Difference between revisions of "Phosphatase Subfamily PTPRB"

Revision as of 18:04, 26 February 2015

Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPRB

PTPRC (CD45) is a vertebrate-specific receptor PTP involved in immune signaling.

Evolution

PTPRB subfamily is found across metazoan. It has multiple copies per genomes in bilateral.

Domain Structure

PTPRQ has at least two isoforms: one transmembrane and one cytosolic [1].

Functions

(summary)

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 [2]. 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 [3]. PTPRB associates with endothelial cell (EC)-selective receptor tyrosine kinase Tie2, which maintains vascular integrity [4, 5, 6, 7]. PTPRB regulates vascular endothelial growth factor receptor 2 activity thereby modulating the VEGF-response during angiogenesis [8].

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

PTPRB mutations are observed in cancers. Its mutations are recurrent in angiosarcoma [10]. PTPRB mediates glial tumor cell adhesion by binding to tenascin C [11].

PTPRB interacts with neuronal receptors and promotes neurite outgrowth [12].

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 [13]. It is downregulated in advanced human hepatocellular carcinoma [14].

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 [15]. 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 [15]. Overexpression of PTPRH also results in the inactivation of both Akt (protein kinase B) and integrin-linked kinase (ILK) [16].

Besides, PTPRH binds to and dephosphorylates kinase Lck therefore regulating T cell function [17].

PTPRJ (CD148/DEP1)

PTPRJ is a tumor suppressor implicated in a range of cancers [18, 19, 20, 21, 22]. It plays a prominent role in negative regulation of growth factor signals, suppressing cell proliferation and transformation [23]. PTPRJ is expressed in several cell types, including vascular endothelial cells and duct epithelial cells [24].

Receptor PTPRJ has ligands:

• Thrombospondin-1 [24], 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 [25], a heparan sulfate proteoglycan participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins.

Substrates:

• EGFR. 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 [26].
• FLT3. Fms-like tyrosine kinase 3 (FLT3) 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 [20, 27]. The activity can be turned off through oxidation of the DEP-1 catalytic cysteine [28].
• Occludin integral plasma-membrane protein which is the main component of the tight junctions [29].
• ZO1 a protein located on a cytoplasmic membrane surface of intercellular tight junctions [30].

PTPRO (GLEPP1/PTP phi)

PTPRO is a tumor suppressor and frequently methylated in various types of cancers [31, 32, 33, 34, 35, 36]. 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 GLEPP1 fusion protein recognized a protein with distribution restricted to the glomerulus in human kidney [37]. Interestingly, dimerization of PTPRO inhibit its activity, as dimerization of a related RPTP, CD148/PTPRJ, increases activity [38].

PTPRO dephosphorylates kinases SYK at BCR-triggered tyrosyl phosphorylation [39], ZAP70 (SYK family kinase) [40], Lyn (Src family kinase)[40], TrkC (Trk family kinase) [38], and ErbB2 (EGFR family kinase) [41]. PTPRO also dephosphorylates paxillin [42, 43] and VCP/p97 [36].

PTPRO interacts with Toll-like receptor 4 (TLR4) a gene plays diverse roles in HCC tumorigenesis and progression [44]. PTPRO dephosphorylates and inactivates the oncogenic fusion protein BCR/ABL [45].

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 [46].

PTPRO regulates the growth of specific B-cell subpopulations by promoting G0/G1 arrest [47]. PTPRO mutations can cause autosomal-recessive nephrotic syndrome [48].

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. Independent research has shown PTPRQ has a strong preferences for PI(3,4,5)P3 over other PI substrates [49]. The activity depends on the WPE motif in place of the WPD motif, rather than substitutions in Cx5R motif. 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. All the evidences above has shown that PTPRQ is a real phosphatidylinositol phosphatase [50].

Mutations in PTPRQ can cause hearing impairment (DFNB84) in a nonconsanguineous Dutch family and a consanguineous Moroccan family with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). Sequence analysis of the PTPRQ gene in members of the families revealed a nonsense mutation in the Dutch family and a missense mutation in the Moroccan family. The missense mutation is located in one of the FN3 domains. The nonsense mutation results in a truncated protein with only a small number of FN3 domains and no transmembrane or phosphatase domain [51, 52]. Thus, the disease may be caused by the misfunction of transmembrane isoform.

PTPRQ has also been shown to involved in differentiation during adipogenesis of human mesenchymal stem cells [53] and regulation the adhesion and migration of mesangial cells in response to injury [54].

References

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