Description | The protein encoded by PTPRA gene is a member of the protein tyrosine phosphatase (PTP) family. This PTP contains an extracellular domain, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. Three alternatively spliced variants of this gene are well known to encode two distinct isoforms differing only in their extracellular region. The shorter form, expressed in most tissues, has 793 aa of which 123 are extracellular. The longer form, RPTPa802, has nine extra amino acids located just before the transmembrane region and is expressed only in a few tissues, especially in brain. It is noted that extensive N- and O-linked glycosylation of RPTPa gives rise to a mature 130 kD form of the protein (Daum et al., 1994). |
Expression | PTPRA gene was originally isolated by PCR-based PTP identification and cloning from several groups (Sap et al., 1990; Kaplan et al., 1990; Matthews et al., 1990). The protein, RPTPa, is a widely distributed transmembrane molecule that is particularly highly expressed in the brain and kidney (Sap et al., 1990). RPTPa is highly expressed in the developing central and peripheral nervous system of mouse, especially in the dorsal root ganglia, cranial ganglia and adrenal gland (den Hertog et al., 1996). During chicken development, chicken RPTPa (ChPTPa) is expressed in pre-migratory and migrating granule cells, and in Bergmann glia and their radial processes as determined by in situ hybridization and immunostaining (Fang et al., 1996). Taken together, these studies demonstrate that RPTPa is highly expressed in the developing brain of various species (Shock et al., 1995; Yang and Friesel, 1998; den Hertog et al., 1999). |
Localisation | Membrane. A typical single-pass type I membrane protein. |
Function | Generally, RPTPa has been shown to dephosphorylate and activate Src family kinases (SFKs), and is implicated in the regulation of integrin signaling, cell adhesion and proliferation. Studies involving overexpression of RPTPa were the first to demonstrate that PTP can dephosphorylate tyrosine 527 of Src and activate c-Src in vivo and in vitro. This activation causes cellular transformation (Zheng et al., 1992). Dephosphorylation of tyrosine 527 of c-Src in RPTPa overexpressing P19 embryonal carcinoma cells activates c-Src and induces neuronal differentiation (den Hertog et al., 1993). This observation has been independent validated in studied involving RPTPa knockout mice that exhibit a dramatic decrease (50-70%) in c-Src activity in the brain (Ponniah et al., 1999; Su et al., 1999). In addition to Src, RPTPa regulates other Src family kinases. As an example, Fyn dephosphorylation and activation is observed in cells co-expressing RPTPa and Fyn (Bhandari et al., 1998). Additionally, dephosphorylation of c-Src, Fyn and Yes, but not Lyn, was observed in A431 cells expressing RPTPa (Harder et al., 1998), indicating some degree of specificity of RPTPa. It is noteworthy that there is no evidence of gross physical abnormalities in the RPTPa-deficient mice, indicating that RPTPa is not essential for embryonic development. One explanation is that certain functions of RPTPa are compensated for by other PTPs in mice deficient in RPTPa (Pallen, 2003). RPTPa is involved in promoting integrin signaling through activation of SFKs. An earlier study shows that c-Src activation by RPTPa can increase the association of c-Src with focal adhesion kinase (FAK), and enhance tyrosine phosphorylation of the Src/FAK substrate paxillin (Harder et al., 1998). Recently, Sun et al. described a novel molecular complex of RPTPa-BCAR3-Cas-Src that is important in integrin signaling (Sun et al., 2012). This complex forms in response to RPTPaTyr789 phosphorylation and mediates Cas localization to focal adhesions and Cas downstream signaling to promote cell migration (Sun et al., 2012). More recently, Cheng et al. identified two roles of Grb2 in integrin signaling: one as a regulator of paxillin stability and upstream promoter of FAKTyr397 phosphorylation that is required for Src-FAK complex activation and another as an essential coordinator of RPTPa and activation of the Src-FAK interaction thus enabling the phosphorylation of RPTPaTyr789 (Cheng et al., 2014). |
Expression of protein tyrosine phosphatase alpha (RPTPalpha) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo. |
Ardini E, Agresti R, Tagliabue E, Greco M, Aiello P, Yang LT, Menard S, Sap J. |
Oncogene. 2000 Oct 12;19(43):4979-87. |
PMID 11042685 |
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Expression of the transmembrane protein tyrosine phosphatase RPTPalpha in human oral squamous cell carcinoma. |
Berndt A, Luo X, Bohmer FD, Kosmehl H. |
Histochem Cell Biol. 1999 May;111(5):399-403. |
PMID 10403119 |
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Physical and functional interactions between receptor-like protein-tyrosine phosphatase alpha and p59fyn. |
Bhandari V, Lim KL, Pallen CJ. |
J Biol Chem. 1998 Apr 10;273(15):8691-8. |
PMID 9535845 |
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Grb2 promotes integrin-induced focal adhesion kinase (FAK) autophosphorylation and directs the phosphorylation of protein tyrosine phosphatase a by the Src-FAK kinase complex. |
Cheng SY, Sun G, Schlaepfer DD, Pallen CJ. |
Mol Cell Biol. 2014 Feb;34(3):348-61. doi: 10.1128/MCB.00825-13. Epub 2013 Nov 18. |
PMID 24248601 |
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Multiple forms of the human tyrosine phosphatase RPTP alpha. Isozymes and differences in glycosylation. |
Daum G, Regenass S, Sap J, Schlessinger J, Fischer EH. |
J Biol Chem. 1994 Apr 8;269(14):10524-8. |
PMID 8144638 |
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Characterization of chicken protein tyrosine phosphatase alpha and its expression in the central nervous system. |
Fang KS, Martins-Green M, Williams LT, Hanafusa H. |
Brain Res Mol Brain Res. 1996 Apr;37(1-2):1-14. |
PMID 8738130 |
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Regulation of protein-tyrosine phosphatases alpha and epsilon by calpain-mediated proteolytic cleavage. |
Gil-Henn H, Volohonsky G, Elson A. |
J Biol Chem. 2001 Aug 24;276(34):31772-9. Epub 2001 Jun 27. |
PMID 11429406 |
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Protein-tyrosine phosphatase alpha regulates Src family kinases and alters cell-substratum adhesion. |
Harder KW, Moller NP, Peacock JW, Jirik FR. |
J Biol Chem. 1998 Nov 27;273(48):31890-900. |
PMID 9822658 |
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Activation of Src and transformation by an RPTPa splice mutant found in human tumours. |
Huang J, Yao L, Xu R, Wu H, Wang M, White BS, Shalloway D, Zheng X. |
EMBO J. 2011 Jul 1;30(15):3200-11. doi: 10.1038/emboj.2011.212. |
PMID 21725282 |
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Cloning of three human tyrosine phosphatases reveals a multigene family of receptor-linked protein-tyrosine-phosphatases expressed in brain. |
Kaplan R, Morse B, Huebner K, Croce C, Howk R, Ravera M, Ricca G, Jaye M, Schlessinger J. |
Proc Natl Acad Sci U S A. 1990 Sep;87(18):7000-4. |
PMID 2169617 |
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Substrate stiffness and the receptor-type tyrosine-protein phosphatase alpha regulate spreading of colon cancer cells through cytoskeletal contractility. |
Krndija D, Schmid H, Eismann JL, Lother U, Adler G, Oswald F, Seufferlein T, von Wichert G. |
Oncogene. 2010 May 6;29(18):2724-38. doi: 10.1038/onc.2010.25. Epub 2010 Mar 8. |
PMID 20208566 |
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Identification of an additional member of the protein-tyrosine-phosphatase family: evidence for alternative splicing in the tyrosine phosphatase domain. |
Matthews RJ, Cahir ED, Thomas ML. |
Proc Natl Acad Sci U S A. 1990 Jun;87(12):4444-8. |
PMID 2162042 |
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Tyrosine phosphatase PTPa contributes to HER2-evoked breast tumor initiation and maintenance. |
Meyer DS, Aceto N, Sausgruber N, Brinkhaus H, Muller U, Pallen CJ, Bentires-Alj M. |
Oncogene. 2014 Jan 16;33(3):398-402. doi: 10.1038/onc.2012.585. Epub 2013 Jan 14. |
PMID 23318421 |
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Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. |
Morin RD, Mungall K, Pleasance E, Mungall AJ, Goya R, Huff RD, Scott DW, Ding J, Roth A, Chiu R, Corbett RD, Chan FC, Mendez-Lago M, Trinh DL, Bolger-Munro M, Taylor G, Hadj Khodabakhshi A, Ben-Neriah S, Pon J, Meissner B, Woolcock B, Farnoud N, Rogic S, Lim EL, Johnson NA, Shah S, Jones S, Steidl C, Holt R, Birol I, Moore R, Connors JM, Gascoyne RD, Marra MA. |
Blood. 2013 Aug 15;122(7):1256-65. doi: 10.1182/blood-2013-02-483727. Epub 2013 May 22. |
PMID 23699601 |
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Protein tyrosine phosphatase alpha (PTPalpha): a Src family kinase activator and mediator of multiple biological effects. |
Pallen CJ. |
Curr Top Med Chem. 2003;3(7):821-35. (REVIEW) |
PMID 12678847 |
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Targeted disruption of the tyrosine phosphatase PTPalpha leads to constitutive downregulation of the kinases Src and Fyn. |
Ponniah S, Wang DZ, Lim KL, Pallen CJ. |
Curr Biol. 1999 May 20;9(10):535-8. |
PMID 10339428 |
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Cloning and expression of a widely expressed receptor tyrosine phosphatase. |
Sap J, D'Eustachio P, Givol D, Schlessinger J. |
Proc Natl Acad Sci U S A. 1990 Aug;87(16):6112-6. |
PMID 2166945 |
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Protein tyrosine phosphatases expressed in developing brain and retinal Muller glia. |
Shock LP, Bare DJ, Klinz SG, Maness PF. |
Brain Res Mol Brain Res. 1995 Jan;28(1):110-6. |
PMID 7707863 |
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Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts. |
Su J, Muranjan M, Sap J. |
Curr Biol. 1999 May 20;9(10):505-11. |
PMID 10339427 |
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Protein tyrosine phosphatase alpha phosphotyrosyl-789 binds BCAR3 to position Cas for activation at integrin-mediated focal adhesions. |
Sun G, Cheng SY, Chen M, Lim CJ, Pallen CJ. |
Mol Cell Biol. 2012 Sep;32(18):3776-89. doi: 10.1128/MCB.00214-12. Epub 2012 Jul 16. |
PMID 22801373 |
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Increased mRNA expression of the receptor-like protein tyrosine phosphatase alpha in late stage colon carcinomas. |
Tabiti K, Smith DR, Goh HS, Pallen CJ. |
Cancer Lett. 1995 Jul 13;93(2):239-48. |
PMID 7621435 |
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PTPa-mediated Src activation by EGF in human breast cancer cells. |
Wang J, Yu L, Zheng X. |
Acta Biochim Biophys Sin (Shanghai). 2013 Apr;45(4):320-9. doi: 10.1093/abbs/gmt005. |
PMID 23532252 |
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Protein tyrosine-phosphatase expression profiling in gastric cancer tissues. |
Wu CW, Kao HL, Li AF, Chi CW, Lin WC. |
Cancer Lett. 2006 Oct 8;242(1):95-103. Epub 2005 Dec 7. |
PMID 16338072 |
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Identification of a receptor-like protein tyrosine phosphatase expressed during Xenopus development. |
Yang CQ, Friesel R. |
Dev Dyn. 1998 Jul;212(3):403-12. |
PMID 9671944 |
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Apoptosis of estrogen-receptor negative breast cancer and colon cancer cell lines by PTP alpha and src RNAi. |
Zheng X, Resnick RJ, Shalloway D. |
Int J Cancer. 2008 May 1;122(9):1999-2007. doi: 10.1002/ijc.23321. |
PMID 18183590 |
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Cell transformation and activation of pp60c-src by overexpression of a protein tyrosine phosphatase. |
Zheng XM, Wang Y, Pallen CJ. |
Nature. 1992 Sep 24;359(6393):336-9. |
PMID Nature. |
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Receptor protein-tyrosine phosphatase signalling in development. |
den Hertog J, Blanchetot C, Buist A, Overvoorde J, van der Sar A, Tertoolen LG. |
Int J Dev Biol. 1999;43(7):723-33. (REVIEW) |
PMID 10668981 |
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