Phosphatase Subfamily PTPRB

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Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: 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 [1].

Functions

PTPRB from multiple species antagonizes EGFR signaling, in Drosophila tracheal development [2], in C. elegans vulval development [3], and PTPRJ in mammalian cell assays [4], and multiple members dephosphorylate the insulin receptor [5].

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 [6]. 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 [7]. PTPRB associates with endothelial cell (EC)-selective receptor tyrosine kinase Tie2, which maintains vascular integrity [8, 9, 10, 11]. PTPRB regulates vascular endothelial growth factor receptor 2 activity thereby modulating the VEGF-response during angiogenesis [12].

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 [13]. PTPRB is glycosylated protein (phosphacan).

PTPRB mutations are observed in cancers. Its mutations are recurrent in angiosarcoma [14]. PTPRB mediates glial tumor cell adhesion by binding to tenascin C [15].

PTPRB interacts with neuronal receptors and promotes neurite outgrowth [16].

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 [17]. It is downregulated in advanced human hepatocellular carcinoma [18].

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 p130cas/BCAR1, a major focal adhesion (FA)-associated component of the integrin signaling pathway [19]. 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 [19]. Overexpression of PTPRH also results in the inactivation of both Akt (protein kinase B) and integrin-linked kinase (ILK) [20].

Besides, PTPRH binds to and dephosphorylates kinase Lck therefore regulating T cell function [21].

PTPRJ (CD148/DEP1/RPTP eta)

PTPRJ is a tumor suppressor implicated in a range of cancers [22, 23, 24, 25, 26, 27, 28, 29, 30]. However, PTPRJ also mediates the invasive cell program implicating Src activation and the promotion of breast cancer progression [31].

It plays a prominent role in negative regulation of growth factor signals, suppressing cell proliferation and transformation [32]. Thus, PTPRJ is involved in many cellular processes and human diseases. In particular, it is involved in the regulation of human T cell activation [33]. PTPRJ/DEP1 is a putative negative regulator of insulin signaling [34]. PTPRJ is expressed in several cell types [35, 36].

PTPRJ has ligands:

  • Thrombospondin-1 [36], 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.
  • Syndecan-2 [37], 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:

  • 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 [4].
  • VEGFR2, a member of VEGFR subfamily (not EGFR subfamily), receptor tyrosine kinase family [38].
  • Insulin receptor (IR). PTPRJ preferentially dephosphorylated a particular phosphorylation site of the IR: Y960 in the juxtamembrane region and Y1146 in the activation loop [5].
  • RET proto-oncogene, a receptor tyrosine kinase (RTK), gain of which causes various types of cancers [39].
  • 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 [30, 40]. The activity can be turned off through oxidation of the DEP-1 catalytic cysteine [41].
  • platelet-derived growth factor beta, a receptor tyrosine kinase (RTK) [42, 43].
  • 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 [44].
  • c-Src, a tyrosine kinase (TK). PTPRJ dephosphorylates c-Src inhibitory tyrosine phosphorylation site (Tyr 529) [45] PTPN22 can reduce the level of phosphorylation of c-Src as well, but it is unclear whether they work on the same residue [46, 47].
  • ERK1 and 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. [48].
  • p85 regulatory subunit of phosphoinositide 3-kinase (PI3K) [49]
  • Occludin, an integral plasma-membrane protein which is the main component of the tight junctions [50].
  • ZO1, a protein located on a cytoplasmic membrane surface of intercellular tight junctions [51].
  • CTNND1/p120 catenin, a member of the Armadillo protein family, which function in adhesion between cells and signal transduction [52].
  • PTPRJ can reduce phospholipase Cgamma1 (PLCG1) and LAT phosphorylation and inhibit T-cell receptor signal transduction [53].. 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 [54].

PTPRO (GLEPP1/PTP phi)

PTPRO is a tumor suppressor and frequently methylated in various types of cancers [55, 56, 57, 58, 59, 60]. 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 [61]. Interestingly, dimerization of PTPRO inhibit its activity, as dimerization of a related RPTP, CD148/PTPRJ, increases activity [62].

PTPRO dephosphorylates kinases SYK at BCR-triggered tyrosyl phosphorylation [63], ZAP70 (SYK family kinase) [64], Lyn (Src family kinase)[64], TrkC (Trk family kinase) [62], and ErbB2 (EGFR family kinase) [65]. PTPRO also dephosphorylates paxillin [66, 67] and VCP/p97 [60].

PTPRO interacts with Toll-like receptor 4 (TLR4) a gene plays diverse roles in HCC tumorigenesis and progression [68]. PTPRO dephosphorylates and inactivates the oncogenic fusion protein BCR/ABL [69].

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 [70].

PTPRO regulates the growth of specific B-cell subpopulations by promoting G0/G1 arrest [71]. PTPRO mutations can cause autosomal-recessive nephrotic syndrome [72].

PTPRQ

PTPRQ is a phosphatidylinositol phosphatase rather than protein tyrosine phosphatase as all the other members in 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 [73]. 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 [74, 75].

PTPRQ has also been shown to involved in differentiation during adipogenesis of human mesenchymal stem cells [76] and regulation the adhesion and migration of mesangial cells in response to injury [77].

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

References

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