Phosphatase Subfamily PTPRK

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

PTPRG is a receptor PTP family involved in metazoan neural development and maybe cancer.

Evolution

PTPRK subfamily is vertebrate specific. There are four copies in human, which have similar genomic organization, despite great disparities in gene size due to variations in intron length [1].

Domain Structure

PTPRK subfamily has dual intracellular catalytic domains. All human members of PTPRK subfamily has the same extracellular domain combination: a MAM domain, 1 Ig domain and 4 FN3 domain [2, 3, 4].

MAM domain is essential for homophilic cell-cell interaction and helps determine the specificity of these interactions. Truncated PTPRM is properly expressed at the cell surface but fails to promote cell-cell adhesion. Homophilic cell adhesion is fully restored in a chimeric PTPRM molecule containing the MAM domain of PTPRK. However, this chimeric RPTP mu does not interact with either PTPRK or PTPRM [2].

Functions

PTPRK subfamily mediates homophilic cell-cell interaction [2, 5, 6, 7, 8]. They functions in nervous system. They are putative tumor suppressors in various types of cancer.

PTPRK (LAR)

PTPRK is a putative tumor suppressor [9] in various types of cancer, such as breast cancer [10], prostate cancer [11], lymphoma [12] and glioma [13]. It plays its function as tumor suppressor through different mechanisms. PTPRK influences transactivating activity of beta-catenin in non-tumoral and neoplastic cells by regulating the balance between signaling and adhesive beta-catenin which is a molecule endowed with a dual function being involved both in cell adhesion and in Wnt signaling pathway [14]. PTPRK is a key factor in coordinating apoptosis via the regulation of MAPK pathways, in particular the JNK pathway in prostate cancer cells [11]. PTPRK dephosphorylates Epidermal growth factor receptor (EGFR) and thereby regulates EGFR tyrosine phosphorylation and subsequent promotes human keratinocyte survival and proliferation [15]. It is worthy pointing out that PTPRK is the target of transforming growth factor {beta} (TGF-{beta})-Smad, which inhibits proliferation and promotes cell migration [12, 16, 17]. PTPRK also dephosphorylates Src [17].

PTPRK regulates CD4+ T cell development through ERK1/2-mediated signaling [18].

PTPRM

PTPRM mediates homophilic cell-cell adhesion [7].

PTPRT (RPTPrho)

PTPRT is restrictively expressed in the central nervous system and functions in regulating cadherin-mediated cell adhesion cellular adhesion in the central nervous system [8, 19, 20]. In brain, PTPRT regulates synapse formation through interaction with cell adhesion molecules, and this function and the phosphatase activity are attenuated through tyrosine phosphorylation by the synaptic tyrosine kinase Fyn [21].

PTPRT is a putative tumor suppressor in colon cancer. PTPRT specifically dephosphorylated signal transducer and activator of transcription 3 (STAT3) at Y705 is essential for the function of STAT3 (Note: PTPRD dephosphorylate STAT3 Y705, as well). Overexpression of normal PTPRT in colorectal cancer cells reduced the expression of STAT3 target genes [22]. PTPRT knockout mice exhibit increased levels of colonic paxillin phosphorylation at residue Y88, which is found as a common feature of human colon cancers [23].

PTPRT is the most frequently mutated PTP in different types of human cancers and is believed to be a tumor suppressor in colon cancer [24] and head and neck squamous cell carcinoma [25], but it does not play a critical role in the development of common human cancers [26]. It is worthy pointing out that more than half of the identified tumor-derived mutations are located in the extracellular part, particularly MAM domain and Ig domain, which mediates the homophilic interaction of cell-cell adhesion [27].

PTPRU (PTP-RO/hPTP-J/PTP pi/PTP lambda)

PTPRU is predominately found in adult brain, lung, and kidney [28, 29]. PTPRU is glycosylated and expressed at the cell surface. PTPRU localizes to the adherens junctions with cell adhesion molecules like catenin and E-cadherin [6]. PTPRU directly binds and dephosphorylates beta-catenin, which is a key molecule involved in both cell adhesion and Wnt signaling pathway [30, 31]. PTPRU-deficient mice associated with hypertension and low glomerular filtration rate [32].

PTPRU was weakly detected in the peripheral blood lymphocytes, thymus, and spleen even though gene expression was relatively high in the Jurkat T lymphoma cell line. Moreover, PTPRU gene expression was down-regulated after Jurkat cells (an immortalized line of human T lymphocyte cells) were stimulated by either Phorbol myristate acetage (PMA) or calcium ionophore [33, 34].

References

1. Besco J, Popesco MC, Davuluri RV, Frostholm A, and Rotter A. Genomic structure and alternative splicing of murine R2B receptor protein tyrosine phosphatases (PTPkappa, mu, rho and PCP-2). BMC Genomics. 2004 Feb 11;5(1):14. DOI:10.1186/1471-2164-5-14 |
2. Zondag GC, Koningstein GM, Jiang YP, Sap J, Moolenaar WH, and Gebbink MF. Homophilic interactions mediated by receptor tyrosine phosphatases mu and kappa. A critical role for the novel extracellular MAM domain. J Biol Chem. 1995 Jun 16;270(24):14247-50. DOI:10.1074/jbc.270.24.14247 |
3. Crossland S, Smith PD, and Crompton MR. Molecular cloning and characterization of PTP pi, a novel receptor-like protein-tyrosine phosphatase. Biochem J. 1996 Oct 1;319 ( Pt 1)(Pt 1):249-54. DOI:10.1042/bj3190249 |
5. Sap J, Jiang YP, Friedlander D, Grumet M, and Schlessinger J. Receptor tyrosine phosphatase R-PTP-kappa mediates homophilic binding. Mol Cell Biol. 1994 Jan;14(1):1-9. DOI:10.1128/mcb.14.1.1-9.1994 |
6. Wang H, Lian Z, Lerch MM, Chen Z, Xie W, and Ullrich A. Characterization of PCP-2, a novel receptor protein tyrosine phosphatase of the MAM domain family. Oncogene. 1996 Jun 20;12(12):2555-62.
8. McAndrew PE, Frostholm A, White RA, Rotter A, and Burghes AH. Identification and characterization of RPTP rho, a novel RPTP mu/kappa-like receptor protein tyrosine phosphatase whose expression is restricted to the central nervous system. Brain Res Mol Brain Res. 1998 May;56(1-2):9-21. DOI:10.1016/s0169-328x(98)00014-x |
9. Zhang Y, Siebert R, Matthiesen P, Yang Y, Ha H, and Schlegelberger B. Cytogenetical assignment and physical mapping of the human R-PTP-kappa gene (PTPRK) to the putative tumor suppressor gene region 6q22.2-q22.3. Genomics. 1998 Jul 15;51(2):309-11. DOI:10.1006/geno.1998.5323 |
10. Sun PH, Ye L, Mason MD, and Jiang WG. Protein tyrosine phosphatase kappa (PTPRK) is a negative regulator of adhesion and invasion of breast cancer cells, and associates with poor prognosis of breast cancer. J Cancer Res Clin Oncol. 2013 Jul;139(7):1129-39. DOI:10.1007/s00432-013-1421-5 |
11. Sun PH, Ye L, Mason MD, and Jiang WG. Receptor-like protein tyrosine phosphatase κ negatively regulates the apoptosis of prostate cancer cells via the JNK pathway. Int J Oncol. 2013 Nov;43(5):1560-8. DOI:10.3892/ijo.2013.2082 |
12. Flavell JR, Baumforth KR, Wood VH, Davies GL, Wei W, Reynolds GM, Morgan S, Boyce A, Kelly GL, Young LS, and Murray PG. Down-regulation of the TGF-beta target gene, PTPRK, by the Epstein-Barr virus encoded EBNA1 contributes to the growth and survival of Hodgkin lymphoma cells. Blood. 2008 Jan 1;111(1):292-301. DOI:10.1182/blood-2006-11-059881 |
14. Xu Y, Tan LJ, Grachtchouk V, Voorhees JJ, and Fisher GJ. Receptor-type protein-tyrosine phosphatase-kappa regulates epidermal growth factor receptor function. J Biol Chem. 2005 Dec 30;280(52):42694-700. DOI:10.1074/jbc.M507722200 |
15. Xu Y, Tan LJ, Grachtchouk V, Voorhees JJ, and Fisher GJ. Receptor-type protein-tyrosine phosphatase-kappa regulates epidermal growth factor receptor function. J Biol Chem. 2005 Dec 30;280(52):42694-700. DOI:10.1074/jbc.M507722200 |
16. Yang Y, Gil M, Byun SM, Choi I, Pyun KH, and Ha H. Transforming growth factor-beta1 inhibits human keratinocyte proliferation by upregulation of a receptor-type tyrosine phosphatase R-PTP-kappa gene expression. Biochem Biophys Res Commun. 1996 Nov 21;228(3):807-12. DOI:10.1006/bbrc.1996.1736 |
17. Wang SE, Wu FY, Shin I, Qu S, and Arteaga CL. Transforming growth factor {beta} (TGF-{beta})-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-{beta} function. Mol Cell Biol. 2005 Jun;25(11):4703-15. DOI:10.1128/MCB.25.11.4703-4715.2005 |
18. Erdenebayar N, Maekawa Y, Nishida J, Kitamura A, and Yasutomo K. Protein-tyrosine phosphatase-kappa regulates CD4+ T cell development through ERK1/2-mediated signaling. Biochem Biophys Res Commun. 2009 Dec 18;390(3):489-93. DOI:10.1016/j.bbrc.2009.09.117 |
19. McAndrew PE, Frostholm A, Evans JE, Zdilar D, Goldowitz D, Chiu IM, Burghes AH, and Rotter A. Novel receptor protein tyrosine phosphatase (RPTPrho) and acidic fibroblast growth factor (FGF-1) transcripts delineate a rostrocaudal boundary in the granule cell layer of the murine cerebellar cortex. J Comp Neurol. 1998 Feb 22;391(4):444-55. DOI:10.1002/(sici)1096-9861(19980222)391:4<444::aid-cne3>3.0.co;2-0 |
20. Besco JA, Hooft van Huijsduijnen R, Frostholm A, and Rotter A. Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPrho/PTPRT). Brain Res. 2006 Oct 20;1116(1):50-7. DOI:10.1016/j.brainres.2006.07.122 |
21. Lim SH, Kwon SK, Lee MK, Moon J, Jeong DG, Park E, Kim SJ, Park BC, Lee SC, Ryu SE, Yu DY, Chung BH, Kim E, Myung PK, and Lee JR. Synapse formation regulated by protein tyrosine phosphatase receptor T through interaction with cell adhesion molecules and Fyn. EMBO J. 2009 Nov 18;28(22):3564-78. DOI:10.1038/emboj.2009.289 |
22. Zhang X, Guo A, Yu J, Possemato A, Chen Y, Zheng W, Polakiewicz RD, Kinzler KW, Vogelstein B, Velculescu VE, and Wang ZJ. Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4060-4. DOI:10.1073/pnas.0611665104 |
23. Zhao Y, Zhang X, Guda K, Lawrence E, Sun Q, Watanabe T, Iwakura Y, Asano M, Wei L, Yang Z, Zheng W, Dawson D, Willis J, Markowitz SD, Satake M, and Wang Z. Identification and functional characterization of paxillin as a target of protein tyrosine phosphatase receptor T. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2592-7. DOI:10.1073/pnas.0914884107 |
24. Scott A and Wang Z. Tumour suppressor function of protein tyrosine phosphatase receptor-T. Biosci Rep. 2011 Oct;31(5):303-7. DOI:10.1042/BSR20100134 |
25. Lui VW, Peyser ND, Ng PK, Hritz J, Zeng Y, Lu Y, Li H, Wang L, Gilbert BR, General IJ, Bahar I, Ju Z, Wang Z, Pendleton KP, Xiao X, Du Y, Vries JK, Hammerman PS, Garraway LA, Mills GB, Johnson DE, and Grandis JR. Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer. Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1114-9. DOI:10.1073/pnas.1319551111 |
26. Lee JW, Jeong EG, Lee SH, Nam SW, Kim SH, Lee JY, Yoo NJ, and Lee SH. Mutational analysis of PTPRT phosphatase domains in common human cancers. APMIS. 2007 Jan;115(1):47-51. DOI:10.1111/j.1600-0463.2007.apm_554.x |
27. Yu J, Becka S, Zhang P, Zhang X, Brady-Kalnay SM, and Wang Z. Tumor-derived extracellular mutations of PTPRT /PTPrho are defective in cell adhesion. Mol Cancer Res. 2008 Jul;6(7):1106-13. DOI:10.1158/1541-7786.MCR-07-2123 |
28. Cheng J, Wu K, Armanini M, O'Rourke N, Dowbenko D, and Lasky LA. A novel protein-tyrosine phosphatase related to the homotypically adhering kappa and mu receptors. J Biol Chem. 1997 Mar 14;272(11):7264-77. DOI:10.1074/jbc.272.11.7264 |
29. Sommer L, Rao M, and Anderson DJ. RPTP delta and the novel protein tyrosine phosphatase RPTP psi are expressed in restricted regions of the developing central nervous system. Dev Dyn. 1997 Jan;208(1):48-61. DOI:10.1002/(SICI)1097-0177(199701)208:1<48::AID-AJA5>3.0.CO;2-1 |
30. Yan HX, He YQ, Dong H, Zhang P, Zeng JZ, Cao HF, Wu MC, and Wang HY. Physical and functional interaction between receptor-like protein tyrosine phosphatase PCP-2 and beta-catenin. Biochemistry. 2002 Dec 31;41(52):15854-60. DOI:10.1021/bi026095u |
31. Yan HX, Yang W, Zhang R, Chen L, Tang L, Zhai B, Liu SQ, Cao HF, Man XB, Wu HP, Wu MC, and Wang HY. Protein-tyrosine phosphatase PCP-2 inhibits beta-catenin signaling and increases E-cadherin-dependent cell adhesion. J Biol Chem. 2006 Jun 2;281(22):15423-33. DOI:10.1074/jbc.M602607200 |
33. Wang B, Kishihara K, Zhang D, Hara H, and Nomoto K. Molecular cloning and characterization of a novel human receptor protein tyrosine phosphatase gene, hPTP-J: down-regulation of gene expression by PMA and calcium ionophore in Jurkat T lymphoma cells. Biochem Biophys Res Commun. 1997 Feb 3;231(1):77-81. DOI:10.1006/bbrc.1997.6004 |
35. Agarwal S, Al-Keilani MS, Alqudah MA, Sibenaller ZA, Ryken TC, and Assem M. Tumor derived mutations of protein tyrosine phosphatase receptor type k affect its function and alter sensitivity to chemotherapeutics in glioma. PLoS One. 2013;8(5):e62852. DOI:10.1371/journal.pone.0062852 |
36. Kim YS, Jung JA, Kim HJ, Ahn YH, Yoo JS, Oh S, Cho C, Yoo HS, and Ko JH. Galectin-3 binding protein promotes cell motility in colon cancer by stimulating the shedding of protein tyrosine phosphatase kappa by proprotein convertase 5. Biochem Biophys Res Commun. 2011 Jan 7;404(1):96-102. DOI:10.1016/j.bbrc.2010.11.071 |