Phosphatase Subfamily PTPRD

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

PTPRD (LAR) subfamily consists of three members in human.

Evolution

PTPRD subfamily is found in holozoan (metazoan plus it closest relative choanoflagellate). PTPRD subfamily has three gene members in human and most vertebrates: PTPRD, PTPRF and PTPRS. It has single member in most invertebrate metazoan and is under intensive studies in frtui fly. Interestingly, it greatly expanded in sponge.

Domain Structure

All three members of PTPRD subfamily in human has twin intracellular PTP phosphatase domains, and extracellular Ig domains and FN3 domains. Each of them have multiple alternative splicing isoforms (for example, [1]).

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 [2].

PTPRF dephosphorylates phosphorylated tyrosine residues in both the COOH terminus and kinase domain of Fyn in vitro. It binds to Fyn Src homology 2 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 [3].

PTPRF dephosphorylates Death-associated protein kinase (DAPK) at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK [4]. (Note: Upon EGF stimulation, a rapid Src activation leads to subsequent LAR downregulation.)

PTPRF targets to lipid rafts via the interaction with caveolin-1 [5].

PTPRF plays important roles in cell-cell communication. It dephosphorylates E-cadherin (epithelial cadherin) in vitro [6]. The ectopic expression of PTPRF inhibits epithelial cell migration by preventing phosphorylation and the increase in the free pool of beta-catenin [7].

PTPRF is involved in the pathogenesis of insulin resistance by binding and dephosphorylating insulin receptor. Its overexpression in muscle causes insulin resistance [8]. 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 1t 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 [9].

PTPRD

Human PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers [10]. PTPRD loss can cause of aberrant STAT3 activation in gliomas [11]. Human PTPRD is also associated with restless legs syndrome [12], but the underlying mechanism is unclear. PTPRD interacts with MIM-B, a putative metastasis suppressor protein binding to actin [13]. 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 [14].

References

2. 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 |
3. 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.
4. 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 |
5. 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 |
6. 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 |
8. 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 |
9. 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 |
10. 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 |
11. 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 |
12. 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 |
13. 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 |
14. 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 |
15. 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 |