding protein-1), a key component of stress granules. G3BP1 is an RNA-binding protein with endoribonuclease activity that is recruited to 'stress granules' after stress stimuli. Stress granules are large subcellular structures that serve as sites of mRNA sorting, in which untranslated mRNAs accumulate. A mutant active STYXL1, which has been transformed from pseudophosphatase to phosphatase by restoration of HC of the HCx5R motif, has opposite effects to wild-type STYKL1 (inactive). The active mutant STYXL1 induces stress granules and dephosphorylates G3BP-1. <cite>Hinton10, Barr13</cite>.

STYXL1 induces neurite outgrowth in PC12 cells, while the active mutant does not <cite>Flowers</cite>. It is a likely regulator of RhoA signaling in these cells.

=== References ===
<biblio>
#Barr13 pmid=23163895
#Chen pmid=28400531
#Flowers pmid=25479605
#Hinton10 pmid=20180778
#Niemi11 pmid=21262771
#Niemi14 pmid=24709986
</biblio>

Phosphatase Subfamily PRL

2017-07-26T08:01:23Z

Gerard: /* Function */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_PRL|Subfamily PRL]] (PTP4A)

=== Evolution ===
PRL is present in animals, and most basal eukaryotes, but is absent from fungi and plants ([http://resdev.gene.com/gOrtholog/view/cluster/MC0001030/overview unpublished data from gOrtholog]).

=== Domain ===
PRL has a [[Phosphatase_Fold_CC1|CC1]] fold phosphatase domain followed by a polybasic motif and a consensus prenylation motif.

=== Function ===
PRL is short for Phosphatases of Regenerating Liver. There are three PRLs in human, PRL1, PRL2, PRL3 (PTP4A1-3), all of which have been identified as key contributors to metastasis in several human cancers <cite>tremblay14, Von-Hoff06</cite>. The molecular mechanisms of PRL phosphatases has been reviewed <cite>kohn12</cite> in 2012.

PRL3 is implicated in cancer. For instance, deletion of PRL3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice <cite>Cramer15</cite>. PRL3 (PTP4A3) independently predicts metastasis and survival in upper tract urothelial carcinoma treated with radical nephroureterectomy <cite>Yeh15</cite>.

PTP4A3 has a number of reported protein substrates including ezrin <cite>Forte</cite> and p130cas <cite>Matter</cite>. All three human genes have activity against tyrosine-phosphorylated peptides <cite>Pathak</cite>.

=== References ===
<biblio>
#Cramer15 pmid=24950307
#Von-Hoff06 pmid=16275986
#tremblay14 pmid=24632616
#Forte pmid=18078820
#kohn12 pmid=22413991
#Matter pmid=11355880
#Pathak pmid=12516958
#Yeh15 pmid=26070892
</biblio>

Phosphatase Subfamily PRL

2017-07-26T07:57:46Z

Gerard: /* Domain */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]: [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_PRL|Subfamily PRL]] (PTP4A)

=== Evolution ===
PRL is present in animals, and most basal eukaryotes, but is absent from fungi and plants ([http://resdev.gene.com/gOrtholog/view/cluster/MC0001030/overview unpublished data from gOrtholog]).

=== Domain ===
PRL has a [[Phosphatase_Fold_CC1|CC1]] fold phosphatase domain followed by a polybasic motif and a consensus prenylation motif.

=== Function ===
PRL is short for Phosphatases of Regenerating Liver. There are three PRLs in human, PRL1, PRL2, PRL3 (PTP4A1-3), all of which have been identified as key contributors to metastasis in several human cancers <cite>tremblay14, Von-Hoff06</cite>. The molecular mechanisms of PRL phosphatases has been reviewed <cite>kohn12</cite> in 2012.

PRL3 is implicated in cancer. For instance, deletion of PRL3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice <cite>Cramer15</cite>. PRL3 (PTP4A3) independently predicts metastasis and survival in upper tract urothelial carcinoma treated with radical nephroureterectomy <cite>Yeh15</cite>.

PTP4A3 has a number of protein substrates including ezrin <cite>Forte</cite> and p130cas <cite>Matter</cite>. All three human genes have activity against tyrosine-phosphorylated peptides <cite>Pathak</cite>.

=== References ===
<biblio>
#Cramer15 pmid=24950307
#Von-Hoff06 pmid=16275986
#tremblay14 pmid=24632616
#Forte pmid=18078820
#kohn12 pmid=22413991
#Matter pmid=11355880
#Pathak pmid=12516958
#Yeh15 pmid=26070892
</biblio>

Phosphatase Subfamily EYA

2017-07-25T08:00:34Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_HAD|Fold HAD]]: [[Phosphatase_Superfamily_HAD|Superfamily HAD]]: [[Phosphatase_Family_EYA|Family EYA]]: [[Phosphatase_Subfamily_EYA|Subfamily EYA]]

EYA (comes from eyes absent) was first identified in Drosophila as a gene required for eye development. There four members in human, and a single copy in most of the invertebrates. All EYAs belong to [[Phosphatase_Subfamily_EYA|EYA subfamily]], the single subfamily of EYA family.

=== Evolution ===
EYA is found in animals and choanoflagellates, plants and Phytophthora. But in plants and Phytophthora, while the phosphatase domain is conserved and complete, the N-terminal transcription factor domain is very short and may be even not a domain. (in some non-model animals, no N-terminal region was found, either). EYA is only found in Phytophthora genus but not in other heterokonts.

The catalytic motif sequences varies. From Monosiga to human, most of the EYAs have canonical catalytic motif sequence DLDET, except Hydra (DLDDV) and nematodes. All nematodes except Trichinella spiralis have neither conserved nor canonical sequence motif (DIDDI, DLEDV, EMEDV). In plants, the catalytic motif sequence is conserved as DMDET, and in phytophora, that is DLDET again.

Human (and most vertebrates) has four copies of EYAs; Sea urchin has three copies; Non-chordates such as fruit fly and ''C elegans'' have single copy per genome.

=== Domain ===
EYA has two regions corresponding to its two main function. The N-terminal region is transcription factor domain, and the C-terminal region is a HAD-fold phosphatase domain (known as ED) <cite>tootle04</cite>.

=== Function ===
Putative substrates are myelin basic protein, RNA pol II, MAPK, and EYA itself (see Review <cite>Jmec07</cite>).

Recently, Cook et al. showed EYA involved in apoptosis by dephosphorylating H2AX Y142 in mouse <cite>Cook09</cite>, and Hirose showed EYA involved in apoptosis through direct transcriptional activation of egl-1 in C. elegans <cite>Hirose10</cite>. However, the molecular mechanism of how EYA involved in apoptosis may be not conserved, because no Y142 is found in C. elegans (Note: The existence of H2AX in C. elegans is plausible. No H2AX has been identified in C. elegans. Even though some researchers suggest CENP-A function as H2AX, the protein has no Y142.)

== Related kinase ==
WSTF: WSTF is the kinase of H2AX Y142 <cite>Xiao09</cite>.

== Correlated presence/absence of EYA and Y142 ==
The presence/absence of EYA well correlates that of Y142. The Y142 is conserved from Nematostella to human with the exception of nematodes. Surprisingly, Phytophthora also have Y142, though most of the bikonts (plants + heterokonts + alveolates + excavates) do not have Y142. This implies 1) the H2AX Y142 is a real substrate of EYA, 2) EYA has other functions.

== Reference ==
<biblio>
#tootle04 pmid=14628053
#Jmec07 pmid=17341163
#Cook09 pmid=19234442
#Hirose10 pmid=20713707
#Xiao09 pmid=19092802
</biblio>

Phosphatase Subfamily PPM1K

2017-07-25T07:59:07Z

Gerard: /* Functions */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]: [[Phosphatase_Subfamily_PPM1K|Subfamily PPM1K]] (PP2Cκ, PP2Cm, BDP)

PPM1K is a mitochondrial phosphatase that regulates the membrane permeability transition pore and is part of the BCKDA complex.

=== Evolution ===
The PPM1K subfamily emerged in [[Phosphatase_Glossary#Holozoa|holozoa]]. It was lost in [[Phosphatase_Glossary#Ecdysozoa|ecdysozoa]] and sponge. PPM1K is most similar to the ER-anchored phosphatase subfamily [[Phosphatase_Subfamily_PPM1L|PPM1L]].

=== Domain ===
The PPM1K subfamily has an N-terminal mitochondria target signal (MTS) and phosphatase domain <cite>Joshi07, Lu07</cite>. The MTS (predicted by MitoProt) and phosphatase domain are conserved throughout the PPM1K subfamily.

=== Functions ===
PPM1K is localized to mitochondrial matrix <cite>Lu07</cite>. It regulates mitochondrial membrane permeability transition pore (MPTP) opening, but the underlying molecular mechanism(s) is unclear <cite>Lu07</cite>. It also functions as pSer phosphatase of the branched-chain a-keto acid dehydrogenase (BCKD) complex <cite>Joshi07</cite>. Its loss in Ecdysozoa parallels the loss of the opposing [http://kinase.com/wiki/index.php/Kinase_Family_PDHK BCKDK] kinase. Human PPM1K is widely expressed in different tissues, most abundant in heart <cite>Lu07, Joshi07</cite> and [http://www.gtexportal.org/home/gene/PPM1K GTEx database].

=== References ===
<biblio>
#Joshi07 pmid=17336929
#Lu07 pmid=17374715
</biblio>

Phosphatase Family PPM

2017-07-24T16:53:52Z

Gerard: /* PPM1D (WIP1): oncogene in different cancer types */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]

PPM (a.k.a. PP2C) is serine/threonine phosphatase found in all eukaryotes, and related to bacterial sporulation protein SpoIIE.

Human PPMs exclusively dephoshorylate pSer/pThr. All PPMs are active, except that TAB1 has been reported as pseudophosphatase ([http://www.ncbi.nlm.nih.gov/pubmed/16879102 Conner et al. 2006]). Unlike the other major Ser/Thr phosphatase family, PPP, PPM does not generally rely on targeting subunits.

Most PPM require two even three metal ions, either Mg2+ or Mn2+ to activate its phosphatase activity <cite>Tanoue13</cite>.

The PPM subfamilies have different insertions to the core of phosphatase domain, some quite conserved and long, suggesting their importance to the specific functions of individual subfamilies. For instance, the PPM1G subfamily has an inserted acidic region of 54 aa long; PPM1H has an inserted region of ~60 aa; PPM1A has a ~80 aa residues insert to the C-terminal, which consists of three antiparallel alpha helices and form a cleft between it and the catalytic domain.

=== Subfamilies ===
===== [[Phosphatase_Subfamily_PPM1A|PPM1A]] =====
The subfamily is named after one of the three human copies, PPM1A (PP2Cα), PPM1B (PP2Cβ) and PPM1N. It is involved in different pathways, such as MAPK, SAPK/JNK, TGF-beta, NF-kappaB signaling. PPM1As were found across holozoa.

===== [[Phosphatase_Subfamily_PPM1G|PPM1G]] (PP2Cγ): mRNA splicing and histone regulation =====
PPM1G is found across [[Phosphatase_Glossary#Metazoa|metazoa]]. PPM1G has a predicted N-terminal myristoylation site, C-terminal nuclear localization signaling, and a characteristic phosphatase domain inserted by an acidic domain. It is involved in pre-mRNA splicing, histone regulation, and cell cycle.

===== [[Phosphatase_Subfamily_PPM1D|PPM1D]] (WIP1): oncogene in different cancer types =====
The PPM1D subfamily is an oncogene conserved from Monosiga to human. It regulates cell homeostasis in response to DNA damage. It dephosphorylates the DNA damage response kinases ATM and ATR as well as their phosphorylation targets, p53, Mdm2, Chk2 and gH2AX. It also dephosphorylates p38/MAPK, the tumor suppressors INK4A and ARF, and the RelA subunit of NF-kappaB.

===== [[Phosphatase_Subfamily_PPM1E|PPM1E]] (POXP): the phosphatases of CAMKs and PAK =====
The PPM1E subfamily is named after two human PPMs, [[Phosphatase_Gene_PPM1E|PPM1E]] (also known as [http://www.ncbi.nlm.nih.gov/gene/22843 POXP1, PP2CH, caMKN, CaMKP-N]) and [[Phosphatase_Gene_PPM1F|PPM1F]] (also known as [http://www.ncbi.nlm.nih.gov/gene/9647 POXP2, CAMKP, FEM-2, hFEM-2, CaMKPase]). The subfamily has a single copy in most non-vertebrates from Monosiga to ciona, and duplicated when vertebrates emerged. Both PPM1E and PPM1F dephosphorylate kinases CaMK2g and PAK, and PPM1E can also dephosphorylate CaMK4 (of different families from CaMK2g).

===== [[Phosphatase_Subfamily_PPM1H|PPM1H]] =====
The PPM1H subfamily is named after one of the three copies in human, PPM1H (URCC2, ARHCL1, NERPP-2C), PPM1J (PP2Cζ) and PPM1M (PP2Cη), which are expressed in distinct tissues. The PPM1H subfamily are conserved in animals from sponge to human. Usually, it is single-copy in invertebrates from sponge to ciona. The three copies are found in mammals probably arose by two independent duplication events (not whole-genome duplication).

===== [[Phosphatase_Subfamily_PPM1K|PPM1K]] (PP2Cκ, PP2Cm, BDP): mitochondrial phosphatase lost in ecdysozoa =====
The PPM1K subfamily is a mitochondrial phosphatase that regulates mitochondrial permeability transition pore (MPTP). It also dephosphorylates branched-chain alpha-ketoacid dehydrogenase complex. The PPM1K subfamily emerged in [[Phosphatase_Glossary#Holozoa|holozoan]] and lost in [[Phosphatase_Glossary#Ecdysozoa|ecdysozoa]].

===== [[Phosphatase_Subfamily_PPM1L|PPM1L]] (PP2Cε, PP2Ce) =====
Human PPM1L is an ER-anchored phosphatase, where it dephoshorylates ceramide transport protein (CERT). It also dephosphorylates two kinases TAK1 and ASK1. While PPM1L emerged in bilateria, all its known substrates emerged in holozoa or earlier.

===== [[Phosphatase_Subfamily_PTC7|PTC7]]: activating Q6 biosynthesis =====
The PTC7 subfamily is conserved through eukaryotes, dephosphorylates the mitochondrial hydroxylase COQ7 and activates coenzyme Q biosynthesis.

===== [[Phosphatase_Subfamily_PDPc|PDPc]]: the catalytic subunit of pyruvate dehyrogenase phosphatase =====
The PDPc subfamily is the catalytic subunit of Pyruvate Dehyrogenase Phosphatase (PDP). It is found throughout eukaryotes, so are Pyruvate Dehyrogenase Kinase (PDK) and its substrate Pyruvate Dehyrogenase Complex (PDC).

===== [[Phosphatase_Subfamily_ILKAP|ILKAP]] (PP2Cδ): a subunit of TAK1-TAB1 complex =====
integrin-linked kinase (ILK) associated phosphatase binds to ILK and specifically regulates one of its two substrates, Ser-9 on glycogen synthase kinase 3 β (GSK3β). It also dephosphorylates p90 ribosomal S6 kinase 2 (RSK2) at multiple serine or threonine sites in the nuclear. All the three, ILKAP, ILK and RSK2, emerged in [[Phosphatase_Glossary#Holozoa|holozoa]], but ILKAP was lost in arthropods, while ILK and RSK2 were not.

===== [[Phosphatase_Subfamily_PHLPP|PHLPP]]: AGC kinase phosphatase =====
The subfamily is characterized by PH domain and Leucine rich repeats. It dephosphorylates AKT/PKB, PKC and S6 kinase families of AGC kinase group at serines in hydrophobic motif site. The subfamily is found across bilateria.

===== [[Phosphatase_Subfamily_TAB1|TAB1]]: binding to TAK1 and p38 and inducing their autophosphorylation =====
The TAB1 subfamily is most well known for its binding to MAPKs TAK1 and p38. It does not dephosphorylate them. Instead, it binds to them and induces their autophosphorylation. It is found in metazoa except Drosophila. It is found in most other arthropods, which indicates a lineage-specific gene loss in Drosophila. Interestingly, TAK1 and p38 are found in Drosophila and both of them emerged earlier, in holozoa and opisthokont, respectively.

===== [[Phosphatase_Subfamily_PP2D1|PP2D1]] =====
The function of the PP2D1 subfamily is unknown. It is found across the eumetazoa, but frequently lost, including from C. elegans, Drosophila and zebrafish. It has an N-terminal predicted nuclear localization signaling (NLS).

===== [[Phosphatase_Subfamily_CG9801|CG9801]] =====
The CG9801 subfamily found in metazoa but lost in deuterostomes. Its function is unknown.

===== [[Phosphatase_Subfamily_PPM1Z|PPM1Z]]: a phosphatase lost in vertebrates =====
The function of this subfamily is unclear. It emerged in holozoa or metazoa through the duplication of its common ancestral gene with PPM1A.

===== [[Phosphatase_Subfamily_LRR-PPM|LRR-PPM]] =====
The LRR-PPM subfamily has a combination of leucine riches repeats (LRRs) and PPM phosphatase domain. It is found in Amoebozoa. It does not have any clear orthology to the other LRR-PPM family, [[Phosphatase_Subfamily_PHLPP|PHLPP]]

===== [[Phosphatase_Subfamily_KAPP-like|KAPP-like]] =====
The subfamily is similar to the plant PPM phosphatase KAPP (see [http://www.ncbi.nlm.nih.gov/gene/832048]), a regulator of the receptor-like kinase (RLK) signaling pathway. Plant RLKs are counterpart of animal receptor kinases. This subfamily is found in Dictyostelids and lacks the FHA domain found in plant KAPPs.

=== Unclassified phosphatases ===
Below are unclassified phosphatases of PPM family, the functions of which have been known.

* Budding yeast [[Phosphatase_Gene_PTC1|PTC1]]. Its functions have been reviewed in <cite> Arino11, Sharmin14 </cite>. PTC1 is found in most fungi (see our [http://resdev.gene.com/gOrtholog/view/cluster/MC0007538/overview internal data]).

* Budding yeast [[Phosphatase_Gene_PTC6|PTC6]] is found in a broad of fungi. In budding yeast, Ptp6p locates both in the intermembrane and mitochondria. Along with Ptc5p, it regulates the phosphorylation state of Pda1p, the E1alpha subunit of the pyruvate dehydrogenase (PDH). PTC6 and PTC5 (of [[Phosphatase_Subfamily_PDPc|PDPc subfamily]] share a large overlap of phenotypes, but they may have distinct molecular functions <cite> Arino11 </cite>.

* Budding yeast [[Phosphatase_Gene_CYR1|CYR1]] encodes adenylate cyclase in budding yeast. The protein has a domain combination of 1) Adenylate cyclase G-alpha binding domain, 2) Ubiquitin domain CYR1 adenylate cyclase, 3) Leucine repeats, 4) PPM phosphatase domain, and 5) cyclase homology domain. CYR1 is found in most fungi including both Ascomycota and Basidiomycota (also by BLAST NR database and [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Search&term=18511290 Newton's review]). CYR1 is close to PHLPP in phosphatase domain sequence, but they have distinct domain structure and molecular function.

* Dictyostelium [[Phosphatase_Gene_spnA|spnA]] has two domains, Galpha subunit family of GTP binding proteins at N-terminal, and PPM phosphatase domain at C-terminal. It functions cell autonomously for prestalk differentiation, and cell non-autonomously for prespore differentiation (see summary from [http://dictybase.org/gene/DDB_G0276155 DictyBase]).

=== Phosphatase domain structure ===
The PPM phosphatase domain (PD) has a central β sandwich, flanked by helices. The catalytic core locates at the cleft between the two β sheets. The dephosphorylation reaction is mediated by two or three metal ions located at the base of the cleft (reviewed in <cite>Shi09</cite>). Both of the two β sheets are anti-parallel.

The PPM PDs have largely the same secondary structure combination, E1, E2, E3, H1, H2, E4, E5, E6, E7, H3, E8, E9, H4, H5, H6, E10. The E1, E10, E9, E6, E7 forms one of the anti-parallel beta sheet; the E2, E3, E4, E5, E8 forms another anti-parallel beta sheet.

Based upon the structure-based sequence alignment, there are 7 conserved motifs:
* M1: ED at E2
* M2: VxDG at E3
* M3: GxT at E4
* M4: GDS between E5 and E6
* M5: RxxG at eukaryotic flap
* M6: DG at H4
* M7: DN at E10

The motifs carry the residues coordinate the metal ions mediated the reaction, which are:
* R and D at M1
* D and G at M2
* D at M4
* D at M7

The available structures of PPM PDs show diversity in the regions beyond catalytic core. For instance, the region of H1 and H2 has the helices of different numbers and lengths. The so-called flap region is different in eukaryotes and prokaryotes.

Note:
* A few PPMs (e.g. PPM1A) have an additional N-terminal beta strand (E1'). PPM1A has three helices at C termini. Because these SS elements are not conserved across PPM PDs, we do not include them as part of PPM PD.
* The flag is a surface loop close to the active site was shown to play an important role in regulating substrate access to the catalytic center.
* D of M6 coordinate the third metal is required for activity as shown by D to A substitution <cite>Su11</cite>.

=== References ===
<biblio>
#Arino11 pmid=21076010
#Sharmin14 pmid=25088474
#Shi09 pmid=19879837
#Su11 pmid=21310952
#Tanoue13 pmid=23906386
</biblio>

Phosphatase Family PPM

2017-07-24T16:51:50Z

Gerard: /* PPM1G (PP2Cγ): mRNA splicing and histone regulation */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]

PPM (a.k.a. PP2C) is serine/threonine phosphatase found in all eukaryotes, and related to bacterial sporulation protein SpoIIE.

Human PPMs exclusively dephoshorylate pSer/pThr. All PPMs are active, except that TAB1 has been reported as pseudophosphatase ([http://www.ncbi.nlm.nih.gov/pubmed/16879102 Conner et al. 2006]). Unlike the other major Ser/Thr phosphatase family, PPP, PPM does not generally rely on targeting subunits.

Most PPM require two even three metal ions, either Mg2+ or Mn2+ to activate its phosphatase activity <cite>Tanoue13</cite>.

The PPM subfamilies have different insertions to the core of phosphatase domain, some quite conserved and long, suggesting their importance to the specific functions of individual subfamilies. For instance, the PPM1G subfamily has an inserted acidic region of 54 aa long; PPM1H has an inserted region of ~60 aa; PPM1A has a ~80 aa residues insert to the C-terminal, which consists of three antiparallel alpha helices and form a cleft between it and the catalytic domain.

=== Subfamilies ===
===== [[Phosphatase_Subfamily_PPM1A|PPM1A]] =====
The subfamily is named after one of the three human copies, PPM1A (PP2Cα), PPM1B (PP2Cβ) and PPM1N. It is involved in different pathways, such as MAPK, SAPK/JNK, TGF-beta, NF-kappaB signaling. PPM1As were found across holozoa.

===== [[Phosphatase_Subfamily_PPM1G|PPM1G]] (PP2Cγ): mRNA splicing and histone regulation =====
PPM1G is found across [[Phosphatase_Glossary#Metazoa|metazoa]]. PPM1G has a predicted N-terminal myristoylation site, C-terminal nuclear localization signaling, and a characteristic phosphatase domain inserted by an acidic domain. It is involved in pre-mRNA splicing, histone regulation, and cell cycle.

===== [[Phosphatase_Subfamily_PPM1D|PPM1D]] (WIP1): oncogene in different cancer types =====
The PPM1D subfamily is an oncogene conserved from Monosiga to human. It regulates cell homeostasis in response to DNA damage. It dephosphorylates p53 and its various target kinases, such as ATM, Chk1 and Chk2. It also dephosphorylates p38/MAPK, tumor suppressors INK4A and ARF, RelA subunit of NF-kappaB, gamma-H2AX and etc. (PS: ATM and PPM1D have a significant overlap of their substrate proteins, -the same residues on a set of proteins, including p53, Mdm2, Chk2 and gamma-H2AX at least.)

===== [[Phosphatase_Subfamily_PPM1E|PPM1E]] (POXP): the phosphatases of CAMKs and PAK =====
The PPM1E subfamily is named after two human PPMs, [[Phosphatase_Gene_PPM1E|PPM1E]] (also known as [http://www.ncbi.nlm.nih.gov/gene/22843 POXP1, PP2CH, caMKN, CaMKP-N]) and [[Phosphatase_Gene_PPM1F|PPM1F]] (also known as [http://www.ncbi.nlm.nih.gov/gene/9647 POXP2, CAMKP, FEM-2, hFEM-2, CaMKPase]). The subfamily has a single copy in most non-vertebrates from Monosiga to ciona, and duplicated when vertebrates emerged. Both PPM1E and PPM1F dephosphorylate kinases CaMK2g and PAK, and PPM1E can also dephosphorylate CaMK4 (of different families from CaMK2g).

===== [[Phosphatase_Subfamily_PPM1H|PPM1H]] =====
The PPM1H subfamily is named after one of the three copies in human, PPM1H (URCC2, ARHCL1, NERPP-2C), PPM1J (PP2Cζ) and PPM1M (PP2Cη), which are expressed in distinct tissues. The PPM1H subfamily are conserved in animals from sponge to human. Usually, it is single-copy in invertebrates from sponge to ciona. The three copies are found in mammals probably arose by two independent duplication events (not whole-genome duplication).

===== [[Phosphatase_Subfamily_PPM1K|PPM1K]] (PP2Cκ, PP2Cm, BDP): mitochondrial phosphatase lost in ecdysozoa =====
The PPM1K subfamily is a mitochondrial phosphatase that regulates mitochondrial permeability transition pore (MPTP). It also dephosphorylates branched-chain alpha-ketoacid dehydrogenase complex. The PPM1K subfamily emerged in [[Phosphatase_Glossary#Holozoa|holozoan]] and lost in [[Phosphatase_Glossary#Ecdysozoa|ecdysozoa]].

===== [[Phosphatase_Subfamily_PPM1L|PPM1L]] (PP2Cε, PP2Ce) =====
Human PPM1L is an ER-anchored phosphatase, where it dephoshorylates ceramide transport protein (CERT). It also dephosphorylates two kinases TAK1 and ASK1. While PPM1L emerged in bilateria, all its known substrates emerged in holozoa or earlier.

===== [[Phosphatase_Subfamily_PTC7|PTC7]]: activating Q6 biosynthesis =====
The PTC7 subfamily is conserved through eukaryotes, dephosphorylates the mitochondrial hydroxylase COQ7 and activates coenzyme Q biosynthesis.

===== [[Phosphatase_Subfamily_PDPc|PDPc]]: the catalytic subunit of pyruvate dehyrogenase phosphatase =====
The PDPc subfamily is the catalytic subunit of Pyruvate Dehyrogenase Phosphatase (PDP). It is found throughout eukaryotes, so are Pyruvate Dehyrogenase Kinase (PDK) and its substrate Pyruvate Dehyrogenase Complex (PDC).

===== [[Phosphatase_Subfamily_ILKAP|ILKAP]] (PP2Cδ): a subunit of TAK1-TAB1 complex =====
integrin-linked kinase (ILK) associated phosphatase binds to ILK and specifically regulates one of its two substrates, Ser-9 on glycogen synthase kinase 3 β (GSK3β). It also dephosphorylates p90 ribosomal S6 kinase 2 (RSK2) at multiple serine or threonine sites in the nuclear. All the three, ILKAP, ILK and RSK2, emerged in [[Phosphatase_Glossary#Holozoa|holozoa]], but ILKAP was lost in arthropods, while ILK and RSK2 were not.

===== [[Phosphatase_Subfamily_PHLPP|PHLPP]]: AGC kinase phosphatase =====
The subfamily is characterized by PH domain and Leucine rich repeats. It dephosphorylates AKT/PKB, PKC and S6 kinase families of AGC kinase group at serines in hydrophobic motif site. The subfamily is found across bilateria.

===== [[Phosphatase_Subfamily_TAB1|TAB1]]: binding to TAK1 and p38 and inducing their autophosphorylation =====
The TAB1 subfamily is most well known for its binding to MAPKs TAK1 and p38. It does not dephosphorylate them. Instead, it binds to them and induces their autophosphorylation. It is found in metazoa except Drosophila. It is found in most other arthropods, which indicates a lineage-specific gene loss in Drosophila. Interestingly, TAK1 and p38 are found in Drosophila and both of them emerged earlier, in holozoa and opisthokont, respectively.

===== [[Phosphatase_Subfamily_PP2D1|PP2D1]] =====
The function of the PP2D1 subfamily is unknown. It is found across the eumetazoa, but frequently lost, including from C. elegans, Drosophila and zebrafish. It has an N-terminal predicted nuclear localization signaling (NLS).

===== [[Phosphatase_Subfamily_CG9801|CG9801]] =====
The CG9801 subfamily found in metazoa but lost in deuterostomes. Its function is unknown.

===== [[Phosphatase_Subfamily_PPM1Z|PPM1Z]]: a phosphatase lost in vertebrates =====
The function of this subfamily is unclear. It emerged in holozoa or metazoa through the duplication of its common ancestral gene with PPM1A.

===== [[Phosphatase_Subfamily_LRR-PPM|LRR-PPM]] =====
The LRR-PPM subfamily has a combination of leucine riches repeats (LRRs) and PPM phosphatase domain. It is found in Amoebozoa. It does not have any clear orthology to the other LRR-PPM family, [[Phosphatase_Subfamily_PHLPP|PHLPP]]

===== [[Phosphatase_Subfamily_KAPP-like|KAPP-like]] =====
The subfamily is similar to the plant PPM phosphatase KAPP (see [http://www.ncbi.nlm.nih.gov/gene/832048]), a regulator of the receptor-like kinase (RLK) signaling pathway. Plant RLKs are counterpart of animal receptor kinases. This subfamily is found in Dictyostelids and lacks the FHA domain found in plant KAPPs.

=== Unclassified phosphatases ===
Below are unclassified phosphatases of PPM family, the functions of which have been known.

* Budding yeast [[Phosphatase_Gene_PTC1|PTC1]]. Its functions have been reviewed in <cite> Arino11, Sharmin14 </cite>. PTC1 is found in most fungi (see our [http://resdev.gene.com/gOrtholog/view/cluster/MC0007538/overview internal data]).

* Budding yeast [[Phosphatase_Gene_PTC6|PTC6]] is found in a broad of fungi. In budding yeast, Ptp6p locates both in the intermembrane and mitochondria. Along with Ptc5p, it regulates the phosphorylation state of Pda1p, the E1alpha subunit of the pyruvate dehydrogenase (PDH). PTC6 and PTC5 (of [[Phosphatase_Subfamily_PDPc|PDPc subfamily]] share a large overlap of phenotypes, but they may have distinct molecular functions <cite> Arino11 </cite>.

* Budding yeast [[Phosphatase_Gene_CYR1|CYR1]] encodes adenylate cyclase in budding yeast. The protein has a domain combination of 1) Adenylate cyclase G-alpha binding domain, 2) Ubiquitin domain CYR1 adenylate cyclase, 3) Leucine repeats, 4) PPM phosphatase domain, and 5) cyclase homology domain. CYR1 is found in most fungi including both Ascomycota and Basidiomycota (also by BLAST NR database and [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Search&term=18511290 Newton's review]). CYR1 is close to PHLPP in phosphatase domain sequence, but they have distinct domain structure and molecular function.

* Dictyostelium [[Phosphatase_Gene_spnA|spnA]] has two domains, Galpha subunit family of GTP binding proteins at N-terminal, and PPM phosphatase domain at C-terminal. It functions cell autonomously for prestalk differentiation, and cell non-autonomously for prespore differentiation (see summary from [http://dictybase.org/gene/DDB_G0276155 DictyBase]).

=== Phosphatase domain structure ===
The PPM phosphatase domain (PD) has a central β sandwich, flanked by helices. The catalytic core locates at the cleft between the two β sheets. The dephosphorylation reaction is mediated by two or three metal ions located at the base of the cleft (reviewed in <cite>Shi09</cite>). Both of the two β sheets are anti-parallel.

The PPM PDs have largely the same secondary structure combination, E1, E2, E3, H1, H2, E4, E5, E6, E7, H3, E8, E9, H4, H5, H6, E10. The E1, E10, E9, E6, E7 forms one of the anti-parallel beta sheet; the E2, E3, E4, E5, E8 forms another anti-parallel beta sheet.

Based upon the structure-based sequence alignment, there are 7 conserved motifs:
* M1: ED at E2
* M2: VxDG at E3
* M3: GxT at E4
* M4: GDS between E5 and E6
* M5: RxxG at eukaryotic flap
* M6: DG at H4
* M7: DN at E10

The motifs carry the residues coordinate the metal ions mediated the reaction, which are:
* R and D at M1
* D and G at M2
* D at M4
* D at M7

The available structures of PPM PDs show diversity in the regions beyond catalytic core. For instance, the region of H1 and H2 has the helices of different numbers and lengths. The so-called flap region is different in eukaryotes and prokaryotes.

Note:
* A few PPMs (e.g. PPM1A) have an additional N-terminal beta strand (E1'). PPM1A has three helices at C termini. Because these SS elements are not conserved across PPM PDs, we do not include them as part of PPM PD.
* The flag is a surface loop close to the active site was shown to play an important role in regulating substrate access to the catalytic center.
* D of M6 coordinate the third metal is required for activity as shown by D to A substitution <cite>Su11</cite>.

=== References ===
<biblio>
#Arino11 pmid=21076010
#Sharmin14 pmid=25088474
#Shi09 pmid=19879837
#Su11 pmid=21310952
#Tanoue13 pmid=23906386
</biblio>

Phosphatase Family PPM

2017-07-24T16:51:09Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]

PPM (a.k.a. PP2C) is serine/threonine phosphatase found in all eukaryotes, and related to bacterial sporulation protein SpoIIE.

Human PPMs exclusively dephoshorylate pSer/pThr. All PPMs are active, except that TAB1 has been reported as pseudophosphatase ([http://www.ncbi.nlm.nih.gov/pubmed/16879102 Conner et al. 2006]). Unlike the other major Ser/Thr phosphatase family, PPP, PPM does not generally rely on targeting subunits.

Most PPM require two even three metal ions, either Mg2+ or Mn2+ to activate its phosphatase activity <cite>Tanoue13</cite>.

The PPM subfamilies have different insertions to the core of phosphatase domain, some quite conserved and long, suggesting their importance to the specific functions of individual subfamilies. For instance, the PPM1G subfamily has an inserted acidic region of 54 aa long; PPM1H has an inserted region of ~60 aa; PPM1A has a ~80 aa residues insert to the C-terminal, which consists of three antiparallel alpha helices and form a cleft between it and the catalytic domain.

=== Subfamilies ===
===== [[Phosphatase_Subfamily_PPM1A|PPM1A]] =====
The subfamily is named after one of the three human copies, PPM1A (PP2Cα), PPM1B (PP2Cβ) and PPM1N. It is involved in different pathways, such as MAPK, SAPK/JNK, TGF-beta, NF-kappaB signaling. PPM1As were found across holozoa.

===== [[Phosphatase_Subfamily_PPM1G|PPM1G]] (PP2Cγ): mRNA splicing and histone regulation =====
The PPM1G subfamily is found across [[Phosphatase_Glossary#Metazoa|metazoa]]. PPM1G has a predicted N-terminal myristoylation site, C-terminal nuclear localization signaling, and a characteristic phosphatase domain inserted by an acidic domain. It is involved in pre-mRNA splicing, histone regulation, and cell cycle.

===== [[Phosphatase_Subfamily_PPM1D|PPM1D]] (WIP1): oncogene in different cancer types =====
The PPM1D subfamily is an oncogene conserved from Monosiga to human. It regulates cell homeostasis in response to DNA damage. It dephosphorylates p53 and its various target kinases, such as ATM, Chk1 and Chk2. It also dephosphorylates p38/MAPK, tumor suppressors INK4A and ARF, RelA subunit of NF-kappaB, gamma-H2AX and etc. (PS: ATM and PPM1D have a significant overlap of their substrate proteins, -the same residues on a set of proteins, including p53, Mdm2, Chk2 and gamma-H2AX at least.)

===== [[Phosphatase_Subfamily_PPM1E|PPM1E]] (POXP): the phosphatases of CAMKs and PAK =====
The PPM1E subfamily is named after two human PPMs, [[Phosphatase_Gene_PPM1E|PPM1E]] (also known as [http://www.ncbi.nlm.nih.gov/gene/22843 POXP1, PP2CH, caMKN, CaMKP-N]) and [[Phosphatase_Gene_PPM1F|PPM1F]] (also known as [http://www.ncbi.nlm.nih.gov/gene/9647 POXP2, CAMKP, FEM-2, hFEM-2, CaMKPase]). The subfamily has a single copy in most non-vertebrates from Monosiga to ciona, and duplicated when vertebrates emerged. Both PPM1E and PPM1F dephosphorylate kinases CaMK2g and PAK, and PPM1E can also dephosphorylate CaMK4 (of different families from CaMK2g).

===== [[Phosphatase_Subfamily_PPM1H|PPM1H]] =====
The PPM1H subfamily is named after one of the three copies in human, PPM1H (URCC2, ARHCL1, NERPP-2C), PPM1J (PP2Cζ) and PPM1M (PP2Cη), which are expressed in distinct tissues. The PPM1H subfamily are conserved in animals from sponge to human. Usually, it is single-copy in invertebrates from sponge to ciona. The three copies are found in mammals probably arose by two independent duplication events (not whole-genome duplication).

===== [[Phosphatase_Subfamily_PPM1K|PPM1K]] (PP2Cκ, PP2Cm, BDP): mitochondrial phosphatase lost in ecdysozoa =====
The PPM1K subfamily is a mitochondrial phosphatase that regulates mitochondrial permeability transition pore (MPTP). It also dephosphorylates branched-chain alpha-ketoacid dehydrogenase complex. The PPM1K subfamily emerged in [[Phosphatase_Glossary#Holozoa|holozoan]] and lost in [[Phosphatase_Glossary#Ecdysozoa|ecdysozoa]].

===== [[Phosphatase_Subfamily_PPM1L|PPM1L]] (PP2Cε, PP2Ce) =====
Human PPM1L is an ER-anchored phosphatase, where it dephoshorylates ceramide transport protein (CERT). It also dephosphorylates two kinases TAK1 and ASK1. While PPM1L emerged in bilateria, all its known substrates emerged in holozoa or earlier.

===== [[Phosphatase_Subfamily_PTC7|PTC7]]: activating Q6 biosynthesis =====
The PTC7 subfamily is conserved through eukaryotes, dephosphorylates the mitochondrial hydroxylase COQ7 and activates coenzyme Q biosynthesis.

===== [[Phosphatase_Subfamily_PDPc|PDPc]]: the catalytic subunit of pyruvate dehyrogenase phosphatase =====
The PDPc subfamily is the catalytic subunit of Pyruvate Dehyrogenase Phosphatase (PDP). It is found throughout eukaryotes, so are Pyruvate Dehyrogenase Kinase (PDK) and its substrate Pyruvate Dehyrogenase Complex (PDC).

===== [[Phosphatase_Subfamily_ILKAP|ILKAP]] (PP2Cδ): a subunit of TAK1-TAB1 complex =====
integrin-linked kinase (ILK) associated phosphatase binds to ILK and specifically regulates one of its two substrates, Ser-9 on glycogen synthase kinase 3 β (GSK3β). It also dephosphorylates p90 ribosomal S6 kinase 2 (RSK2) at multiple serine or threonine sites in the nuclear. All the three, ILKAP, ILK and RSK2, emerged in [[Phosphatase_Glossary#Holozoa|holozoa]], but ILKAP was lost in arthropods, while ILK and RSK2 were not.

===== [[Phosphatase_Subfamily_PHLPP|PHLPP]]: AGC kinase phosphatase =====
The subfamily is characterized by PH domain and Leucine rich repeats. It dephosphorylates AKT/PKB, PKC and S6 kinase families of AGC kinase group at serines in hydrophobic motif site. The subfamily is found across bilateria.

===== [[Phosphatase_Subfamily_TAB1|TAB1]]: binding to TAK1 and p38 and inducing their autophosphorylation =====
The TAB1 subfamily is most well known for its binding to MAPKs TAK1 and p38. It does not dephosphorylate them. Instead, it binds to them and induces their autophosphorylation. It is found in metazoa except Drosophila. It is found in most other arthropods, which indicates a lineage-specific gene loss in Drosophila. Interestingly, TAK1 and p38 are found in Drosophila and both of them emerged earlier, in holozoa and opisthokont, respectively.

===== [[Phosphatase_Subfamily_PP2D1|PP2D1]] =====
The function of the PP2D1 subfamily is unknown. It is found across the eumetazoa, but frequently lost, including from C. elegans, Drosophila and zebrafish. It has an N-terminal predicted nuclear localization signaling (NLS).

===== [[Phosphatase_Subfamily_CG9801|CG9801]] =====
The CG9801 subfamily found in metazoa but lost in deuterostomes. Its function is unknown.

===== [[Phosphatase_Subfamily_PPM1Z|PPM1Z]]: a phosphatase lost in vertebrates =====
The function of this subfamily is unclear. It emerged in holozoa or metazoa through the duplication of its common ancestral gene with PPM1A.

===== [[Phosphatase_Subfamily_LRR-PPM|LRR-PPM]] =====
The LRR-PPM subfamily has a combination of leucine riches repeats (LRRs) and PPM phosphatase domain. It is found in Amoebozoa. It does not have any clear orthology to the other LRR-PPM family, [[Phosphatase_Subfamily_PHLPP|PHLPP]]

===== [[Phosphatase_Subfamily_KAPP-like|KAPP-like]] =====
The subfamily is similar to the plant PPM phosphatase KAPP (see [http://www.ncbi.nlm.nih.gov/gene/832048]), a regulator of the receptor-like kinase (RLK) signaling pathway. Plant RLKs are counterpart of animal receptor kinases. This subfamily is found in Dictyostelids and lacks the FHA domain found in plant KAPPs.

=== Unclassified phosphatases ===
Below are unclassified phosphatases of PPM family, the functions of which have been known.

* Budding yeast [[Phosphatase_Gene_PTC1|PTC1]]. Its functions have been reviewed in <cite> Arino11, Sharmin14 </cite>. PTC1 is found in most fungi (see our [http://resdev.gene.com/gOrtholog/view/cluster/MC0007538/overview internal data]).

* Budding yeast [[Phosphatase_Gene_PTC6|PTC6]] is found in a broad of fungi. In budding yeast, Ptp6p locates both in the intermembrane and mitochondria. Along with Ptc5p, it regulates the phosphorylation state of Pda1p, the E1alpha subunit of the pyruvate dehydrogenase (PDH). PTC6 and PTC5 (of [[Phosphatase_Subfamily_PDPc|PDPc subfamily]] share a large overlap of phenotypes, but they may have distinct molecular functions <cite> Arino11 </cite>.

* Budding yeast [[Phosphatase_Gene_CYR1|CYR1]] encodes adenylate cyclase in budding yeast. The protein has a domain combination of 1) Adenylate cyclase G-alpha binding domain, 2) Ubiquitin domain CYR1 adenylate cyclase, 3) Leucine repeats, 4) PPM phosphatase domain, and 5) cyclase homology domain. CYR1 is found in most fungi including both Ascomycota and Basidiomycota (also by BLAST NR database and [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Search&term=18511290 Newton's review]). CYR1 is close to PHLPP in phosphatase domain sequence, but they have distinct domain structure and molecular function.

* Dictyostelium [[Phosphatase_Gene_spnA|spnA]] has two domains, Galpha subunit family of GTP binding proteins at N-terminal, and PPM phosphatase domain at C-terminal. It functions cell autonomously for prestalk differentiation, and cell non-autonomously for prespore differentiation (see summary from [http://dictybase.org/gene/DDB_G0276155 DictyBase]).

=== Phosphatase domain structure ===
The PPM phosphatase domain (PD) has a central β sandwich, flanked by helices. The catalytic core locates at the cleft between the two β sheets. The dephosphorylation reaction is mediated by two or three metal ions located at the base of the cleft (reviewed in <cite>Shi09</cite>). Both of the two β sheets are anti-parallel.

The PPM PDs have largely the same secondary structure combination, E1, E2, E3, H1, H2, E4, E5, E6, E7, H3, E8, E9, H4, H5, H6, E10. The E1, E10, E9, E6, E7 forms one of the anti-parallel beta sheet; the E2, E3, E4, E5, E8 forms another anti-parallel beta sheet.

Based upon the structure-based sequence alignment, there are 7 conserved motifs:
* M1: ED at E2
* M2: VxDG at E3
* M3: GxT at E4
* M4: GDS between E5 and E6
* M5: RxxG at eukaryotic flap
* M6: DG at H4
* M7: DN at E10

The motifs carry the residues coordinate the metal ions mediated the reaction, which are:
* R and D at M1
* D and G at M2
* D at M4
* D at M7

The available structures of PPM PDs show diversity in the regions beyond catalytic core. For instance, the region of H1 and H2 has the helices of different numbers and lengths. The so-called flap region is different in eukaryotes and prokaryotes.

Note:
* A few PPMs (e.g. PPM1A) have an additional N-terminal beta strand (E1'). PPM1A has three helices at C termini. Because these SS elements are not conserved across PPM PDs, we do not include them as part of PPM PD.
* The flag is a surface loop close to the active site was shown to play an important role in regulating substrate access to the catalytic center.
* D of M6 coordinate the third metal is required for activity as shown by D to A substitution <cite>Su11</cite>.

=== References ===
<biblio>
#Arino11 pmid=21076010
#Sharmin14 pmid=25088474
#Shi09 pmid=19879837
#Su11 pmid=21310952
#Tanoue13 pmid=23906386
</biblio>

Phosphatase Subfamily PPM1D

2017-07-24T16:49:11Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]: [[Phosphatase_Subfamily_PPM1D|Subfamily PPM1D]] (WIP1)

PPM1D (WIP1) negatively regulates the DNA damage response through dephosphorylation of ATM/ATR and their substrates, and is implicated in cancer.

=== Evolution ===
The PPM1D (WIP1) subfamily most likely emerged in holozoa. It is single copy in most genomes, including human. See [http://resdev.gene.com/gOrtholog/view/cluster/MC0005181/overview internal gOrtholog database].

=== Domain ===
PPM1D has an N-terminal PPM phosphatase domain, typically followed by an unconserved C-terminal region of similar length.

=== Function ===

===== Cancer =====
Consistent with its moleuclar function (see below), human PPM1D is implicated in different cancer types <cite>Emelyanov14</cite>:
* PPM1D promotes progression and invasion of aggressive medulloblastoma variants, crosstalking with CXCR5 and GRK5 <cite>Buss15</cite>.
* PPM1D is highly expressed in non-small-cell lung cancer (NSCLC)<cite>Fu14</cite>. Truncating mutations at exon 6 of PPM1D were found in blood DNA of NSCLC, which suggests that it could be used as a biomarker for NSCLC <cite> Zajkowicz15</cite>.
* PPM1D regulates the proliferation and invasiveness of nasopharyngeal carcinoma (NPC) cells in vitro <cite>Zhang14b</cite>.
* PPM1D is a frequent target of somatic mutation in brainstem gliomas <cite>Zhang14a</cite>.

Several inhibitors target PPM1D to suppress cancer (e.g. <cite>Ogasawara15</cite>).

===== Cell cell checkpoint and DNA damage response =====
Human PPM1D is also known as Wild-type p53-induced phosphatase 1 (WIP1). It functions as a negative regulator of several tumor suppressor genes and as a modulator of the epigenetic state of the genome <cite>Filipponi13</cite>. It plays a key role in the DNA damage response (DDR), by dephosphorylating multiple proteins in the DDR and cell cycle checkpoint pathways, including ATM, p53, Chk1, Chk2, Mdm2, Mdm4 and p38 MAPK <cite>Emelyanov14</cite>.

===== Other functions =====
PPM1D is highly expressed in haematopoietic stem cells (HSC) but decreases with age, and WIP1-deficient (Wip1-/-) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity <cite>Chen15</cite>.

PPM1D (WIP1) controls antigen-independent B cell development in a p53-dependent manner <cite>Yi15</cite>.

PPM1D negatively regulates neutrophil migration and inflammation, probably through more than one signaling pathways, such as p38 MAPK and NF-κB <cite>Sun14</cite>.

Human PPM1D (WIP1) positively modulates the Hedgehog pathway by enhancing transcription factor GLI1 function, in a manner dependent on its phosphatase activity, but no direct evidence has shown PPM1D dephosphorylates GLI1 <cite>Pandolfi13</cite>.

=== References ===
<biblio>
#Buss15 pmid=24632620
#Chen15 pmid=25879755
#Emelyanov14 pmid=25381821
#Filipponi13 pmid=24135283
#Fu14 pmid=24272082
#Ogasawara15 pmid=26358280
#Pandolfi13 pmid=23146903
#Sun14 pmid=24395919
#Yi15 pmid=26012568
#Zajkowicz15 pmid=25742468
#Zhang14a pmid=24880341
#Zhang14b pmid=24801909
</biblio>

Phosphatase Subfamily PPM1D

2017-07-24T16:49:03Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM]]: [[Phosphatase_Family_PPM|Family PPM]]: [[Phosphatase_Subfamily_PPM1D|Subfamily PPM1D]] (WIP1)

PPM1D (WIP1) negatively regulates the DNA damage response through dephosphorylation of ATM/ATR and their substrates, and is implicated in cancer.

=== Evolution ===
The PPM1D (WIP1) subfamily most likely emerged in holozoa. It is single copy in most genomes, including human. See [http://resdev.gene.com/gOrtholog/view/cluster/MC0005181/overview internal gOrtholog database].

=== Domain ===
PPM1D has an N-terminal PPM phosphatase domain, typically followed by an unconserved C-terminal region of similar length.

=== Function ===

===== Cancer =====
Consistent with its moleuclar function (see below), human PPM1D is implicated in different cancer types <cite>Emelyanov14</cite>:
* PPM1D promotes progression and invasion of aggressive medulloblastoma variants, crosstalking with CXCR5 and GRK5 <cite>Buss15</cite>.
* PPM1D is highly expressed in non-small-cell lung cancer (NSCLC)<cite>Fu14</cite>. Truncating mutations at exon 6 of PPM1D were found in blood DNA of NSCLC, which suggests that it could be used as a biomarker for NSCLC <cite> Zajkowicz15</cite>.
* PPM1D regulates the proliferation and invasiveness of nasopharyngeal carcinoma (NPC) cells in vitro <cite>Zhang14b</cite>.
* PPM1D is a frequent target of somatic mutation in brainstem gliomas <cite>Zhang14a</cite>.

Several inhibitors target PPM1D to suppress cancer (e.g. <cite>Ogasawara15</cite>).

===== Cell cell checkpoint and DNA damage response =====
Human PPM1D is also known as Wild-type p53-induced phosphatase 1 (WIP1). It functions as a negative regulator of several tumor suppressor genes and as a modulator of the epigenetic state of the genome <cite>Filipponi13</cite>. It plays a key role in the DNA damage response (DDR), by dephosphorylating multiple proteins in the DDR and cell cycle checkpoint pathways, including ATM, p53, Chk1, Chk2, Mdm2, Mdm4 and p38 MAPK <cite>Emelyanov14</cite>.

===== Other functions =====
PPM1D is highly expressed in haematopoietic stem cells (HSC) but decreases with age, and WIP1-deficient (Wip1-/-) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity <cite>Chen15</cite>.

PPM1D (WIP1) controls antigen-independent B cell development in a p53-dependent manner <cite>Yi15</cite>.

PPM1D negatively regulates neutrophil migration and inflammation, probably through more than one signaling pathways, such as p38 MAPK and NF-κB <cite>Sun14</cite>.

Human PPM1D (WIP1) positively modulates the Hedgehog pathway by enhancing transcription factor GLI1 function, in a manner dependent on its phosphatase activity, but no direct evidence has shown PPM1D dephosphorylates GLI1 <cite>Pandolfi13</cite>.

=== References ===
<biblio>
#Buss15 pmid=24632620
#Chen15 pmid=25879755
#Emelyanov14 pmid=25381821
#Filipponi13 pmid=24135283
#Fu14 pmid=24272082
#Ogasawara15 pmid=26358280
#Pandolfi13 pmid=23146903
#Sun14 pmid=24395919
#Yi15 pmid=26012568
#Zajkowicz15 pmid=25742468
#Zhang14a pmid=24880341
#Zhang14b pmid=24801909
</biblio>

Phosphatase Subfamily PPM1D

2017-07-24T16:48:28Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PPM1D|Subfamily PPM1D]] (WIP1)

PPM1D (WIP1) negatively regulates the DNA damage response through dephosphorylation of ATM/ATR and their substrates, and is implicated in cancer.

=== Evolution ===
The PPM1D (WIP1) subfamily most likely emerged in holozoa. It is single copy in most genomes, including human. See [http://resdev.gene.com/gOrtholog/view/cluster/MC0005181/overview internal gOrtholog database].

=== Domain ===
PPM1D has an N-terminal PPM phosphatase domain, typically followed by an unconserved C-terminal region of similar length.

=== Function ===

===== Cancer =====
Consistent with its moleuclar function (see below), human PPM1D is implicated in different cancer types <cite>Emelyanov14</cite>:
* PPM1D promotes progression and invasion of aggressive medulloblastoma variants, crosstalking with CXCR5 and GRK5 <cite>Buss15</cite>.
* PPM1D is highly expressed in non-small-cell lung cancer (NSCLC)<cite>Fu14</cite>. Truncating mutations at exon 6 of PPM1D were found in blood DNA of NSCLC, which suggests that it could be used as a biomarker for NSCLC <cite> Zajkowicz15</cite>.
* PPM1D regulates the proliferation and invasiveness of nasopharyngeal carcinoma (NPC) cells in vitro <cite>Zhang14b</cite>.
* PPM1D is a frequent target of somatic mutation in brainstem gliomas <cite>Zhang14a</cite>.

Several inhibitors target PPM1D to suppress cancer (e.g. <cite>Ogasawara15</cite>).

===== Cell cell checkpoint and DNA damage response =====
Human PPM1D is also known as Wild-type p53-induced phosphatase 1 (WIP1). It functions as a negative regulator of several tumor suppressor genes and as a modulator of the epigenetic state of the genome <cite>Filipponi13</cite>. It plays a key role in the DNA damage response (DDR), by dephosphorylating multiple proteins in the DDR and cell cycle checkpoint pathways, including ATM, p53, Chk1, Chk2, Mdm2, Mdm4 and p38 MAPK <cite>Emelyanov14</cite>.

===== Other functions =====
PPM1D is highly expressed in haematopoietic stem cells (HSC) but decreases with age, and WIP1-deficient (Wip1-/-) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity <cite>Chen15</cite>.

PPM1D (WIP1) controls antigen-independent B cell development in a p53-dependent manner <cite>Yi15</cite>.

PPM1D negatively regulates neutrophil migration and inflammation, probably through more than one signaling pathways, such as p38 MAPK and NF-κB <cite>Sun14</cite>.

Human PPM1D (WIP1) positively modulates the Hedgehog pathway by enhancing transcription factor GLI1 function, in a manner dependent on its phosphatase activity, but no direct evidence has shown PPM1D dephosphorylates GLI1 <cite>Pandolfi13</cite>.

=== References ===
<biblio>
#Buss15 pmid=24632620
#Chen15 pmid=25879755
#Emelyanov14 pmid=25381821
#Filipponi13 pmid=24135283
#Fu14 pmid=24272082
#Ogasawara15 pmid=26358280
#Pandolfi13 pmid=23146903
#Sun14 pmid=24395919
#Yi15 pmid=26012568
#Zajkowicz15 pmid=25742468
#Zhang14a pmid=24880341
#Zhang14b pmid=24801909
</biblio>

Phosphatase Subfamily PPM1D

2017-07-24T16:46:59Z

Gerard: /* Domain */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PPM1D|Subfamily PPM1D]] (WIP1)

=== Evolution ===
The PPM1D (WIP1) subfamily most likely emerged in holozoa. It is single copy in most genomes, including human. See [http://resdev.gene.com/gOrtholog/view/cluster/MC0005181/overview internal gOrtholog database].

=== Domain ===
PPM1D has an N-terminal PPM phosphatase domain, typically followed by an unconserved C-terminal region of similar length.

=== Function ===

===== Cancer =====
Consistent with its moleuclar function (see below), human PPM1D is implicated in different cancer types <cite>Emelyanov14</cite>:
* PPM1D promotes progression and invasion of aggressive medulloblastoma variants, crosstalking with CXCR5 and GRK5 <cite>Buss15</cite>.
* PPM1D is highly expressed in non-small-cell lung cancer (NSCLC)<cite>Fu14</cite>. Truncating mutations at exon 6 of PPM1D were found in blood DNA of NSCLC, which suggests that it could be used as a biomarker for NSCLC <cite> Zajkowicz15</cite>.
* PPM1D regulates the proliferation and invasiveness of nasopharyngeal carcinoma (NPC) cells in vitro <cite>Zhang14b</cite>.
* PPM1D is a frequent target of somatic mutation in brainstem gliomas <cite>Zhang14a</cite>.

Several inhibitors target PPM1D to suppress cancer (e.g. <cite>Ogasawara15</cite>).

===== Cell cell checkpoint and DNA damage response =====
Human PPM1D is also known as Wild-type p53-induced phosphatase 1 (WIP1). It functions as a negative regulator of several tumor suppressor genes and as a modulator of the epigenetic state of the genome <cite>Filipponi13</cite>. It plays a key role in the DNA damage response (DDR), by dephosphorylating multiple proteins in the DDR and cell cycle checkpoint pathways, including ATM, p53, Chk1, Chk2, Mdm2, Mdm4 and p38 MAPK <cite>Emelyanov14</cite>.

===== Other functions =====
PPM1D is highly expressed in haematopoietic stem cells (HSC) but decreases with age, and WIP1-deficient (Wip1-/-) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity <cite>Chen15</cite>.

PPM1D (WIP1) controls antigen-independent B cell development in a p53-dependent manner <cite>Yi15</cite>.

PPM1D negatively regulates neutrophil migration and inflammation, probably through more than one signaling pathways, such as p38 MAPK and NF-κB <cite>Sun14</cite>.

Human PPM1D (WIP1) positively modulates the Hedgehog pathway by enhancing transcription factor GLI1 function, in a manner dependent on its phosphatase activity, but no direct evidence has shown PPM1D dephosphorylates GLI1 <cite>Pandolfi13</cite>.

=== References ===
<biblio>
#Buss15 pmid=24632620
#Chen15 pmid=25879755
#Emelyanov14 pmid=25381821
#Filipponi13 pmid=24135283
#Fu14 pmid=24272082
#Ogasawara15 pmid=26358280
#Pandolfi13 pmid=23146903
#Sun14 pmid=24395919
#Yi15 pmid=26012568
#Zajkowicz15 pmid=25742468
#Zhang14a pmid=24880341
#Zhang14b pmid=24801909
</biblio>

Phosphatase Subfamily PPM1D

2017-07-24T16:43:18Z

Gerard: /* Evolution */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PPM1D|Subfamily PPM1D]] (WIP1)

=== Evolution ===
The PPM1D (WIP1) subfamily most likely emerged in holozoa. It is single copy in most genomes, including human. See [http://resdev.gene.com/gOrtholog/view/cluster/MC0005181/overview internal gOrtholog database].

=== Domain ===
PPM1D has a single domain, the phosphatase domain of PPM (PP2C) fold.

=== Function ===

===== Cancer =====
Consistent with its moleuclar function (see below), human PPM1D is implicated in different cancer types <cite>Emelyanov14</cite>:
* PPM1D promotes progression and invasion of aggressive medulloblastoma variants, crosstalking with CXCR5 and GRK5 <cite>Buss15</cite>.
* PPM1D is highly expressed in non-small-cell lung cancer (NSCLC)<cite>Fu14</cite>. Truncating mutations at exon 6 of PPM1D were found in blood DNA of NSCLC, which suggests that it could be used as a biomarker for NSCLC <cite> Zajkowicz15</cite>.
* PPM1D regulates the proliferation and invasiveness of nasopharyngeal carcinoma (NPC) cells in vitro <cite>Zhang14b</cite>.
* PPM1D is a frequent target of somatic mutation in brainstem gliomas <cite>Zhang14a</cite>.

Several inhibitors target PPM1D to suppress cancer (e.g. <cite>Ogasawara15</cite>).

===== Cell cell checkpoint and DNA damage response =====
Human PPM1D is also known as Wild-type p53-induced phosphatase 1 (WIP1). It functions as a negative regulator of several tumor suppressor genes and as a modulator of the epigenetic state of the genome <cite>Filipponi13</cite>. It plays a key role in the DNA damage response (DDR), by dephosphorylating multiple proteins in the DDR and cell cycle checkpoint pathways, including ATM, p53, Chk1, Chk2, Mdm2, Mdm4 and p38 MAPK <cite>Emelyanov14</cite>.

===== Other functions =====
PPM1D is highly expressed in haematopoietic stem cells (HSC) but decreases with age, and WIP1-deficient (Wip1-/-) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity <cite>Chen15</cite>.

PPM1D (WIP1) controls antigen-independent B cell development in a p53-dependent manner <cite>Yi15</cite>.

PPM1D negatively regulates neutrophil migration and inflammation, probably through more than one signaling pathways, such as p38 MAPK and NF-κB <cite>Sun14</cite>.

Human PPM1D (WIP1) positively modulates the Hedgehog pathway by enhancing transcription factor GLI1 function, in a manner dependent on its phosphatase activity, but no direct evidence has shown PPM1D dephosphorylates GLI1 <cite>Pandolfi13</cite>.

=== References ===
<biblio>
#Buss15 pmid=24632620
#Chen15 pmid=25879755
#Emelyanov14 pmid=25381821
#Filipponi13 pmid=24135283
#Fu14 pmid=24272082
#Ogasawara15 pmid=26358280
#Pandolfi13 pmid=23146903
#Sun14 pmid=24395919
#Yi15 pmid=26012568
#Zajkowicz15 pmid=25742468
#Zhang14a pmid=24880341
#Zhang14b pmid=24801909
</biblio>

Phosphatase Subfamily PPM1D

2017-07-24T16:42:56Z

Gerard:

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PPM1D|Subfamily PPM1D]] (WIP1)

=== Evolution ===
The PPM1D (WIP1) subfamily most likely emerged in holozoa. It is single copy in most genomes, including human genome. See [http://resdev.gene.com/gOrtholog/view/cluster/MC0005181/overview internal gOrtholog database].

=== Domain ===
PPM1D has a single domain, the phosphatase domain of PPM (PP2C) fold.

=== Function ===

===== Cancer =====
Consistent with its moleuclar function (see below), human PPM1D is implicated in different cancer types <cite>Emelyanov14</cite>:
* PPM1D promotes progression and invasion of aggressive medulloblastoma variants, crosstalking with CXCR5 and GRK5 <cite>Buss15</cite>.
* PPM1D is highly expressed in non-small-cell lung cancer (NSCLC)<cite>Fu14</cite>. Truncating mutations at exon 6 of PPM1D were found in blood DNA of NSCLC, which suggests that it could be used as a biomarker for NSCLC <cite> Zajkowicz15</cite>.
* PPM1D regulates the proliferation and invasiveness of nasopharyngeal carcinoma (NPC) cells in vitro <cite>Zhang14b</cite>.
* PPM1D is a frequent target of somatic mutation in brainstem gliomas <cite>Zhang14a</cite>.

Several inhibitors target PPM1D to suppress cancer (e.g. <cite>Ogasawara15</cite>).

===== Cell cell checkpoint and DNA damage response =====
Human PPM1D is also known as Wild-type p53-induced phosphatase 1 (WIP1). It functions as a negative regulator of several tumor suppressor genes and as a modulator of the epigenetic state of the genome <cite>Filipponi13</cite>. It plays a key role in the DNA damage response (DDR), by dephosphorylating multiple proteins in the DDR and cell cycle checkpoint pathways, including ATM, p53, Chk1, Chk2, Mdm2, Mdm4 and p38 MAPK <cite>Emelyanov14</cite>.

===== Other functions =====
PPM1D is highly expressed in haematopoietic stem cells (HSC) but decreases with age, and WIP1-deficient (Wip1-/-) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity <cite>Chen15</cite>.

PPM1D (WIP1) controls antigen-independent B cell development in a p53-dependent manner <cite>Yi15</cite>.

PPM1D negatively regulates neutrophil migration and inflammation, probably through more than one signaling pathways, such as p38 MAPK and NF-κB <cite>Sun14</cite>.

Human PPM1D (WIP1) positively modulates the Hedgehog pathway by enhancing transcription factor GLI1 function, in a manner dependent on its phosphatase activity, but no direct evidence has shown PPM1D dephosphorylates GLI1 <cite>Pandolfi13</cite>.

=== References ===
<biblio>
#Buss15 pmid=24632620
#Chen15 pmid=25879755
#Emelyanov14 pmid=25381821
#Filipponi13 pmid=24135283
#Fu14 pmid=24272082
#Ogasawara15 pmid=26358280
#Pandolfi13 pmid=23146903
#Sun14 pmid=24395919
#Yi15 pmid=26012568
#Zajkowicz15 pmid=25742468
#Zhang14a pmid=24880341
#Zhang14b pmid=24801909
</biblio>

Phosphatase Subfamily PPM1D

2017-07-24T09:46:19Z

Gerard: /* Other functions */

[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPM|Fold PPM (PP2C)]]: [[Phosphatase_Superfamily_PPM|Superfamily PPM (PP2C)]]: [[Phosphatase_Family_PPM|Family PPM (PP2C)]]: [[Phosphatase_Subfamily_PPM1D|Subfamily PPM1D]] (WIP1)

=== Evolution ===
The PPM1D (WIP1) subfamily most likely emerged in holozoa. It is single copy in most genomes, including human genome. See [http://resdev.gene.com/gOrtholog/view/cluster/MC0005181/overview internal gOrtholog database].

=== Domain ===
PPM1D has a single domain, the phosphatase domain of PPM (PP2C) fold.

=== Function ===

===== Cancer =====
Consistent with its moleuclar function (see below), human PPM1D is implicated in different cancer types <cite>Emelyanov14</cite>:
* PPM1D promotes progression and invasion of aggressive medulloblastoma variants, crosstalking with CXCR5 and GRK5 <cite>Buss15</cite>.
* PPM1D is highly expressed in non-small-cell lung cancer (NSCLC)<cite>Fu14</cite>. Truncating mutations at exon 6 of PPM1D were found in blood DNA of NSCLC, which suggests that it could be used as a biomarker for NSCLC <cite> Zajkowicz15</cite>.
* PPM1D regulates the proliferation and invasiveness of nasopharyngeal carcinoma (NPC) cells in vitro <cite>Zhang14b</cite>.
* PPM1D is a frequent target of somatic mutation in brainstem gliomas <cite>Zhang14a</cite>.

Several inhibitors target PPM1D to suppress cancer (e.g. <cite>Ogasawara15</cite>).

===== Cell cell checkpoint and DNA damage response =====
Human PPM1D is also known as Wild-type p53-induced phosphatase 1 (WIP1). It functions as a negative regulator of several tumor suppressor genes and as a modulator of the epigenetic state of the genome <cite>Filipponi13</cite>. It plays a key role in the DNA damage response (DDR), by dephosphorylating multiple proteins in the DDR and cell cycle checkpoint pathways, including ATM, p53, Chk1, Chk2, Mdm2, Mdm4 and p38 MAPK <cite>Emelyanov14</cite>.

===== Other functions =====
PPM1D is highly expressed in haematopoietic stem cells (HSC) but decreases with age, and WIP1-deficient (Wip1-/-) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity <cite>Chen15</cite>.

PPM1D (WIP1) controls antigen-independent B cell development in a p53-dependent manner <cite>Yi15</cite>.

PPM1D negatively regulates neutrophil migration and inflammation, probably through more than one signaling pathways, such as p38 MAPK and NF-κB <cite>Sun14</cite>.

Human PPM1D (WIP1) positively modulates the Hedgehog pathway by enhancing transcription factor GLI1 function, in a manner dependent on its phosphatase activity, but no direct evidence has shown PPM1D dephosphorylates GLI1 <cite>Pandolfi13</cite>.

=== References ===
<biblio>
#Buss15 pmid=24632620
#Chen15 pmid=25879755
#Emelyanov14 pmid=25381821
#Filipponi13 pmid=24135283
#Fu14 pmid=24272082
#Ogasawara15 pmid=26358280
#Pandolfi13 pmid=23146903
#Sun14 pmid=24395919
#Yi15 pmid=26012568
#Zajkowicz15 pmid=25742468
#Zhang14a pmid=24880341
#Zhang14b pmid=24801909
</biblio>