Phosphatase Subfamily PTPN6

2017-01-07T20:36:24Z

Mark: /* PTPN11/SHP2 */

Phosphatase Subfamily PTPRB

2017-01-06T14:13:58Z

Mark: /* References */

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

PTPRB (aka R3) is a metazoan-specific subfamily of receptor PTPs, with diverse functions.

===Evolution===
PTPRB is found across metazoa, often with multiple members per species. Human members are PTPRB, PTPRH, PTPRJ, PTPRO, and PTPRQ, while C. elegans has a single gene, dep-1 and Drosophila has two: PTP4E and PTP10D.

===Domain Structure===
The canonical domain structure is multiple fibronectin type III (Fn3) domains in the extracellular region and a single cytoplasmic phosphatase domain. Human PTPRQ also encodes a cytoplasmic isoform lacking the extracellular region, due to alternative promoter usage <cite>Seifert03</cite>.

===Functions===
PTPRB from multiple species antagonizes EGFR signaling, in Drosophila tracheal development <cite>Jeon</cite>, in C. elegans vulval development <cite>Berset05</cite>, and PTPRJ in mammalian cell assays <cite>Tarcic09</cite>, and multiple members dephosphorylate the insulin receptor <cite>Shintani15</cite>.

Human PTPRB genes have varied functions, and are selectively expressed in different cell types and/or tissues and have different substrates or binding partners. They function in various tissues, such as nervous system and immune system. They are also putative tumor suppressors. They share common features, including localization at cell-cell contact sites, and involved in cell proliferation and transformation.

====== PTPRB (VE-PTP) ======
PTPRB, a.k.a. vascular endothelial protein tyrosine phosphatase (VE-PTP), is expressed specifically in endothelial cells and regulates the spreading and migration of endothelial cells during angiogenesis <cite>Mori10</cite>.
PTPRB binds to vascular E-cadherin (VE-cadherin) through an extracellular domain and reduces the tyrosine phosphorylation of VE-cadherin. But, the reduction of tyrosine phosphorylation seems independently of its enzymatic activity, since catalytically inactive mutant form of PTPRB had the same effect on VE-cadherin phosphorylation <cite>Nawroth02</cite>.
PTPRB associates with endothelial cell (EC)-selective receptor tyrosine kinase Tie2, which maintains vascular integrity <cite>Fachinger99, Winderlich09, Yacyshyn09, Shen14</cite>.
PTPRB regulates vascular endothelial growth factor receptor 2 activity thereby modulating the VEGF-response during angiogenesis <cite>Mellberg09</cite>.

PTPRB is intrinsically active and its inactivation is dependent on its ligand pleiotrophin (PTN) which is a platelet-derived growth factor-inducible, 18-kDa heparin-binding cytokine that signals diverse phenotypes in normal and deregulated cellular growth and differentiation <cite>Meng00</cite>. PTPRB is glycosylated protein (phosphacan).

PTPRB mutations are observed in cancers. Its mutations are recurrent in [http://en.wikipedia.org/wiki/Angiosarcoma angiosarcoma] <cite>Behjati14</cite>. PTPRB mediates glial tumor cell adhesion by binding to [http://en.wikipedia.org/wiki/Tenascin_C#Role_in_cancer tenascin C] <cite>Adamsky01</cite>.

PTPRB interacts with neuronal receptors and promotes neurite outgrowth <cite>Garwood03</cite>.

====== PTPRH (SAP-1) ======
PTPRH was mainly expressed in brain and liver and at a lower level in heart and stomach as a 4.2-kilobase mRNA, but it was not detected in pancreas or colon. In contrast, among cancer cell lines tested, PTPRH was highly expressed in pancreatic and colorectal cancer cells <cite>Matozaki94</cite>. It is downregulated in advanced human hepatocellular carcinoma <cite>Nagano03</cite>.

PTPRH induces apoptotic cell death and inhibit cell growth and motility. PTPRH inhibits integrin signaling by mediating the dephosphorylation of focal adhesion-associated proteins. It dephosphorylates [http://en.wikipedia.org/wiki/BCAR1 p130cas/BCAR1], a major focal adhesion (FA)-associated component of the integrin signaling pathway <cite>Noguchi01</cite>. Forced expression of recombinant PTPRH results in the dephosphorylation of several additional FA-associated proteins, including focal adhesion kinase (FAK) and Dok-1 as well as in impairment of reorganization of the actin-based cytoskeleton <cite>Noguchi01</cite>. Overexpression of PTPRH also results in the inactivation of both Akt (protein kinase B) and integrin-linked kinase (ILK) <cite>Takada02</cite>.

Besides, PTPRH binds to and dephosphorylates kinase Lck therefore regulating T cell function <cite>Ito03</cite>.

====== PTPRJ (CD148/DEP1/RPTP eta) ======
PTPRJ is a tumor suppressor implicated in a range of cancers <cite>Massa04, Trapasso04, Iuliano04, Balavenkatraman06, Venkatachalam10, Omerovic10, AyaBonilla13, Petermann11, Arora11</cite>. However, PTPRJ also mediates the invasive cell program implicating Src activation and the promotion of breast cancer progression <cite>Spring15</cite>.

It plays a prominent role in negative regulation of growth factor signals, suppressing cell proliferation and transformation <cite>Smart12</cite>. Thus, PTPRJ is involved in many cellular processes and human diseases. In particular, it is involved in the regulation of human T cell activation <cite>Tangye98</cite>. PTPRJ/DEP1 is a putative negative regulator of insulin signaling <cite>Kruger15</cite>. PTPRJ is expressed in several cell types <cite>Autschbach99, Takahashi12</cite>.

PTPRJ has ligands:

* [http://en.wikipedia.org/wiki/Thrombospondin_1 Thrombospondin-1] <cite>Takahashi12</cite>, an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. It is a natural inhibitor of neovascularization and tumorigenesis in healthy tissue.
* [http://en.wikipedia.org/wiki/SDC2 Syndecan-2] <cite>Whiteford11</cite>, a heparan sulfate proteoglycan participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins.

PTPRJ dephosphorylates growth factor receptors as well as other substrates:

* [http://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor EGFR], a subfamily of receptor tyrosine kinases (RTKs). PTPRJ dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex. Interestingly, the interactions of DEP-1 and EGFR are followed by physical segregation: whereas EGFR undergoes endocytosis, DEP-1 remains confined to the cell surface <cite>Tarcic09</cite>.
* [http://en.wikipedia.org/wiki/VEGF_receptors VEGFR2], a member of VEGFR subfamily (not EGFR subfamily), receptor tyrosine kinase family <cite>Chabot09</cite>.
* Insulin receptor (IR). PTPRJ preferentially dephosphorylated a particular phosphorylation site of the IR: Y960 in the juxtamembrane region and Y1146 in the activation loop <cite> Shintani15</cite>.
* [http://en.wikipedia.org/wiki/RET_proto-oncogene RET proto-oncogene], a receptor tyrosine kinase (RTK), gain of which causes various types of cancers <cite>Iervolino06</cite>.
* [http://en.wikipedia.org/wiki/CD135 CD135/FLT3], a receptor tyrosine kinase (RTK) plays an important role in hematopoietic differentiation, and constitutively active FLT3 mutant proteins contribute to the development of acute myeloid leukemia. PTPRJ negatively regulates FLT3 phosphorylation and signaling <cite>Arora11, Bohmer13</cite>. The activity can be turned off through oxidation of the DEP-1 catalytic cysteine <cite>Godfrey12</cite>.
* [http://en.wikipedia.org/wiki/Platelet-derived_growth_factor_receptor platelet-derived growth factor beta], a receptor tyrosine kinase (RTK) <cite>Kovalenko00, Persson02</cite>.
* [http://en.wikipedia.org/wiki/C-Met Met proto-oncogene (aka hepatocyte growth factor receptor (HGFR))], a receptor tyrosine kinase (RTK). PTPRJ preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)), whereas tyrosine residues in the activation loop of Met (Tyr(1230), Tyr(1234), and Tyr(1235)) were not preferred targets of the PTP <cite>Palka03</cite>.
* [http://en.wikipedia.org/wiki/Tyrosine-protein_kinase_CSK c-Src], a tyrosine kinase (TK). PTPRJ dephosphorylates c-Src inhibitory tyrosine phosphorylation site (Tyr 529) <cite>Pera05</cite> PTPN22 can reduce the level of phosphorylation of c-Src as well, but it is unclear whether they work on the same residue <cite>Fiorillo04, Stepanek11</cite>.
* [http://en.wikipedia.org/wiki/MAPK3 ERK1] and [http://en.wikipedia.org/wiki/MAPK1 ERK2]. Eextracellular signal-regulated kinase (ERKs) belong to Mitogen-Activated Protein Kinase (MAPK) family. They act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. PTPRJ specifically dephosphorylated tyrosine 204 of ERK1/2. <cite>Sacco09</cite>.
* [http://en.wikipedia.org/wiki/Phosphoinositide_3-kinase p85 regulatory subunit of phosphoinositide 3-kinase (PI3K)] <cite>Tsuboi08</cite>
* [http://en.wikipedia.org/wiki/Occludin Occludin], an integral plasma-membrane protein which is the main component of the tight junctions <cite>Sallee09</cite>.
* [http://en.wikipedia.org/wiki/Tight_junction_protein_1 ZO1], a protein located on a cytoplasmic membrane surface of intercellular tight junctions <cite>Salle09</cite>.
* [http://en.wikipedia.org/wiki/CTNND1 CTNND1/p120 catenin], a member of the Armadillo protein family, which function in adhesion between cells and signal transduction <cite>Holsinger02</cite>.
* PTPRJ can reduce phospholipase Cgamma1 ([http://en.wikipedia.org/wiki/PLCG1 PLCG1]) and LAT phosphorylation and inhibit T-cell receptor signal transduction <cite>Baker01</cite>.. But, it is unclear whether they are PTPRJ's physiological substrates. In fact, PTPRC/CD45 also reduces PLCG1 phosphorylation.

PTPRJ has functions independent of its phosphatase activity.

PTPRJ has a putative shorter spliced variant (denoted as sPTPRJ), coding for a 539 aa protein corresponding to the extracellular N-terminus. It is a soluble protein secreted into the supernatant of both endothelial and tumor cells. Like PTPRJ, sPTPRJ undergoes post-translational modifications such as glycosylation, as assessed by sPTPRJ immunoprecipitation <cite>Bilotta2016</cite>.

====== PTPRO (GLEPP1/PTP phi) ======
PTPRO is a tumor suppressor and frequently methylated in various types of cancers <cite>Motiwala04, Motiwala07, Ramaswamy09, You12, Huang13, Hsu13</cite>. PTPRO can be reliably detected in peripheral blood samples, and is a potential biomarker in cancer diagnosis and prognosis.
PTPRO has multiple isoforms. Monoclonal and polyclonal antibodies raised against a human PTPRO fusion protein recognized a protein with distribution restricted to the glomerulus in human kidney <cite>Wiggins95</cite>.
Interestingly, dimerization of PTPRO inhibit its activity, as dimerization of a related RPTP, CD148/PTPRJ, increases activity <cite>Hower09</cite>.

PTPRO dephosphorylates kinases SYK at BCR-triggered tyrosyl phosphorylation <cite>Chen06</cite>, ZAP70 (SYK family kinase) <cite>Motiwala10</cite>, Lyn (Src family kinase)<cite>Motiwala10</cite>, TrkC (Trk family kinase) <cite>Hower09</cite>, and ErbB2 (EGFR family kinase) <cite>Yu12</cite>.
PTPRO also dephosphorylates [http://en.wikipedia.org/wiki/Paxillin paxillin] <cite>Pixley95, Pixley11</cite> and VCP/p97 <cite>Hsu13</cite>.

PTPRO interacts with Toll-like receptor 4 (TLR4) a gene plays diverse roles in HCC tumorigenesis and progression <cite>Xu14</cite>.
PTPRO dephosphorylates and inactivates the oncogenic fusion protein BCR/ABL <cite>Motiwala09</cite>.

In human and mouse models of hepatic ischemia reperfusion (IR) injury, PTPRO activates NF-κB in a positive feedback manner. PTPRO level was decreased in the early phase but reversed in the late phase. In vitro studies demonstrated that NF-κB up-regulated PTPRO transcription. PTPRO deficiency in mouse resulted in reduction of NF-κB activation in both hepatocytes and macrophages and was correlated to c-Src phosphorylation; PTPRO in hepatocytes alleviated, but PTPROt in macrophages exacerbated IR injury <cite>Hou14</cite>.

PTPRO regulates the growth of specific B-cell subpopulations by promoting G0/G1 arrest <cite>Aguiar99</cite>.
PTPRO mutations can cause autosomal-recessive nephrotic syndrome <cite>Ozaltin11</cite>.

====== PTPRQ ======
PTPRQ is a phosphatidylinositol phosphatase rather than protein tyrosine phosphatase as all the other members in [[Phosphatase_Family_PTP|PTP family]]. PTPRQ has low phosphatase activity against tyrosine-phosphorylated peptide and protein substrates but can dephosphorylate a broad range of phosphatidylinositol phosphates, including phosphatidylinositol 3,4,5-trisphosphate and most phosphatidylinositol monophosphates and diphosphates, with a preference for PI(3,4,5)P3 <cite>Yu13</cite>. This shift in activity correlates with a change of the WPD tyrosine-specific motif to WPE. Overexpression of PTPRQ in cultured cells inhibits proliferation and induces apoptosis. An E2171D mutation that retains or increases tyrosine phosphatase activity but eliminates phosphatidylinositol phosphatase activity, eliminates the inhibitory effects on proliferation and apoptosis.

Mutations in PTPRQ can cause hearing impairment (DFNB84), including one missense mutation in an FN3 domain and a nonsense mutation early in the extracellular region <cite>Shahin10, Schraders10</cite>.

PTPRQ has also been shown to involved in differentiation during adipogenesis of human mesenchymal stem cells <cite>Jung09</cite> and regulation the adhesion and migration of mesangial cells in response to injury <cite>Wright98</cite>.

PTPRQ is seen in all vertebrates, and a likely ortholog (XP_002123247.3) also exists in Ciona intestinalis.

===References===
<biblio>
#Adamsky01 pmid=11313993
#Aguiar99 pmid=10498613
#Arora11 pmid=21262971
#Autschbach99 pmid=10599888
#AyaBonilla13 pmid=23341091
#Baker01 pmid=11259588
#Balavenkatraman06 pmid=16682945
#Behjati14 pmid=24633157
#Berset05 pmid=15901674
#Bilotta2016 pmid=28052032
#Bohmer13 pmid=23650535
#Brunner11 pmid=21304107
#Chabot09 pmid=18936167
#Chen06 pmid=16888096
#Fachinger99 pmid=10557082
#Fiorillo04 pmid=20538612
#Garwood03 pmid=12700241
#Godfrey12 pmid=22438257
#Holsinger02 pmid=12370829
#Hower09 pmid=19573017
#Huang13 pmid=24090193
#Hsu13 pmid=23533167
#Iervolino06 pmid=16778204
#Ito03 pmid=12837766
#Iuliano04 pmid=15378013
#Jeon pmid=19675131
#Jung09 pmid=19351528
#Kovalenko00 pmid=10821867
#Kruger15 pmid=25830095
#Wright98 pmid=9727007
#Massa04 pmid=15123617
#Motiwala04 pmid=15356345
#Motiwala07 pmid=17545520
#Motiwala09 pmid=18997174
#Motiwala10 pmid=20564182
#Matozaki94 pmid=8294459
#Mellberg09 pmid=19136612
#Meng00 pmid=10706604
#Mori10 pmid=20301196
#Nagano03 pmid=12879010
#Noguchi01 pmid=11278335
#Nawroth02 pmid=12234928
#Omerovic10 pmid=19922411
#Ozaltin11 pmid=21722858
#Palka03 pmid=12475979
#Petermann11 pmid=21091576
#Pera05 pmid=15735685
#Persson02 pmid=12062403
#Pixley95 pmid=7592997
#Pixley01 pmid=11238916
#Ramaswamy09 pmid=19095770
#Sacco09 pmid=19494114
#Sallee09 pmid=19122201
#Schraders10 pmid=20346435
#Seifert03 pmid=12837292
#Shen14 pmid=25180601
#Shahin10 pmid=20472657
#Shintani15 pmid=26063811
#Smart12 pmid=22815804
#Spring15 pmid=25772245
#Stepanek11 pmid=21543337
#Takada02 pmid=12101188
#Takahashi12 pmid=22308318
#Tangye98 pmid=9759839
#Tarcic09 pmid=19836242
#Trapasso04 pmid=15231692
#Tsuboi08 pmid=18348712
#Venkatachalam10 pmid=21036128
#Whiteford11 pmid=21813734
#Wiggins95 pmid=7665166
#Winderlich09 pmid=19451274
#Xu14 pmid=25034527
#Yacyshyn09 pmid=19116766
#You12 pmid=22099875
#Yu12 pmid=22851698
#Yu13 pmid=23897475
</biblio>

Phosphatase Subfamily PTPRB

2017-01-06T14:13:06Z

Mark: /* PTPRJ (CD148/DEP1/RPTP eta) */

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

PTPRB (aka R3) is a metazoan-specific subfamily of receptor PTPs, with diverse functions.

===Evolution===
PTPRB is found across metazoa, often with multiple members per species. Human members are PTPRB, PTPRH, PTPRJ, PTPRO, and PTPRQ, while C. elegans has a single gene, dep-1 and Drosophila has two: PTP4E and PTP10D.

===Domain Structure===
The canonical domain structure is multiple fibronectin type III (Fn3) domains in the extracellular region and a single cytoplasmic phosphatase domain. Human PTPRQ also encodes a cytoplasmic isoform lacking the extracellular region, due to alternative promoter usage <cite>Seifert03</cite>.

===Functions===
PTPRB from multiple species antagonizes EGFR signaling, in Drosophila tracheal development <cite>Jeon</cite>, in C. elegans vulval development <cite>Berset05</cite>, and PTPRJ in mammalian cell assays <cite>Tarcic09</cite>, and multiple members dephosphorylate the insulin receptor <cite>Shintani15</cite>.

Human PTPRB genes have varied functions, and are selectively expressed in different cell types and/or tissues and have different substrates or binding partners. They function in various tissues, such as nervous system and immune system. They are also putative tumor suppressors. They share common features, including localization at cell-cell contact sites, and involved in cell proliferation and transformation.

====== PTPRB (VE-PTP) ======
PTPRB, a.k.a. vascular endothelial protein tyrosine phosphatase (VE-PTP), is expressed specifically in endothelial cells and regulates the spreading and migration of endothelial cells during angiogenesis <cite>Mori10</cite>.
PTPRB binds to vascular E-cadherin (VE-cadherin) through an extracellular domain and reduces the tyrosine phosphorylation of VE-cadherin. But, the reduction of tyrosine phosphorylation seems independently of its enzymatic activity, since catalytically inactive mutant form of PTPRB had the same effect on VE-cadherin phosphorylation <cite>Nawroth02</cite>.
PTPRB associates with endothelial cell (EC)-selective receptor tyrosine kinase Tie2, which maintains vascular integrity <cite>Fachinger99, Winderlich09, Yacyshyn09, Shen14</cite>.
PTPRB regulates vascular endothelial growth factor receptor 2 activity thereby modulating the VEGF-response during angiogenesis <cite>Mellberg09</cite>.

PTPRB is intrinsically active and its inactivation is dependent on its ligand pleiotrophin (PTN) which is a platelet-derived growth factor-inducible, 18-kDa heparin-binding cytokine that signals diverse phenotypes in normal and deregulated cellular growth and differentiation <cite>Meng00</cite>. PTPRB is glycosylated protein (phosphacan).

PTPRB mutations are observed in cancers. Its mutations are recurrent in [http://en.wikipedia.org/wiki/Angiosarcoma angiosarcoma] <cite>Behjati14</cite>. PTPRB mediates glial tumor cell adhesion by binding to [http://en.wikipedia.org/wiki/Tenascin_C#Role_in_cancer tenascin C] <cite>Adamsky01</cite>.

PTPRB interacts with neuronal receptors and promotes neurite outgrowth <cite>Garwood03</cite>.

====== PTPRH (SAP-1) ======
PTPRH was mainly expressed in brain and liver and at a lower level in heart and stomach as a 4.2-kilobase mRNA, but it was not detected in pancreas or colon. In contrast, among cancer cell lines tested, PTPRH was highly expressed in pancreatic and colorectal cancer cells <cite>Matozaki94</cite>. It is downregulated in advanced human hepatocellular carcinoma <cite>Nagano03</cite>.

PTPRH induces apoptotic cell death and inhibit cell growth and motility. PTPRH inhibits integrin signaling by mediating the dephosphorylation of focal adhesion-associated proteins. It dephosphorylates [http://en.wikipedia.org/wiki/BCAR1 p130cas/BCAR1], a major focal adhesion (FA)-associated component of the integrin signaling pathway <cite>Noguchi01</cite>. Forced expression of recombinant PTPRH results in the dephosphorylation of several additional FA-associated proteins, including focal adhesion kinase (FAK) and Dok-1 as well as in impairment of reorganization of the actin-based cytoskeleton <cite>Noguchi01</cite>. Overexpression of PTPRH also results in the inactivation of both Akt (protein kinase B) and integrin-linked kinase (ILK) <cite>Takada02</cite>.

Besides, PTPRH binds to and dephosphorylates kinase Lck therefore regulating T cell function <cite>Ito03</cite>.

====== PTPRJ (CD148/DEP1/RPTP eta) ======
PTPRJ is a tumor suppressor implicated in a range of cancers <cite>Massa04, Trapasso04, Iuliano04, Balavenkatraman06, Venkatachalam10, Omerovic10, AyaBonilla13, Petermann11, Arora11</cite>. However, PTPRJ also mediates the invasive cell program implicating Src activation and the promotion of breast cancer progression <cite>Spring15</cite>.

It plays a prominent role in negative regulation of growth factor signals, suppressing cell proliferation and transformation <cite>Smart12</cite>. Thus, PTPRJ is involved in many cellular processes and human diseases. In particular, it is involved in the regulation of human T cell activation <cite>Tangye98</cite>. PTPRJ/DEP1 is a putative negative regulator of insulin signaling <cite>Kruger15</cite>. PTPRJ is expressed in several cell types <cite>Autschbach99, Takahashi12</cite>.

PTPRJ has ligands:

* [http://en.wikipedia.org/wiki/Thrombospondin_1 Thrombospondin-1] <cite>Takahashi12</cite>, an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. It is a natural inhibitor of neovascularization and tumorigenesis in healthy tissue.
* [http://en.wikipedia.org/wiki/SDC2 Syndecan-2] <cite>Whiteford11</cite>, a heparan sulfate proteoglycan participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins.

PTPRJ dephosphorylates growth factor receptors as well as other substrates:

* [http://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor EGFR], a subfamily of receptor tyrosine kinases (RTKs). PTPRJ dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex. Interestingly, the interactions of DEP-1 and EGFR are followed by physical segregation: whereas EGFR undergoes endocytosis, DEP-1 remains confined to the cell surface <cite>Tarcic09</cite>.
* [http://en.wikipedia.org/wiki/VEGF_receptors VEGFR2], a member of VEGFR subfamily (not EGFR subfamily), receptor tyrosine kinase family <cite>Chabot09</cite>.
* Insulin receptor (IR). PTPRJ preferentially dephosphorylated a particular phosphorylation site of the IR: Y960 in the juxtamembrane region and Y1146 in the activation loop <cite> Shintani15</cite>.
* [http://en.wikipedia.org/wiki/RET_proto-oncogene RET proto-oncogene], a receptor tyrosine kinase (RTK), gain of which causes various types of cancers <cite>Iervolino06</cite>.
* [http://en.wikipedia.org/wiki/CD135 CD135/FLT3], a receptor tyrosine kinase (RTK) plays an important role in hematopoietic differentiation, and constitutively active FLT3 mutant proteins contribute to the development of acute myeloid leukemia. PTPRJ negatively regulates FLT3 phosphorylation and signaling <cite>Arora11, Bohmer13</cite>. The activity can be turned off through oxidation of the DEP-1 catalytic cysteine <cite>Godfrey12</cite>.
* [http://en.wikipedia.org/wiki/Platelet-derived_growth_factor_receptor platelet-derived growth factor beta], a receptor tyrosine kinase (RTK) <cite>Kovalenko00, Persson02</cite>.
* [http://en.wikipedia.org/wiki/C-Met Met proto-oncogene (aka hepatocyte growth factor receptor (HGFR))], a receptor tyrosine kinase (RTK). PTPRJ preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)), whereas tyrosine residues in the activation loop of Met (Tyr(1230), Tyr(1234), and Tyr(1235)) were not preferred targets of the PTP <cite>Palka03</cite>.
* [http://en.wikipedia.org/wiki/Tyrosine-protein_kinase_CSK c-Src], a tyrosine kinase (TK). PTPRJ dephosphorylates c-Src inhibitory tyrosine phosphorylation site (Tyr 529) <cite>Pera05</cite> PTPN22 can reduce the level of phosphorylation of c-Src as well, but it is unclear whether they work on the same residue <cite>Fiorillo04, Stepanek11</cite>.
* [http://en.wikipedia.org/wiki/MAPK3 ERK1] and [http://en.wikipedia.org/wiki/MAPK1 ERK2]. Eextracellular signal-regulated kinase (ERKs) belong to Mitogen-Activated Protein Kinase (MAPK) family. They act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. PTPRJ specifically dephosphorylated tyrosine 204 of ERK1/2. <cite>Sacco09</cite>.
* [http://en.wikipedia.org/wiki/Phosphoinositide_3-kinase p85 regulatory subunit of phosphoinositide 3-kinase (PI3K)] <cite>Tsuboi08</cite>
* [http://en.wikipedia.org/wiki/Occludin Occludin], an integral plasma-membrane protein which is the main component of the tight junctions <cite>Sallee09</cite>.
* [http://en.wikipedia.org/wiki/Tight_junction_protein_1 ZO1], a protein located on a cytoplasmic membrane surface of intercellular tight junctions <cite>Salle09</cite>.
* [http://en.wikipedia.org/wiki/CTNND1 CTNND1/p120 catenin], a member of the Armadillo protein family, which function in adhesion between cells and signal transduction <cite>Holsinger02</cite>.
* PTPRJ can reduce phospholipase Cgamma1 ([http://en.wikipedia.org/wiki/PLCG1 PLCG1]) and LAT phosphorylation and inhibit T-cell receptor signal transduction <cite>Baker01</cite>.. But, it is unclear whether they are PTPRJ's physiological substrates. In fact, PTPRC/CD45 also reduces PLCG1 phosphorylation.

PTPRJ has functions independent of its phosphatase activity.

PTPRJ has a putative shorter spliced variant (denoted as sPTPRJ), coding for a 539 aa protein corresponding to the extracellular N-terminus. It is a soluble protein secreted into the supernatant of both endothelial and tumor cells. Like PTPRJ, sPTPRJ undergoes post-translational modifications such as glycosylation, as assessed by sPTPRJ immunoprecipitation <cite>Bilotta2016</cite>.

====== PTPRO (GLEPP1/PTP phi) ======
PTPRO is a tumor suppressor and frequently methylated in various types of cancers <cite>Motiwala04, Motiwala07, Ramaswamy09, You12, Huang13, Hsu13</cite>. PTPRO can be reliably detected in peripheral blood samples, and is a potential biomarker in cancer diagnosis and prognosis.
PTPRO has multiple isoforms. Monoclonal and polyclonal antibodies raised against a human PTPRO fusion protein recognized a protein with distribution restricted to the glomerulus in human kidney <cite>Wiggins95</cite>.
Interestingly, dimerization of PTPRO inhibit its activity, as dimerization of a related RPTP, CD148/PTPRJ, increases activity <cite>Hower09</cite>.

PTPRO dephosphorylates kinases SYK at BCR-triggered tyrosyl phosphorylation <cite>Chen06</cite>, ZAP70 (SYK family kinase) <cite>Motiwala10</cite>, Lyn (Src family kinase)<cite>Motiwala10</cite>, TrkC (Trk family kinase) <cite>Hower09</cite>, and ErbB2 (EGFR family kinase) <cite>Yu12</cite>.
PTPRO also dephosphorylates [http://en.wikipedia.org/wiki/Paxillin paxillin] <cite>Pixley95, Pixley11</cite> and VCP/p97 <cite>Hsu13</cite>.

PTPRO interacts with Toll-like receptor 4 (TLR4) a gene plays diverse roles in HCC tumorigenesis and progression <cite>Xu14</cite>.
PTPRO dephosphorylates and inactivates the oncogenic fusion protein BCR/ABL <cite>Motiwala09</cite>.

In human and mouse models of hepatic ischemia reperfusion (IR) injury, PTPRO activates NF-κB in a positive feedback manner. PTPRO level was decreased in the early phase but reversed in the late phase. In vitro studies demonstrated that NF-κB up-regulated PTPRO transcription. PTPRO deficiency in mouse resulted in reduction of NF-κB activation in both hepatocytes and macrophages and was correlated to c-Src phosphorylation; PTPRO in hepatocytes alleviated, but PTPROt in macrophages exacerbated IR injury <cite>Hou14</cite>.

PTPRO regulates the growth of specific B-cell subpopulations by promoting G0/G1 arrest <cite>Aguiar99</cite>.
PTPRO mutations can cause autosomal-recessive nephrotic syndrome <cite>Ozaltin11</cite>.

====== PTPRQ ======
PTPRQ is a phosphatidylinositol phosphatase rather than protein tyrosine phosphatase as all the other members in [[Phosphatase_Family_PTP|PTP family]]. PTPRQ has low phosphatase activity against tyrosine-phosphorylated peptide and protein substrates but can dephosphorylate a broad range of phosphatidylinositol phosphates, including phosphatidylinositol 3,4,5-trisphosphate and most phosphatidylinositol monophosphates and diphosphates, with a preference for PI(3,4,5)P3 <cite>Yu13</cite>. This shift in activity correlates with a change of the WPD tyrosine-specific motif to WPE. Overexpression of PTPRQ in cultured cells inhibits proliferation and induces apoptosis. An E2171D mutation that retains or increases tyrosine phosphatase activity but eliminates phosphatidylinositol phosphatase activity, eliminates the inhibitory effects on proliferation and apoptosis.

Mutations in PTPRQ can cause hearing impairment (DFNB84), including one missense mutation in an FN3 domain and a nonsense mutation early in the extracellular region <cite>Shahin10, Schraders10</cite>.

PTPRQ has also been shown to involved in differentiation during adipogenesis of human mesenchymal stem cells <cite>Jung09</cite> and regulation the adhesion and migration of mesangial cells in response to injury <cite>Wright98</cite>.

PTPRQ is seen in all vertebrates, and a likely ortholog (XP_002123247.3) also exists in Ciona intestinalis.

===References===
<biblio>
#Adamsky01 pmid=11313993
#Aguiar99 pmid=10498613
#Arora11 pmid=21262971
#Autschbach99 pmid=10599888
#AyaBonilla13 pmid=23341091
#Baker01 pmid=11259588
#Balavenkatraman06 pmid=16682945
#Behjati14 pmid=24633157
#Berset05 pmid=15901674
#Bohmer13 pmid=23650535
#Brunner11 pmid=21304107
#Chabot09 pmid=18936167
#Chen06 pmid=16888096
#Fachinger99 pmid=10557082
#Fiorillo04 pmid=20538612
#Garwood03 pmid=12700241
#Godfrey12 pmid=22438257
#Holsinger02 pmid=12370829
#Hower09 pmid=19573017
#Huang13 pmid=24090193
#Hsu13 pmid=23533167
#Iervolino06 pmid=16778204
#Ito03 pmid=12837766
#Iuliano04 pmid=15378013
#Jeon pmid=19675131
#Jung09 pmid=19351528
#Kovalenko00 pmid=10821867
#Kruger15 pmid=25830095
#Wright98 pmid=9727007
#Massa04 pmid=15123617
#Motiwala04 pmid=15356345
#Motiwala07 pmid=17545520
#Motiwala09 pmid=18997174
#Motiwala10 pmid=20564182
#Matozaki94 pmid=8294459
#Mellberg09 pmid=19136612
#Meng00 pmid=10706604
#Mori10 pmid=20301196
#Nagano03 pmid=12879010
#Noguchi01 pmid=11278335
#Nawroth02 pmid=12234928
#Omerovic10 pmid=19922411
#Ozaltin11 pmid=21722858
#Palka03 pmid=12475979
#Petermann11 pmid=21091576
#Pera05 pmid=15735685
#Persson02 pmid=12062403
#Pixley95 pmid=7592997
#Pixley01 pmid=11238916
#Ramaswamy09 pmid=19095770
#Sacco09 pmid=19494114
#Sallee09 pmid=19122201
#Schraders10 pmid=20346435
#Seifert03 pmid=12837292
#Shen14 pmid=25180601
#Shahin10 pmid=20472657
#Shintani15 pmid=26063811
#Smart12 pmid=22815804
#Spring15 pmid=25772245
#Stepanek11 pmid=21543337
#Takada02 pmid=12101188
#Takahashi12 pmid=22308318
#Tangye98 pmid=9759839
#Tarcic09 pmid=19836242
#Trapasso04 pmid=15231692
#Tsuboi08 pmid=18348712
#Venkatachalam10 pmid=21036128
#Whiteford11 pmid=21813734
#Wiggins95 pmid=7665166
#Winderlich09 pmid=19451274
#Xu14 pmid=25034527
#Yacyshyn09 pmid=19116766
#You12 pmid=22099875
#Yu12 pmid=22851698
#Yu13 pmid=23897475
</biblio>

Phosphatase Subfamily PPP7C

2017-01-06T13:55:12Z

Mark: /* References */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_PPPL|Fold PPPL]]: [[Phosphatase_Superfamily_PPPL|Superfamily PPPL]]: [[Phosphatase_Family_PPPc|Family PPPc]]: [[Phosphatase_Subfamily_PPP7C|Subfamily PPP7C]]
Note: the page is under construction.

=== Evolution ===
The PPP7C subfamily is found in eumetazoa and Placozoa ''Trichoplax adhaerens'', but it is not present in sponge.

=== Domain ===
PPP7Cs typically have a domain combination of [[Protein_Domain#IQ|IQ calmodulin-binding motif]], [[Protein_Domain#TPR|TPR structural motif]] mediating protein-protein interaction, PPP phosphatase domain, and tandem [[Protein_Domain#EF_hand|EF hand structural motifs]] binding to calcium. The domain combination makes it easier and more confident to identify PPP7Cs. Drosophila melanogaster PPP7C, rdgC, has two TPR motifs.

=== Functions ===
Human has two members in PPP7C subfamily, PPEF1 (PPP7CA) and PPEF2 (PPP7CB).

==== PPEF1 (PPP7CA) ====

PPEF-1 interacts with and dephosphorylates Programmed cell death 5 (PDCD5) at Ser-119, which leads to PDCD5 destabilization. It is believed to play a crucial role in p53 activation <cite>Park2017</cite>.

=== References ===
<biblio>
#Park2017 pmid=28051100
</biblio>

Phosphatase Subfamily PPP7C

2017-01-06T13:54:56Z

Mark: /* Functions */

Phosphatase Subfamily PPP3C

2017-01-03T17:39:54Z

Mark: /* PPP3CC */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_MTDP|Fold MTDP]]: [[Phosphatase_Superfamily_MTDP|Superfamily MTDP]]: [[Phosphatase_Family_PPP|Family PPP]]: [[Phosphatase_Subfamily_PPP3C|Subfamily PPP3C]] (PP2B, calcineurin)

PPP3C, the catalytic subunit of PP2B (calcineurin) holoeynzme, is a calcium-dependent serine/threonine phosphatase conserved in eukaryotes. It is involved in various biological processes and has significantly clinic relevance.

=== Evolution ===
PPP3C is found throughout eukaryotes, including [[Phosphatase_Glossary#Opisthokonta|opisthokonta]], amoebazoa, plants and etc.

=== Domain ===
PPP3C has a single domain - phosphatase domain.

=== Functions ===
PPP3C is the catalytic subunit of Protein Phosphatase 2B (PP2B) holoenzyme (aka calcineurin). The holoenzyme is heterodimer complex consisting of one catalytic subunit and one regulatory subunit participates in very various cellular processes, from cell cycle progression to cardiac hypertrophy <cite>Rusnak00</cite>. Below are some examples of its function:

* PP2B (calcineurin) activates the T cells of the immune system in mammals. When an antigen-preseting cell interacts with a T cell receptor on T cells, the cytoplasmic level of calcium increases, which activates calcineurin. PP2B (calcineurin) is used as a target for several immunosuppressive drugs, e.g. [http://en.wikipedia.org/wiki/Tacrolimus tacrolimus] which is an immunosuppressive drug used mainly after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection <cite>Wang15</cite>.

* PP2B (calcineurin) is included as a key player in mediating calcium-triggered and -accelerated vesicle endocytosis <cite>Wu14</cite>.

* PP2B (calcineurin) activates a vertebrate-specific transcription factor called NFATc.

* PPP3C (PP2B, calcineurin) modulates potassium channel, perhaps by directly controlling the phosphorylation state of potassium channel in collaboration with PKA <cite>Orie09, Brignell15</cite>.

* PPP3C interacts with Nuclear factor (NF)-κB-inducing kinase (NIK) and attenuates NIK-dependent gene expression <cite>Shinzawa15</cite>.

* In fission yeast, calcineurin interacts with and dephosphorylates kinase Cki3, belonging to CK1-G subfamily, CK1 family, CK1 group. Cki3 autophosphorylate itself in the C terminus, which result in the inhibition of its kinase activity <cite> Koyano15</cite>.

This phosphatase has clinical significance for schizophrenia and diabetes (see [http://en.wikipedia.org/wiki/Calcineurin wikipedia]).

Besides, PPP3C (PP2B, calcineurin) is an attractive antifungal drug target <cite> Matsoukas15</cite>, and its inhibitor (FK506 or cyclosporin A) can be combined with azoles or echinocandins for use against multidrug-resistant Candida species <cite>Yu15</cite>.

==== PPP3CC ====

PPP3CC is a component of a constitutive intrinsic inflammatory signaling circuit composed of miR-196b, Meis2, PPP3CC, and p65. The signaling circuit drives prostate cancer castration resistance <cite>Jeong2016</cite> (Entitled A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance).

=== References ===
<biblio>
#Brignell15 pmid=25793374
#Koyano15 pmid=25691662
#Matsoukas15 pmid=26106221
#Orie09 pmid=19422382
#Rusnak00 pmid=11015619
#Shinzawa15 pmid=26029823
#Wang15 pmid=25452304
#Wu14 pmid=24835995
#Yu15 pmid=25878052
</biblio>

Phosphatase Subfamily PPP3C

2017-01-03T17:38:08Z

Mark: /* Functions */

__NOTOC__
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_MTDP|Fold MTDP]]: [[Phosphatase_Superfamily_MTDP|Superfamily MTDP]]: [[Phosphatase_Family_PPP|Family PPP]]: [[Phosphatase_Subfamily_PPP3C|Subfamily PPP3C]] (PP2B, calcineurin)

PPP3C, the catalytic subunit of PP2B (calcineurin) holoeynzme, is a calcium-dependent serine/threonine phosphatase conserved in eukaryotes. It is involved in various biological processes and has significantly clinic relevance.

=== Evolution ===
PPP3C is found throughout eukaryotes, including [[Phosphatase_Glossary#Opisthokonta|opisthokonta]], amoebazoa, plants and etc.

=== Domain ===
PPP3C has a single domain - phosphatase domain.

=== Functions ===
PPP3C is the catalytic subunit of Protein Phosphatase 2B (PP2B) holoenzyme (aka calcineurin). The holoenzyme is heterodimer complex consisting of one catalytic subunit and one regulatory subunit participates in very various cellular processes, from cell cycle progression to cardiac hypertrophy <cite>Rusnak00</cite>. Below are some examples of its function:

* PP2B (calcineurin) activates the T cells of the immune system in mammals. When an antigen-preseting cell interacts with a T cell receptor on T cells, the cytoplasmic level of calcium increases, which activates calcineurin. PP2B (calcineurin) is used as a target for several immunosuppressive drugs, e.g. [http://en.wikipedia.org/wiki/Tacrolimus tacrolimus] which is an immunosuppressive drug used mainly after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection <cite>Wang15</cite>.

* PP2B (calcineurin) is included as a key player in mediating calcium-triggered and -accelerated vesicle endocytosis <cite>Wu14</cite>.

* PP2B (calcineurin) activates a vertebrate-specific transcription factor called NFATc.

* PPP3C (PP2B, calcineurin) modulates potassium channel, perhaps by directly controlling the phosphorylation state of potassium channel in collaboration with PKA <cite>Orie09, Brignell15</cite>.

* PPP3C interacts with Nuclear factor (NF)-κB-inducing kinase (NIK) and attenuates NIK-dependent gene expression <cite>Shinzawa15</cite>.

* In fission yeast, calcineurin interacts with and dephosphorylates kinase Cki3, belonging to CK1-G subfamily, CK1 family, CK1 group. Cki3 autophosphorylate itself in the C terminus, which result in the inhibition of its kinase activity <cite> Koyano15</cite>.

This phosphatase has clinical significance for schizophrenia and diabetes (see [http://en.wikipedia.org/wiki/Calcineurin wikipedia]).

Besides, PPP3C (PP2B, calcineurin) is an attractive antifungal drug target <cite> Matsoukas15</cite>, and its inhibitor (FK506 or cyclosporin A) can be combined with azoles or echinocandins for use against multidrug-resistant Candida species <cite>Yu15</cite>.

==== PPP3CC ====

PPP3CC is a component of a constitutive intrinsic inflammatory signaling circuit composed of miR-196b, Meis2, PPP3CC, and p65. The signaling circuit drives prostate cancer castration resistance <cite>Jeong2016</cite>.

=== References ===
<biblio>
#Brignell15 pmid=25793374
#Koyano15 pmid=25691662
#Matsoukas15 pmid=26106221
#Orie09 pmid=19422382
#Rusnak00 pmid=11015619
#Shinzawa15 pmid=26029823
#Wang15 pmid=25452304
#Wu14 pmid=24835995
#Yu15 pmid=25878052
</biblio>

Wiki Management

2016-11-10T21:16:45Z

Mark: Created page with "=== Citations === We use BiblioPlus for automated retrieval and formatting of citations from PubMed and the ISBN databases. However, it failed in Nov, 2016, because [https:..."

=== Citations ===

We use BiblioPlus for automated retrieval and formatting of citations from PubMed and the ISBN databases.

However, it failed in Nov, 2016, because [https://www.ncbi.nlm.nih.gov/home/develop/https-guidance.shtml NCBI switched from http to https]. Since the latest version (1.27) does not solve the problem, we changed "http" to "https" in the scripts, found by the command "grep http *" in the extension directory. The problem was then solved.

Main Page

2016-11-10T21:10:16Z

Mark: /* Technical notes */

__NOTOC__
Welcome to Phosphatase Wiki, a resource for phosphatases and phosphatase signaling focused on genomics and evolution. This is a pilot project for sharing and publication of discoveries that do not fit into traditional publications or haven't yet been polished for publication. Initial content is mostly from the Manning lab at Salk (moved to Genentech in 2012), but we welcome anyone who would like to contribute. Like other wikis, just go to the login page to request an account.

== [[Introduction to Phosphatases]] ==
* [[Phosphatases_and_Diseases|Phosphatases and diseases]]
* [[Drug_Targeting_Phosphatases|Phosphatases as drug and/or inhibitor targets]]
* [[Biological_Significance_of_Phosphorylation|Miscellaneous biological and clinic significance of phosphorylation]]
* [[Dephosphorylation_on_unusual_amino_acids|(De)phosphorylation on unusual amino acids]]: unusual evidence for phosphorylation on histidine, aspartate, cysteine, lysine, and arginine.
* [[regulatory_subunits|Regulatory subunits]]: some phosphatases, particularly PPPs, consist of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits.

== [[phosphatase classification|Protein Phosphatase Classification and Evolution]] ==
===== [[Phosphatase_classification#Classification_Chart_of_Protein_Phosphatases|Classification chart]] =====
In contrast with kinases, there are multiple folds of protein phosphatases, which means protein phosphatases have multiple independent evolutionary origins, while most kinases have a single origin. We classified protein phosphatases into a hierarchy scheme of four levels: fold, superfamily, family and subfamily.

===== [[Pseudophosphatases|Catalytically inactive phosphatases]] (pseudophosphatases) =====
Protein phosphatases have various functions. Some protein phosphatases lack catalytically activity, but them play critical roles in various cellular signaling pathways.

===== Protein phosphatase evolution =====
Each of the protein phosphatase fold are able to be found in early eukaryotes, so are most of the protein phosphatase families. The subfamilies have a dynamic evolutionary pattern. Some subfamilies have been lost multiple times through independent evolutionary events. While many subfamilies expanded in gene number in vertebrates, some subfamily has a single member in almost all the sequenced eukaryotic genomes. Protein phosphatase also underwent [[Accesory_Domain_Gains_and_Losses|gains and losses of accessory domain]].

===== [[Human_Protein_Phosphatase_Pseudogene|Human protein phosphatase pseudogenes]] =====
There are about 80 pseudogenes which originated from the protein-coding genes that encode protein phosphatases in human. They are functional at least in some cases. For instance, PTENP1 is a processed pseudogene of PTEN and regulates PTEN by both sense and antisense RNAs.

== Glossary ==
* [[Phosphatase_Glossary|Miscellaneous]]
* [[Protein_Domain|Protein domain and motif]]
* [[Signaling_Pathway_And_Proteins|Signaling pathways and proteins]]

== Technical notes ==
* [[Phosphatome_Computational_Tools_and_Resources|Phosphatome computational tools and resources]]
* [[Notes_of_Sequenced_Genomes|Notes of Sequenced Genomes]]
* [[HMM|HMMs]]
* [[Wiki_Management|Wiki Management]]

2016-05-08T20:22:56Z

Mark: /* 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 test; meanwhile, the trees in different studies have different topologies as you can image <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) is a subfamily that functions in the nervous system. The three human members, PTPRF (LAR), PTPRD (RPTPdelta) and PTPRS (RPTPsigma) dephoshorylate different proteins mostly involved in cell signaling. PTPRD is found in animals and choanoflagellates.

* [[Phosphatase_Subfamily_PTPRG|PTPRG]] is an eumetazoan subfamily functions in nervous system and maybe cancer. Human has 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 nervous system. Human has four members, 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. One particular interesting example is that 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_Ptp69D|Ptp69D]] is a subfamily similar to PTPRD. It involved in neuronal pathfinding. It emerged in metazoa but absent from vertebrates.

* [[Phosphatase_Subfamily_CG42327|CG42327]] is found in arthropods. Its function is unclear.

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

* [[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 ecdysozoan. 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 ecdysozoan. PTPN13 has a single member in human: PTPN13/FAP-1/PTP1E/PTPL1/PTP-BAS.

* [[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_PTPN20|PTPN20]] is a phosphatase involved in cytoskeleton organization. It emerged in sarcopterygii.

* [[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_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. 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_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).

=== 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 GeneID CeleP222

2016-05-08T20:16:52Z

Mark: Created page with "It is predicted to be receptor PTP based upon the presence of signal peptide predicted by SignalP."

It is predicted to be receptor PTP based upon the presence of signal peptide predicted by SignalP.

Phosphatase GeneID AqueP047

2016-05-08T20:13:48Z

Mark: Created page with "It is predicted to be receptor PTP based upon the presence of signal peptide predicted by SignalP."

It is predicted to be receptor PTP based upon the presence of signal peptide predicted by SignalP.