Phosphatase Subfamily PTPN3

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Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN3


The PTPN3 subfamily emerged in holozoa and duplicated in vertebrates. Human has two members, PTPN3 (PTPH1) and PTPN4 (PTP-MEG).


The PTPN3 subfamily has a domain combination of FERM domain, PEST sequence, PDZ domain and phosphatase domain [1, 2, 3]. PDZ domain can bind to other proteins and modulate the phosphatase domain [4].


The expression pattern, substrates and interacting partners of PTPN3/PTPH1 and PTPN4 have limited overlap.


PTPN3/PTPH1 is widely expressed in different tissues; it is expressed at a relatively higher level in skin and skeletal muscle according to GTEx. Substrates include:

  • Cell cycle regulator VCP (p97/CDC48) [5].
  • T cell receptor zeta subunit [6].
  • Estrogen receptor at Tyr-537 [7].
  • Epidermal growth factor receptor (EGFR) pathway substrate 15 (Eps15) at Tyr-849[8].
  • EGFR [9].
  • p38γ mitogen-activated protein kinase (MAPK). The interaction is mediated through PDZ binding [10], and vice versa, p38γ is also a kinase of PTPN3 [11].

PTPN3 interacts with and regulates Cardiac sodium channel Na(v)1.5. The interaction is mediated by the PDZ domain of PTPN3 and the PDZ-domain binding motif of Na(v)1.5 [12]. PTPN3 is a negative regulator of Tumor necrosis factor alpha-convertase (TACE), a metalloprotease-disintegrin involved in the ectodomain shedding of several proteins and is critical for proper murine development. The interaction is mediated via binding of the PDZ domain of PTPN2 to the COOH terminus of TACE [13]. PTPN3 interacts with adaptor protein 14-3-3beta in a manner dependent on the phosphorylation state of PTPN3 [14]. PTPN3 binds to vitamin D receptor (VDR) and increases VDR's cytoplasmic accumulation, leading to their mutual stabilization and stimulating breast cancer growth [15]. PTPN3 controls growth hormone receptor (GHR) signaling [16].

PTPN3 is implicated in breast cancer [7, 15], intrahepatic cholangiocarcinoma [17], and human hepatocellular carcinomas [18].


PTPN4/PTPMEG primarily locates in the membrane and cytoskeleton [19, 20]. PTPN4/PTPMEG has been shown to be specifically expressed in testis [21]. However, RNA-seq data in GTEx shows it is widely expressed in different tissues, most abundantly in cerebellum and the expression level in testis is close to the average.

PTPN4 dephosphorylates T cell receptor (TCR) at ITAM motifs, a conserved signaling motif and are present in one or more copies in the cytoplasmic tails of the CD3 γ, δ, ε and TCR ζ subunits [22].

PTPN4 dephosphorylates TRIF-related adaptor molecule (TRAM, also known as TICAM2), therefore inhibiting TRIF-dependent TLR4 pathway [23].

PTPN4/PTPMEG interacts with but does not directly phosphorylates glutamate receptor delta 2 and epsilon subunits [24].


  1. Yang Q and Tonks NK. Isolation of a cDNA clone encoding a human protein-tyrosine phosphatase with homology to the cytoskeletal-associated proteins band 4.1, ezrin, and talin. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):5949-53. DOI:10.1073/pnas.88.14.5949 | PubMed ID:1648725 | HubMed [Yang91]
  2. Itoh F, Ikuta S, Hinoda Y, Arimura Y, Ohe M, Adachi M, Ariyama T, Inazawa J, Imai K, and Yachi A. Expression and chromosomal assignment of PTPH1 gene encoding a cytosolic protein tyrosine phosphatase homologous to cytoskeletal-associated proteins. Int J Cancer. 1993 Dec 2;55(6):947-51. DOI:10.1002/ijc.2910550612 | PubMed ID:8253532 | HubMed [Itoh93]
  3. Gu M, Meng K, and Majerus PW. The effect of overexpression of the protein tyrosine phosphatase PTPMEG on cell growth and on colony formation in soft agar in COS-7 cells. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12980-5. DOI:10.1073/pnas.93.23.12980 | PubMed ID:8917530 | HubMed [Gu96b]
  4. Maisonneuve P, Caillet-Saguy C, Raynal B, Gilquin B, Chaffotte A, Pérez J, Zinn-Justin S, Delepierre M, Buc H, Cordier F, and Wolff N. Regulation of the catalytic activity of the human phosphatase PTPN4 by its PDZ domain. FEBS J. 2014 Nov;281(21):4852-65. DOI:10.1111/febs.13024 | PubMed ID:25158884 | HubMed [Maisonneuve14]
  5. Zhang SH, Liu J, Kobayashi R, and Tonks NK. Identification of the cell cycle regulator VCP (p97/CDC48) as a substrate of the band 4.1-related protein-tyrosine phosphatase PTPH1. J Biol Chem. 1999 Jun 18;274(25):17806-12. DOI:10.1074/jbc.274.25.17806 | PubMed ID:10364224 | HubMed [Zhang99]
  6. Sozio MS, Mathis MA, Young JA, Wälchli S, Pitcher LA, Wrage PC, Bartók B, Campbell A, Watts JD, Aebersold R, Hooft van Huijsduijnen R, and van Oers NS. PTPH1 is a predominant protein-tyrosine phosphatase capable of interacting with and dephosphorylating the T cell receptor zeta subunit. J Biol Chem. 2004 Feb 27;279(9):7760-9. DOI:10.1074/jbc.M309994200 | PubMed ID:14672952 | HubMed [Sozio04]
  7. Suresh PS, Ma S, Migliaccio A, and Chen G. Protein-tyrosine phosphatase H1 increases breast cancer sensitivity to antiestrogens by dephosphorylating estrogen receptor at Tyr537. Mol Cancer Ther. 2014 Jan;13(1):230-8. DOI:10.1158/1535-7163.MCT-13-0610 | PubMed ID:24227889 | HubMed [Suresh14]
  8. Chen KE, Li MY, Chou CC, Ho MR, Chen GC, Meng TC, and Wang AH. Substrate specificity and plasticity of FERM-containing protein tyrosine phosphatases. Structure. 2015 Apr 7;23(4):653-64. DOI:10.1016/j.str.2015.01.017 | PubMed ID:25728925 | HubMed [Chen15]
  9. Ma S, Yin N, Qi X, Pfister SL, Zhang MJ, Ma R, and Chen G. Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER). Oncotarget. 2015 May 30;6(15):13320-33. DOI:10.18632/oncotarget.3645 | PubMed ID:26079946 | HubMed [Ma15]
  10. Hou SW, Zhi HY, Pohl N, Loesch M, Qi XM, Li RS, Basir Z, and Chen G. PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction. Cancer Res. 2010 Apr 1;70(7):2901-10. DOI:10.1158/0008-5472.CAN-09-3229 | PubMed ID:20332238 | HubMed [Hou10]
  11. Hou S, Suresh PS, Qi X, Lepp A, Mirza SP, and Chen G. p38γ Mitogen-activated protein kinase signals through phosphorylating its phosphatase PTPH1 in regulating ras protein oncogenesis and stress response. J Biol Chem. 2012 Aug 10;287(33):27895-905. DOI:10.1074/jbc.M111.335794 | PubMed ID:22730326 | HubMed [Hou11]
  12. Jespersen T, Gavillet B, van Bemmelen MX, Cordonier S, Thomas MA, Staub O, and Abriel H. Cardiac sodium channel Na(v)1.5 interacts with and is regulated by the protein tyrosine phosphatase PTPH1. Biochem Biophys Res Commun. 2006 Oct 6;348(4):1455-62. DOI:10.1016/j.bbrc.2006.08.014 | PubMed ID:16930557 | HubMed [Jespersen06]
  13. Zheng Y, Schlondorff J, and Blobel CP. Evidence for regulation of the tumor necrosis factor alpha-convertase (TACE) by protein-tyrosine phosphatase PTPH1. J Biol Chem. 2002 Nov 8;277(45):42463-70. DOI:10.1074/jbc.M207459200 | PubMed ID:12207026 | HubMed [Zheng02]
  14. Zhang SH, Kobayashi R, Graves PR, Piwnica-Worms H, and Tonks NK. Serine phosphorylation-dependent association of the band 4.1-related protein-tyrosine phosphatase PTPH1 with 14-3-3beta protein. J Biol Chem. 1997 Oct 24;272(43):27281-7. DOI:10.1074/jbc.272.43.27281 | PubMed ID:9341175 | HubMed [Zhang97]
  15. Zhi HY, Hou SW, Li RS, Basir Z, Xiang Q, Szabo A, and Chen G. PTPH1 cooperates with vitamin D receptor to stimulate breast cancer growth through their mutual stabilization. Oncogene. 2011 Apr 7;30(14):1706-15. DOI:10.1038/onc.2010.543 | PubMed ID:21119599 | HubMed [Zhi11]
  16. Pilecka I, Patrignani C, Pescini R, Curchod ML, Perrin D, Xue Y, Yasenchak J, Clark A, Magnone MC, Zaratin P, Valenzuela D, Rommel C, and Hooft van Huijsduijnen R. Protein-tyrosine phosphatase H1 controls growth hormone receptor signaling and systemic growth. J Biol Chem. 2007 Nov 30;282(48):35405-15. DOI:10.1074/jbc.M705814200 | PubMed ID:17921143 | HubMed [Pilecka07]
  17. Gao Q, Zhao YJ, Wang XY, Guo WJ, Gao S, Wei L, Shi JY, Shi GM, Wang ZC, Zhang YN, Shi YH, Ding J, Ding ZB, Ke AW, Dai Z, Wu FZ, Wang H, Qiu ZP, Chen ZA, Zhang ZF, Qiu SJ, Zhou J, He XH, and Fan J. Activating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence in patients. Gastroenterology. 2014 May;146(5):1397-407. DOI:10.1053/j.gastro.2014.01.062 | PubMed ID:24503127 | HubMed [Gao14]
  18. Ikuta S, Itoh F, Hinoda Y, Toyota M, Makiguchi Y, Imai K, and Yachi A. Expression of cytoskeletal-associated protein tyrosine phosphatase PTPH1 mRNA in human hepatocellular carcinoma. J Gastroenterol. 1994 Dec;29(6):727-32. DOI:10.1007/BF02349278 | PubMed ID:7874267 | HubMed [Ikuta94]
  19. Gu MX, York JD, Warshawsky I, and Majerus PW. Identification, cloning, and expression of a cytosolic megakaryocyte protein-tyrosine-phosphatase with sequence homology to cytoskeletal protein 4.1. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5867-71. DOI:10.1073/pnas.88.13.5867 | PubMed ID:1648233 | HubMed [Gu91]
  20. Gu M and Majerus PW. The properties of the protein tyrosine phosphatase PTPMEG. J Biol Chem. 1996 Nov 1;271(44):27751-9. DOI:10.1074/jbc.271.44.27751 | PubMed ID:8910369 | HubMed [Gu96a]
  21. Park KW, Lee EJ, Lee S, Lee JE, Choi E, Kim BJ, Hwang R, Park KA, and Baik J. Molecular cloning and characterization of a protein tyrosine phosphatase enriched in testis, a putative murine homologue of human PTPMEG. Gene. 2000 Oct 17;257(1):45-55. DOI:10.1016/s0378-1119(00)00351-6 | PubMed ID:11054567 | HubMed [Park00]
  22. Young JA, Becker AM, Medeiros JJ, Shapiro VS, Wang A, Farrar JD, Quill TA, Hooft van Huijsduijnen R, and van Oers NS. The protein tyrosine phosphatase PTPN4/PTP-MEG1, an enzyme capable of dephosphorylating the TCR ITAMs and regulating NF-kappaB, is dispensable for T cell development and/or T cell effector functions. Mol Immunol. 2008 Aug;45(14):3756-66. DOI:10.1016/j.molimm.2008.05.023 | PubMed ID:18614237 | HubMed [Young08]
  23. Huai W, Song H, Wang L, Li B, Zhao J, Han L, Gao C, Jiang G, Zhang L, and Zhao W. Phosphatase PTPN4 preferentially inhibits TRIF-dependent TLR4 pathway by dephosphorylating TRAM. J Immunol. 2015 May 1;194(9):4458-65. DOI:10.4049/jimmunol.1402183 | PubMed ID:25825441 | HubMed [Huai15]
  24. Hironaka K, Umemori H, Tezuka T, Mishina M, and Yamamoto T. The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor delta 2 and epsilon subunits. J Biol Chem. 2000 May 26;275(21):16167-73. DOI:10.1074/jbc.M909302199 | PubMed ID:10748123 | HubMed [Hironaka00]
All Medline abstracts: PubMed | HubMed