Phosphatase Subfamily PTPRB

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 binds to and dephosphorylates kinase Lck therefore regulating T cell function [13].

SAP-1 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, SAP-1 was highly expressed in pancreatic and colorectal cancer cells [14].

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 [15]. 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 [16].

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 [17, 18]. 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 [19] and regulation the adhesion and migration of mesangial cells in response to injury [20].

References

1. Seifert RA, Coats SA, Oganesian A, Wright MB, Dishmon M, Booth CJ, Johnson RJ, Alpers CE, and Bowen-Pope DF. PTPRQ is a novel phosphatidylinositol phosphatase that can be expressed as a cytoplasmic protein or as a subcellularly localized receptor-like protein. Exp Cell Res. 2003 Jul 15;287(2):374-86. DOI:10.1016/s0014-4827(03)00121-6 |
2. Mori M, Murata Y, Kotani T, Kusakari S, Ohnishi H, Saito Y, Okazawa H, Ishizuka T, Mori M, and Matozaki T. Promotion of cell spreading and migration by vascular endothelial-protein tyrosine phosphatase (VE-PTP) in cooperation with integrins. J Cell Physiol. 2010 Jul;224(1):195-204. DOI:10.1002/jcp.22122 |
3. Nawroth R, Poell G, Ranft A, Kloep S, Samulowitz U, Fachinger G, Golding M, Shima DT, Deutsch U, and Vestweber D. VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts. EMBO J. 2002 Sep 16;21(18):4885-95. DOI:10.1093/emboj/cdf497 |
4. Fachinger G, Deutsch U, and Risau W. Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the angiopoietin receptor Tie-2. Oncogene. 1999 Oct 21;18(43):5948-53. DOI:10.1038/sj.onc.1202992 |
5. Winderlich M, Keller L, Cagna G, Broermann A, Kamenyeva O, Kiefer F, Deutsch U, Nottebaum AF, and Vestweber D. VE-PTP controls blood vessel development by balancing Tie-2 activity. J Cell Biol. 2009 May 18;185(4):657-71. DOI:10.1083/jcb.200811159 |
6. Yacyshyn OK, Lai PF, Forse K, Teichert-Kuliszewska K, Jurasz P, and Stewart DJ. Tyrosine phosphatase beta regulates angiopoietin-Tie2 signaling in human endothelial cells. Angiogenesis. 2009;12(1):25-33. DOI:10.1007/s10456-008-9126-0 |
7. Shen J, Frye M, Lee BL, Reinardy JL, McClung JM, Ding K, Kojima M, Xia H, Seidel C, Lima e Silva R, Dong A, Hackett SF, Wang J, Howard BW, Vestweber D, Kontos CD, Peters KG, and Campochiaro PA. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014 Oct;124(10):4564-76. DOI:10.1172/JCI74527 |
8. Mellberg S, Dimberg A, Bahram F, Hayashi M, Rennel E, Ameur A, Westholm JO, Larsson E, Lindahl P, Cross MJ, and Claesson-Welsh L. Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis. FASEB J. 2009 May;23(5):1490-502. DOI:10.1096/fj.08-123810 |
9. Meng K, Rodriguez-Peña A, Dimitrov T, Chen W, Yamin M, Noda M, and Deuel TF. Pleiotrophin signals increased tyrosine phosphorylation of beta beta-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase beta/zeta. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2603-8. DOI:10.1073/pnas.020487997 |
10. Behjati S, Tarpey PS, Sheldon H, Martincorena I, Van Loo P, Gundem G, Wedge DC, Ramakrishna M, Cooke SL, Pillay N, Vollan HKM, Papaemmanuil E, Koss H, Bunney TD, Hardy C, Joseph OR, Martin S, Mudie L, Butler A, Teague JW, Patil M, Steers G, Cao Y, Gumbs C, Ingram D, Lazar AJ, Little L, Mahadeshwar H, Protopopov A, Al Sannaa GA, Seth S, Song X, Tang J, Zhang J, Ravi V, Torres KE, Khatri B, Halai D, Roxanis I, Baumhoer D, Tirabosco R, Amary MF, Boshoff C, McDermott U, Katan M, Stratton MR, Futreal PA, Flanagan AM, Harris A, and Campbell PJ. Recurrent PTPRB and PLCG1 mutations in angiosarcoma. Nat Genet. 2014 Apr;46(4):376-379. DOI:10.1038/ng.2921 |
11. Adamsky K, Schilling J, Garwood J, Faissner A, and Peles E. Glial tumor cell adhesion is mediated by binding of the FNIII domain of receptor protein tyrosine phosphatase beta (RPTPbeta) to tenascin C. Oncogene. 2001 Feb 1;20(5):609-18. DOI:10.1038/sj.onc.1204119 |
12. Garwood J, Heck N, Reichardt F, and Faissner A. Phosphacan short isoform, a novel non-proteoglycan variant of phosphacan/receptor protein tyrosine phosphatase-beta, interacts with neuronal receptors and promotes neurite outgrowth. J Biol Chem. 2003 Jun 27;278(26):24164-73. DOI:10.1074/jbc.M211721200 |
13. Ito T, Okazawa H, Maruyama K, Tomizawa K, Motegi S, Ohnishi H, Kuwano H, Kosugi A, and Matozaki T. Interaction of SAP-1, a transmembrane-type protein-tyrosine phosphatase, with the tyrosine kinase Lck. Roles in regulation of T cell function. J Biol Chem. 2003 Sep 12;278(37):34854-63. DOI:10.1074/jbc.M300648200 |
14. Matozaki T, Suzuki T, Uchida T, Inazawa J, Ariyama T, Matsuda K, Horita K, Noguchi H, Mizuno H, and Sakamoto C. Molecular cloning of a human transmembrane-type protein tyrosine phosphatase and its expression in gastrointestinal cancers. J Biol Chem. 1994 Jan 21;269(3):2075-81.
15. Yu KR, Kim YJ, Jung SK, Ku B, Park H, Cho SY, Jung H, Chung SJ, Bae KH, Lee SC, Kim BY, Erikson RL, Ryu SE, and Kim SJ. Structural basis for the dephosphorylating activity of PTPRQ towards phosphatidylinositide substrates. Acta Crystallogr D Biol Crystallogr. 2013 Aug;69(Pt 8):1522-9. DOI:10.1107/S0907444913010457 |
16. Oganesian A, Poot M, Daum G, Coats SA, Wright MB, Seifert RA, and Bowen-Pope DF. Protein tyrosine phosphatase RQ is a phosphatidylinositol phosphatase that can regulate cell survival and proliferation. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7563-8. DOI:10.1073/pnas.1336511100 |
17. Shahin H, Rahil M, Abu Rayan A, Avraham KB, King MC, Kanaan M, and Walsh T. Nonsense mutation of the stereociliar membrane protein gene PTPRQ in human hearing loss DFNB84. J Med Genet. 2010 Sep;47(9):643-5. DOI:10.1136/jmg.2009.075697 |
18. Schraders M, Oostrik J, Huygen PL, Strom TM, van Wijk E, Kunst HP, Hoefsloot LH, Cremers CW, Admiraal RJ, and Kremer H. Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction. Am J Hum Genet. 2010 Apr 9;86(4):604-10. DOI:10.1016/j.ajhg.2010.02.015 |
19. Jung H, Kim WK, Kim DH, Cho YS, Kim SJ, Park SG, Park BC, Lim HM, Bae KH, and Lee SC. Involvement of PTP-RQ in differentiation during adipogenesis of human mesenchymal stem cells. Biochem Biophys Res Commun. 2009 May 29;383(2):252-7. DOI:10.1016/j.bbrc.2009.04.001 |
20. Wright MB, Hugo C, Seifert R, Disteche CM, and Bowen-Pope DF. Proliferating and migrating mesangial cells responding to injury express a novel receptor protein-tyrosine phosphatase in experimental mesangial proliferative glomerulonephritis. J Biol Chem. 1998 Sep 11;273(37):23929-37. DOI:10.1074/jbc.273.37.23929 |