Difference between revisions of "Phosphatase Family DSP"

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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]:  [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]
 
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]:  [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]
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__NOTOC__
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This family consists of the dual-specific protein phosphatases (DSPs) that dephosphorylate both tyrosine and serine/threonine, as well as related non-protein phosphatases.
  
This family consists of the dual-specific protein phosphatases (DSPs) that dephosphorylate both tyrosine and serine/threonine, as well as related non-protein phosphatases. Based upon sequence similarity, domain combination and known functions, the subfamilies of DSP can be grouped as below.
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== Subfamilies ==
  
__TOC__
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=== 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>.
  
==== MAP Kinase Phosphatase (MKP)  ====
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===== [[Phosphatase_Subfamily_DSP1|DSP1]] =====
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.. As implied by its name, MKP is involved in [http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase#Signalling_cascades MAPK signaling cascades]. The Rhodanese domains are regulatory and targeting, and include kinase-interacting motifs (KIMs) for MAPK binding <cite>keyse06</cite>.  
+
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_DSP1|DSP1 subfamily]] =====
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===== [[Phosphatase_Subfamily_DSP6|DSP6]] =====
The subfamily is also known as inducible nuclear MKPs, which has four members in human, DUSP1 (MKP-1), DUSP2 (PAC-1), DUSP4 (MKP-2) and DUSP5 (hVH3). The subfamily is found in animals, plants, amoeba, and a few basal eukaryotes, but is absent from ecdysozoa (nematode and arthropoda), most fungi and monosiga (unpublished data, [http://resdev.gene.com/gOrtholog/view/cluster/MC0008107/overview DUSP1], [http://resdev.gene.com/gOrtholog/view/cluster/MC0013833/overview DUSP2], [http://resdev.gene.com/gOrtholog/view/cluster/MC0006670/overview DUSP4], [http://resdev.gene.com/gOrtholog/view/cluster/MC0008873/overview DUSP5]).
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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_DSP6|DSP6 subfamily]] =====
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===== [[Phosphatase_Subfamily_DSP8|DSP8]] =====
These are cytoplasmic ERK-specific MKPs, with three human members, DUSP6 (MKP-3), DUSP7 (MKP-X) and DUSP9 (MKP-4). The subfamily is found throughout [[metazoa]].
+
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_DSP8|DSP8 subfamily]] =====
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===== [[Phosphatase_Subfamily_DSP10|DSP10]] =====
Jnk/p38-selective MKPs, with two members in human, DUSP8 (hVH5) and DUSP16 (MKP-7). Found in [[metazoa]] other than arthropods.
+
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_DSP10|DSP10 subfamily]] =====
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===== [[Phosphatase_Subfamily_STYXL1|STYXL1]] =====
The only member in human is DSP10 (MKP5). Similar to DSP8 subfamily, it is supposed to be JNK/p38 selective. It is found in most [[metazoa]] except nematodes.
+
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.
  
===== [[Phosphatase_Subfamily_STYXL1|STYXL1 subfamily]] =====
 
STYXL1 subfamily is pseudophosphatase (catalytically inactive). It has a single member in human, STYXL1 (MK-STYX). It is found in [[metazoa]] but lost in [[ecdysozoa]] (arthropoda and nematoda).
 
  
==== ''Atypical'' DSPs that may act as MKPs ====
 
Here, ''Atypical'' generally means these DSPs lack rhodanese domain found in MKPs. Some of these ''Atypical'' DSPs are MAPK phosphatases, and may have other substrates.
 
  
===== [[Phosphatase_Subfamily_DSP3|DSP3 subfamily]] =====
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===Likely MKPs without a Rhondanese Domain===
  
===== [[Phosphatase_Subfamily_DSP14|DSP14 subfamily]] =====
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===== [[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.
  
DSP14 subfamily has four members in human, DUSP14, DUSP18, DUSP21, DUSP28. It is found in eumetazoa.
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===== [[Phosphatase_Subfamily_DSP14|DSP14]] =====
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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 subfamily]] =====
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===== [[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.
  
DSP15 subfamily has two members in human, DUSP15 and DUSP22. The subfamily is characterized by a N-terminal myristoylation site. It is found throughout [[metazoa]] ([http://resdev.gene.com/gOrtholog/view/cluster/MC0002932/overview see gOrtholog]).
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===== [[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_DSP19|DSP19 subfamily]] =====
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===== [[Phosphatase_Subfamily_STYX|STYX]] =====
 +
The STYX subfamily of catalytically inactive phosphatases found in most opisthokonts but lost in nematodes.
  
DSP19 subfamily has a single member in human DUSP19 (SKRP1). It is found in most eukaryotes except fungi ([http://resdev.gene.com/gOrtholog/view/cluster/MC0004288/overview unpublished data from gOrtholog]). DUSP19 appears to play a specific role in the regulation of jun-kinase (JNK) signaling; however, the precise mechanism by which it regulates this pathway remains controversial.
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===== [[Phosphatase_Subfamily_DSP23|DSP23]] =====
 +
Human DUSP23 is a nuclear phosphatase found in metazoa but lost in ecdysozoa.
  
===== [[Phosphatase_Subfamily_STYX|STYX subfamily]] =====
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===Cyclin-dependent kinase phosphatases===
  
A pseudophosphatase subfamily with a single human member. STYX localizes to the nucleus, competes with DUSP4 for binding to ERK, and acts as a nuclear anchor that regulates ERK nuclear export <cite>farhan13</cite>. The subfamily is found in most opisthokonts but lost in nematodes. Although It is not found in Drosophila and budding yeast, it is found in other arthropoda and fungi ([http://resdev.gene.com/gOrtholog/view/cluster/MC0005385/overview unpublished data from gOrtholog]).
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===== [[Phosphatase_Subfamily_CDC14|CDC14]] =====
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CDC14 is a cell cycle phosphatase found in most eukaryotes other than higher plants.
  
===== [[Phosphatase_Subfamily_DSP23|DSP23 subfamily]] =====
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===== [[Phosphatase_Subfamily_CDKN3|CDKN3]] =====
 +
CDKN3 (KAP) is a chordate-specific phosphatase targeting Cyclin-dependent kinases (CDKs) CDK1 and CDK2.
  
DSP23 subfamily has a single member in human, DUSP23. It is found in metazoan but lost in nematodes and most arthropods ([http://resdev.gene.com/gOrtholog/view/cluster/MC0006453/overview unpublished data from gOrtholog]). Its physiological substrate is unclear.
 
  
==== Other ''atypical'' DSPs ====
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===DSPs with non-protein substrates===
  
===== [[Phosphatase_Subfamily_DSP12|DSP12 subfamily]] =====
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===== [[Phosphatase_Subfamily_DSP12|DSP12]] =====
The subfamily is conserved throughout unikonts and usually a single copy in each genome. The human DUSP12 is localized primarily in the nucleus and is involved in glucokinase regulation. The yeast ortholog [http://www.yeastgenome.org/cgi-bin/locus.fpl?locus=YIR026c YHV1] is a tyrosine-specific protein phosphatase associates with pre-60S ribosome.
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The DSP12 subfamily is found throughout unikonts, with suggested roles in fat and glucose metabolism, MAPK regulation, ribosome biogenesis and cell cycle progression.
  
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===== [[Phosphatase_Subfamily_RNGTT|RNGTT]] =====
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The RNGTT subfamily is an mRNA capping enzyme found in [[holozoa]]. It has a phosphatase domain and guanylyltransferase.
  
===== [[Phosphatase_Subfamily_RNGTT|RNGTT subfamily]] =====
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===== [[Phosphatase_Subfamily_DSP11|DSP11]] =====
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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).
  
RNGTT is RNA guanylyltransferase and 5'-phosphatase. Besides phosphatase domain, it has mRNA capping enzyme domain. It is ubiquitous in eukaryotes and usually there is a single copy in each organism ([http://resdev.gene.com/gOrtholog/view/cluster/MC0005385/overview unpublished data from gOrtholog]).
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===== [[Phosphatase_Subfamily_Laforin|Laforin]] =====
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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_DSP11|DSP11 subfamily]] =====
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===== [[Phosphatase_Subfamily_PTPMT1|PTPMT1]] =====
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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.
  
DSP subfamily has a single member in human, DUSP11 (PIR1). Its exact physiological substrate is unknown, but several lines of evidence link this phosphatase to RNA splicing. This is not surprising given that it is close to another ''atypical'' DSP, RNGTT, RNA guanylyltransferase and 5'-phosphatase. DSP11 subfamily is found through metazoan ([http://resdev.gene.com/gOrtholog/view/cluster/MC0004984/overview unpublished data from gOrtholog]).
 
  
===== [[Phosphatase_Subfamily_Laforin|Laforin subfamily]] =====
 
Laforin is a glucan phosphatase, found in vertebrates and scattered other species. It has a single human member, EPM2A, mutations of which have been associated with myoclonic epilepsy of [http://en.wikipedia.org/wiki/Lafora_disease Lafora].
 
  
===== [[Phosphatase_Subfamily_PTPMT1|PTPMT1 subfamily]] =====
 
PTPMT1 is a mitochondrial non-protein phosphatase that converts phosphatidylglycerolphosphate (PGP) to phosphatidylglycerol, during ''de novo'' 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.
 
  
==== PRL ====
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===Other subfamilies found in human===
  
===== [[Phosphatase_Subfamily_PRL|PRL subfamily]] =====
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===== [[Phosphatase_Subfamily_PTPDC1|PTPDC1]] =====
PRL is short for Phosphatases of Regenerating Liver. There are three PRLs in human, PRL1, PRL2, PRL3, all of which have been identified as key contributors to metastasis in several human cancers. PRL 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 unpublish data from gOrtholog]).  [[Subfamily_PRL|Read more]].
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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]] =====
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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.
  
==== CDK phosphatases ====
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===== [[Phosphatase_Subfamily_Slingshot|Slingshot]] =====
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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.
  
The subfamilies below are known as or supposed to be cyclin-dependent kinase phosphatase.
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=== Non-human subfamilies and unclassified DSPs ===
  
===== [[Phosphatase_Subfamily_CDC14|CDC14 subfamily]] =====
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===== ''Dictyostelium [[Phosphatase_Gene_dupA|dupA]]'' =====
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''Dictyostelium DupA'' has an active kinase domain and an inactive phosphatase domain. The cysteine at CX<sub>5</sub>R 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>.
  
CDC14 subfamily is found throughout eukaryotes ([http://resdev.gene.com/gOrtholog/view/cluster/MC0000760/overview unpublished data from gOrtholog]), but may have different functions <cite>schiebel10</cite>. It has three copies in human, CDC14A, CDC14B and CDC14C.
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===== ''Dictyostelium'' LRR-DSP =====
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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_Subfamily_CDKN3|CDKN3 subfamily]] =====
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== Phosphatase domain structures ==
CDKN3 subfamily is found in vertebrates, usually one copy per organism. Human CDKN3 inhibits cyclin-dependent kinase (CDK) by interacting with and dephosphorylating CDK2 kinase.
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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.
  
===== [[Phosphatase_Subfamily_PTPDC1|PTPDC1 subfamily]] =====
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DSPs have dramatic diversity in structure, although they generally share the same SS combination, especially at the following two regions:
PTPDC1 (aka PTP9Q22) is found in [[holozoa]] and excavata. It is absent from most of arthropoda. It is function is unclear. Human PTPDC1 has a C-terminal region to the predicted phosphatase catalytic domain.
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* 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.
  
==== Slingshot ====
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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.
  
===== [[Phosphatase_Subfamily_Slingshot|Slingshot subfamily]] =====
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Technical notes: the SS elements were annotated by using the program Stride to infer SS from PDB files.
  
Slingshot subfamily consists for three genes in human, SSH1, SSH2, SSH3. Slingshot phosphatases dephosphorylates [http://en.wikipedia.org/wiki/Actin-Depolymerizing_Factor ADF] and [http://en.wikipedia.org/wiki/Cofilin cofilin], and thus suppresses actin filament assembly induced by the kinases TESK1 (testis-specific kinase 1) and LIMK1 (LIM domain kinase 1). Slingshots are seen throughout the [[holozoa]]).
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== 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>

Latest revision as of 19:26, 12 September 2018

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP

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 MAPK Kinases and share an N-terminal non-catalytic rhodanese domain. These are named MKP, (MAP Kinase Phosphatase). 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 [1, 2]). The rhodanese domains usually contain kinase-interacting motifs (KIMs) for MAPK binding [1].

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.

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).

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.

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.

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 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

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.

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.

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.

DSP19

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

STYX

The STYX subfamily of catalytically inactive phosphatases found in most opisthokonts but lost in nematodes.

DSP23

Human DUSP23 is a nuclear phosphatase found in metazoa but lost in ecdysozoa.

Cyclin-dependent kinase phosphatases

CDC14

CDC14 is a cell cycle phosphatase found in most eukaryotes other than higher plants.

CDKN3

CDKN3 (KAP) is a chordate-specific phosphatase targeting Cyclin-dependent kinases (CDKs) CDK1 and CDK2.


DSPs with non-protein substrates

DSP12

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

RNGTT

The RNGTT subfamily is an mRNA capping enzyme found in holozoa. It has a phosphatase domain and guanylyltransferase.

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).

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 Lafora.

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

PTPDC1

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

PRL

The PRL (PTP4A) subfamily is present in animals, amoeba, and many basal eukaryotes, but is absent from fungi and plants (unpublished data from gOrtholog). The three human members, PRL1, PRL2, PRL3, have all been linked to cancer metastasis.

Slingshot

The slingshot subfamily is conserved in holozoa but lost in nematodes, regulates cofilin phosphorylation in opposition to LIMK and TESK kinases.

Non-human subfamilies and unclassified DSPs

Dictyostelium 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 [3].

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 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

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  2. Caunt CJ and Keyse SM. Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J. 2013 Jan;280(2):489-504. DOI:10.1111/j.1742-4658.2012.08716.x | PubMed ID:22812510 | HubMed [Caunt13]
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