Phosphatase Subfamily PTPRD

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

PTPRD phosphatases localize to axonal growth cones, regulating neuronal growth and guidance and participating in excitatory synapse formation and maintenance in vertebrates as well as invertebrates.

Evolution

PTPRD is found in holozoa (metazoa plus choanoflagellates). PTPRD has three members in human and most vertebrates: PTPRD, PTPRF and PTPRS. It has single member in most invertebrate metazoa but greatly expanded in sponge.

Domain Structure

All three human PTPRDs have twin intracellular PTP phosphatase domains, and extracellular Ig domains and FN3 domains. Each of them have multiple alternative splicing isoforms [1, 2, 3]. Invertebrate homologs have a similar architecture, though many gene models are incomplete.

Functions

PTPRF (LAR)

The best characterized member of the three human genes in the subfamily is PTPRF, aka LAR. Knock-down of PTPRF by siRNA induced post-receptor insulin resistance with the insulin-induced activation of PKB/Akt and MAP kinases markedly inhibited. But, the phosphorylation and dephosphorylation of the IR and insulin receptor substrate (IRS) proteins were unaffected by PTPRF knock-down [4].

PTPRF dephosphorylates tyrosine residues in both the C-terminus and kinase domain of Fyn in vitro. It binds to Fyn SH2 domain when its 2nd phosphatase was tyrosine phosphorylated by Fyn tyrosine kinase. In addition to Fyn kinase, PTPRF mutants, with Cys to Ser mutation in the catalytic center of 1st phosphatase domain, can bind to tyrosine-phosphorylated Lck kinase [5].

PTPRF dephosphorylates Death-associated protein kinase (DAPK) at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK [6]. (Note: Upon EGF stimulation, a rapid Src activation leads to subsequent LAR downregulation.)

PTPRF targets to lipid rafts via the interaction with caveolin-1 [7].

PTPRF plays important roles in cell-cell communication. PTPRF localizes to cadherin-beta-catenin-based cellular junctions. Assembly and disassembly of these junctions are regulated by tyrosine phosphorylation. PTPRF dephosphorylates E-cadherin (epithelial cadherin) in vitro [8]. The ectopic expression of PTPRF inhibits epithelial cell migration by preventing phosphorylation and the increase in the free pool of beta-catenin [9].

PTPRF also specifically dephosphorylates and destabilizes BCAR1/p130Cas (breast cancer anti-estrogen resistance 1) and may play a role in regulating cell adhesion-mediated cell survival [10].

PTPRF is involved in the pathogenesis of insulin resistance by binding and dephosphorylating insulin receptor. Its overexpression in muscle causes insulin resistance [11]. PTPRF associates with and preferentially dephosphorylates the insulin receptor that was tyrosine phosphorylated by insulin stimulation. When replace cysteine residue at catalytic motif with serine at the 1st phosphatase domain, PTPRF fails to dephosphorylate insulin receptor, which indicates 1st domain carries out the activity []. Replacing cysteine with serine at the 2nd domain resulted in weaker association, which suggests the 2nd domain may play regulatory role [12, 13]. The dephosphorylation of insulin receptor leads to decreased phosphorylation of the adaptor protein IRS-1 and its downstream molecule Akt (also known as PKB).

PTPRF dephosphorylated EphA2 (ephrin type-A receptor 2) at phosphotyrosyl 930, uncoupling Nck1 from EphA2 and thereby attenuating EphA2-mediated cell migration [14].

PTPRF associates with c-Met, and purified PTPRF dephosphorylates tyrosine-phosphorylated c-Met in in vitro [15]. Other PTPs also have shown activities toward c-Met [16], and it is unclear whether c-Met is PTPRF's physiological substrate.

PTPRD (RPTPdelta, PTPδ)

Human PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers. PTPRD dephosphorylates STAT3 Y705, a residue that must be phosphorylated for STAT3 to be active [17]. PTPRD loss can cause of aberrant STAT3 activation in gliomas [18]. Human PTPRD is also associated with restless legs syndrome [19], but the underlying mechanism is unclear. PTPRD interacts with MIM-B, a putative metastasis suppressor protein binding to actin [20]. It is not clear whether MIM-B is its substrate. The 2nd phosphatase domain of PTPRD can bind to inhibit the 1st phosphatase domain of PTPRS [21].

PTPRD is also involved in synaptic differentiation. It can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner [22].

PTPRS (RPTPsigma/RPTPσ)

PTPRS reduce EGFR phosphorylation and therefore modulates signaling of the epidermal growth factor receptor in A431 cells [23]. Frequent deletion of PTPRS was found in head and neck cancers. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations [24].

PTPRS-deficient mice exhibit neurological and neuroendocrine defects [25, 26]. PTPRS interacts with proteoglycans heparan sulfate proteoglycans (HSPGs) and chondroitin sulfate proteoglycans (CSPGs) through extracellular region. The proteoglycans exert opposing effects on neuronal extension by competing to control the oligomerization of PTPRS [27]. The proteoglycan switch is a putative target of rheumatoid arthritis therapy [28].

PTPRS is involved in the regulation of autophagy. Loss of PTPRS increases levels of cellular Phosphatidylinositol-3-phosphate (PtdIns3P) [29]. However, it is unclear whether PtdIns3P is its physiological substrate.

References

1. Pulido R, Serra-Pagès C, Tang M, and Streuli M. The LAR/PTP delta/PTP sigma subfamily of transmembrane protein-tyrosine-phosphatases: multiple human LAR, PTP delta, and PTP sigma isoforms are expressed in a tissue-specific manner and associate with the LAR-interacting protein LIP.1. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11686-90. DOI:10.1073/pnas.92.25.11686 |
2. O'Grady P, Krueger NX, Streuli M, and Saito H. Genomic organization of the human LAR protein tyrosine phosphatase gene and alternative splicing in the extracellular fibronectin type-III domains. J Biol Chem. 1994 Oct 7;269(40):25193-9.
3. Endo N, Rutledge SJ, Opas EE, Vogel R, Rodan GA, and Schmidt A. Human protein tyrosine phosphatase-sigma: alternative splicing and inhibition by bisphosphonates. J Bone Miner Res. 1996 Apr;11(4):535-43. DOI:10.1002/jbmr.5650110415 |
4. Mander A, Hodgkinson CP, and Sale GJ. Knock-down of LAR protein tyrosine phosphatase induces insulin resistance. FEBS Lett. 2005 Jun 6;579(14):3024-8. DOI:10.1016/j.febslet.2005.04.057 |
5. Tsujikawa K, Ichijo T, Moriyama K, Tadotsu N, Sakamoto K, Sakane N, Fukada S, Furukawa T, Saito H, and Yamamoto H. Regulation of Lck and Fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule. Mol Cancer Res. 2002 Dec;1(2):155-63.
6. Hoogenraad CC, Feliu-Mojer MI, Spangler SA, Milstein AD, Dunah AW, Hung AY, and Sheng M. Liprinalpha1 degradation by calcium/calmodulin-dependent protein kinase II regulates LAR receptor tyrosine phosphatase distribution and dendrite development. Dev Cell. 2007 Apr;12(4):587-602. DOI:10.1016/j.devcel.2007.02.006 |
7. Caselli A, Mazzinghi B, Camici G, Manao G, and Ramponi G. Some protein tyrosine phosphatases target in part to lipid rafts and interact with caveolin-1. Biochem Biophys Res Commun. 2002 Aug 23;296(3):692-7. DOI:10.1016/s0006-291x(02)00928-2 |
8. Symons JR, LeVea CM, and Mooney RA. Expression of the leucocyte common antigen-related (LAR) tyrosine phosphatase is regulated by cell density through functional E-cadherin complexes. Biochem J. 2002 Jul 15;365(Pt 2):513-9. DOI:10.1042/BJ20020381 |
9. Müller T, Choidas A, Reichmann E, and Ullrich A. Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinases and tyrosine phosphatases during epithelial cell migration. J Biol Chem. 1999 Apr 9;274(15):10173-83. DOI:10.1074/jbc.274.15.10173 |
10. Weng LP, Wang X, and Yu Q. Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas. Genes Cells. 1999 Mar;4(3):185-96. DOI:10.1046/j.1365-2443.1999.00251.x |
11. Zabolotny JM, Kim YB, Peroni OD, Kim JK, Pani MA, Boss O, Klaman LD, Kamatkar S, Shulman GI, Kahn BB, and Neel BG. Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5187-92. DOI:10.1073/pnas.071050398 |
12. Weng LP, Wang X, and Yu Q. Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas. Genes Cells. 1999 Mar;4(3):185-96. DOI:10.1046/j.1365-2443.1999.00251.x |
13. Tsujikawa K, Kawakami N, Uchino Y, Ichijo T, Furukawa T, Saito H, and Yamamoto H. Distinct functions of the two protein tyrosine phosphatase domains of LAR (leukocyte common antigen-related) on tyrosine dephosphorylation of insulin receptor. Mol Endocrinol. 2001 Feb;15(2):271-80. DOI:10.1210/mend.15.2.0592 |
14. Lee H and Bennett AM. Receptor protein tyrosine phosphatase-receptor tyrosine kinase substrate screen identifies EphA2 as a target for LAR in cell migration. Mol Cell Biol. 2013 Apr;33(7):1430-41. DOI:10.1128/MCB.01708-12 |
15. Machide M, Hashigasako A, Matsumoto K, and Nakamura T. Contact inhibition of hepatocyte growth regulated by functional association of the c-Met/hepatocyte growth factor receptor and LAR protein-tyrosine phosphatase. J Biol Chem. 2006 Mar 31;281(13):8765-72. DOI:10.1074/jbc.M512298200 |
16. Sangwan V, Paliouras GN, Abella JV, Dubé N, Monast A, Tremblay ML, and Park M. Regulation of the Met receptor-tyrosine kinase by the protein-tyrosine phosphatase 1B and T-cell phosphatase. J Biol Chem. 2008 Dec 5;283(49):34374-83. DOI:10.1074/jbc.M805916200 |
17. Veeriah S, Brennan C, Meng S, Singh B, Fagin JA, Solit DB, Paty PB, Rohle D, Vivanco I, Chmielecki J, Pao W, Ladanyi M, Gerald WL, Liau L, Cloughesy TC, Mischel PS, Sander C, Taylor B, Schultz N, Major J, Heguy A, Fang F, Mellinghoff IK, and Chan TA. The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9435-40. DOI:10.1073/pnas.0900571106 |
18. Ortiz B, Fabius AW, Wu WH, Pedraza A, Brennan CW, Schultz N, Pitter KL, Bromberg JF, Huse JT, Holland EC, and Chan TA. Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis. Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):8149-54. DOI:10.1073/pnas.1401952111 |
19. Schormair B, Kemlink D, Roeske D, Eckstein G, Xiong L, Lichtner P, Ripke S, Trenkwalder C, Zimprich A, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Högl B, Frauscher B, Gschliesser V, Poewe W, Peglau I, Vodicka P, Vávrová J, Sonka K, Nevsimalova S, Montplaisir J, Turecki G, Rouleau G, Gieger C, Illig T, Wichmann HE, Holsboer F, Müller-Myhsok B, Meitinger T, and Winkelmann J. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet. 2008 Aug;40(8):946-8. DOI:10.1038/ng.190 |
20. Woodings JA, Sharp SJ, and Machesky LM. MIM-B, a putative metastasis suppressor protein, binds to actin and to protein tyrosine phosphatase delta. Biochem J. 2003 Apr 15;371(Pt 2):463-71. DOI:10.1042/BJ20021962 |
21. Wallace MJ, Fladd C, Batt J, and Rotin D. The second catalytic domain of protein tyrosine phosphatase delta (PTP delta) binds to and inhibits the first catalytic domain of PTP sigma. Mol Cell Biol. 1998 May;18(5):2608-16. DOI:10.1128/MCB.18.5.2608 |
22. Yamagata A, Yoshida T, Sato Y, Goto-Ito S, Uemura T, Maeda A, Shiroshima T, Iwasawa-Okamoto S, Mori H, Mishina M, and Fukai S. Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ-IL1RAPL1/IL-1RAcP for synaptic differentiation. Nat Commun. 2015 Apr 24;6:6926. DOI:10.1038/ncomms7926 |
24. Morris LG, Taylor BS, Bivona TG, Gong Y, Eng S, Brennan CW, Kaufman A, Kastenhuber ER, Banuchi VE, Singh B, Heguy A, Viale A, Mellinghoff IK, Huse J, Ganly I, and Chan TA. Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers. Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):19024-9. DOI:10.1073/pnas.1111963108 |
25. Elchebly M, Wagner J, Kennedy TE, Lanctôt C, Michaliszyn E, Itié A, Drouin J, and Tremblay ML. Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase sigma. Nat Genet. 1999 Mar;21(3):330-3. DOI:10.1038/6859 |
26. Wallace MJ, Batt J, Fladd CA, Henderson JT, Skarnes W, and Rotin D. Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTPsigma. Nat Genet. 1999 Mar;21(3):334-8. DOI:10.1038/6866 |
27. Coles CH, Shen Y, Tenney AP, Siebold C, Sutton GC, Lu W, Gallagher JT, Jones EY, Flanagan JG, and Aricescu AR. Proteoglycan-specific molecular switch for RPTPσ clustering and neuronal extension. Science. 2011 Apr 22;332(6028):484-8. DOI:10.1126/science.1200840 |
28. Doody KM, Stanford SM, Sacchetti C, Svensson MN, Coles CH, Mitakidis N, Kiosses WB, Bartok B, Fos C, Cory E, Sah RL, Liu-Bryan R, Boyle DL, Arnett HA, Mustelin T, Corr M, Esko JD, Tremblay ML, Firestein GS, Aricescu AR, and Bottini N. Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy. Sci Transl Med. 2015 May 20;7(288):288ra76. DOI:10.1126/scitranslmed.aaa4616 |
29. Martin KR, Xu Y, Looyenga BD, Davis RJ, Wu CL, Tremblay ML, Xu HE, and MacKeigan JP. Identification of PTPsigma as an autophagic phosphatase. J Cell Sci. 2011 Mar 1;124(Pt 5):812-9. DOI:10.1242/jcs.080341 |
30. Furlan G, Minowa T, Hanagata N, Kataoka-Hamai C, and Kaizuka Y. Phosphatase CD45 both positively and negatively regulates T cell receptor phosphorylation in reconstituted membrane protein clusters. J Biol Chem. 2014 Oct 10;289(41):28514-25. DOI:10.1074/jbc.M114.574319 |