Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Jun 1;364(Pt 2):377–383. doi: 10.1042/BJ20011372

Interaction of protein tyrosine phosphatase (PTP) 1B with its substrates is influenced by two distinct binding domains.

Shrikrishna Dadke 1, Jonathan Chernoff 1
PMCID: PMC1222582  PMID: 12023880

Abstract

We have shown previously that protein tyrosine phosphatase (PTP) 1B interacts with insulin receptor and negatively regulates insulin signalling by an N-terminal binding domain [Dadke, Kusari and Chernoff (2000) J. Biol. Chem. 275, 23642-23647] and it also negatively regulates integrin signalling through a proline-rich region present in the C-terminus [Liu, Hill and Chernoff (1996) J. Biol. Chem. 271, 31290-31295; Liu, Sells and Chernoff (1998) Curr. Biol. 8, 173-176]. Here we show that PTP1B mutants that are defective in Src homology 3 domain binding fully retain the ability to inhibit insulin signalling, whereas mutants defective in insulin-receptor binding fully retain the ability to inhibit integrin signalling. In contrast, both the C-terminal proline-rich region and the tandem tyrosine residues present in the N-terminal region are required for the activation of Src family kinases. These data show that PTP1B can independently regulate insulin and integrin signals, and that Src might represent a convergence point for regulating signal transduction by this phosphatase.

Full Text

The Full Text of this article is available as a PDF (208.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmad F., Li P. M., Meyerovitch J., Goldstein B. J. Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. J Biol Chem. 1995 Sep 1;270(35):20503–20508. doi: 10.1074/jbc.270.35.20503. [DOI] [PubMed] [Google Scholar]
  2. Arbet-Engels C., Tartare-Deckert S., Eckhart W. C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor. J Biol Chem. 1999 Feb 26;274(9):5422–5428. doi: 10.1074/jbc.274.9.5422. [DOI] [PubMed] [Google Scholar]
  3. Arregui C. O., Balsamo J., Lilien J. Impaired integrin-mediated adhesion and signaling in fibroblasts expressing a dominant-negative mutant PTP1B. J Cell Biol. 1998 Nov 2;143(3):861–873. doi: 10.1083/jcb.143.3.861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bandyopadhyay D., Kusari A., Kenner K. A., Liu F., Chernoff J., Gustafson T. A., Kusari J. Protein-tyrosine phosphatase 1B complexes with the insulin receptor in vivo and is tyrosine-phosphorylated in the presence of insulin. J Biol Chem. 1997 Jan 17;272(3):1639–1645. doi: 10.1074/jbc.272.3.1639. [DOI] [PubMed] [Google Scholar]
  5. Bjorge J. D., Pang A., Fujita D. J. Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. J Biol Chem. 2000 Dec 29;275(52):41439–41446. doi: 10.1074/jbc.M004852200. [DOI] [PubMed] [Google Scholar]
  6. Burnham M. R., Harte M. T., Richardson A., Parsons J. T., Bouton A. H. The identification of p130cas-binding proteins and their role in cellular transformation. Oncogene. 1996 Jun 6;12(11):2467–2472. [PubMed] [Google Scholar]
  7. Byon J. C., Kusari A. B., Kusari J. Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction. Mol Cell Biochem. 1998 May;182(1-2):101–108. [PubMed] [Google Scholar]
  8. Chen H., Cong L. N., Li Y., Yao Z. J., Wu L., Zhang Z. Y., Burke T. R., Jr, Quon M. J. A phosphotyrosyl mimetic peptide reverses impairment of insulin-stimulated translocation of GLUT4 caused by overexpression of PTP1B in rat adipose cells. Biochemistry. 1999 Jan 5;38(1):384–389. doi: 10.1021/bi9816103. [DOI] [PubMed] [Google Scholar]
  9. Chen H., Wertheimer S. J., Lin C. H., Katz S. L., Amrein K. E., Burn P., Quon M. J. Protein-tyrosine phosphatases PTP1B and syp are modulators of insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. J Biol Chem. 1997 Mar 21;272(12):8026–8031. doi: 10.1074/jbc.272.12.8026. [DOI] [PubMed] [Google Scholar]
  10. Chernoff J. Protein tyrosine phosphatases as negative regulators of mitogenic signaling. J Cell Physiol. 1999 Aug;180(2):173–181. doi: 10.1002/(SICI)1097-4652(199908)180:2<173::AID-JCP5>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  11. Clark E. A., Brugge J. S. Integrins and signal transduction pathways: the road taken. Science. 1995 Apr 14;268(5208):233–239. doi: 10.1126/science.7716514. [DOI] [PubMed] [Google Scholar]
  12. Dadke S., Kusari A., Kusari J. Phosphorylation and activation of protein tyrosine phosphatase (PTP) 1B by insulin receptor. Mol Cell Biochem. 2001 May;221(1-2):147–154. doi: 10.1023/a:1010909031310. [DOI] [PubMed] [Google Scholar]
  13. Dadke S., Kusari J., Chernoff J. Down-regulation of insulin signaling by protein-tyrosine phosphatase 1B is mediated by an N-terminal binding region. J Biol Chem. 2000 Aug 4;275(31):23642–23647. doi: 10.1074/jbc.M001063200. [DOI] [PubMed] [Google Scholar]
  14. Elchebly M., Payette P., Michaliszyn E., Cromlish W., Collins S., Loy A. L., Normandin D., Cheng A., Himms-Hagen J., Chan C. C. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science. 1999 Mar 5;283(5407):1544–1548. doi: 10.1126/science.283.5407.1544. [DOI] [PubMed] [Google Scholar]
  15. Feng G. S. Shp-2 tyrosine phosphatase: signaling one cell or many. Exp Cell Res. 1999 Nov 25;253(1):47–54. doi: 10.1006/excr.1999.4668. [DOI] [PubMed] [Google Scholar]
  16. Flint A. J., Tiganis T., Barford D., Tonks N. K. Development of "substrate-trapping" mutants to identify physiological substrates of protein tyrosine phosphatases. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1680–1685. doi: 10.1073/pnas.94.5.1680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goldstein B. J., Bittner-Kowalczyk A., White M. F., Harbeck M. Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. J Biol Chem. 2000 Feb 11;275(6):4283–4289. doi: 10.1074/jbc.275.6.4283. [DOI] [PubMed] [Google Scholar]
  18. Guvakova M. A., Surmacz E. The activated insulin-like growth factor I receptor induces depolarization in breast epithelial cells characterized by actin filament disassembly and tyrosine dephosphorylation of FAK, Cas, and paxillin. Exp Cell Res. 1999 Aug 25;251(1):244–255. doi: 10.1006/excr.1999.4566. [DOI] [PubMed] [Google Scholar]
  19. Ishiki M., Sasaoka T., Ishihara H., Imamura T., Usui I., Takata Y., Kobayashi M. Evidence for functional roles of Crk-II in insulin and epidermal growth factor signaling in Rat-1 fibroblasts overexpressing insulin receptors. Endocrinology. 1997 Nov;138(11):4950–4958. doi: 10.1210/endo.138.11.5510. [DOI] [PubMed] [Google Scholar]
  20. Jin S., Zhai B., Qiu Z., Wu J., Lane M. D., Liao K. c-Crk, a substrate of the insulin-like growth factor-1 receptor tyrosine kinase, functions as an early signal mediator in the adipocyte differentiation process. J Biol Chem. 2000 Nov 3;275(44):34344–34352. doi: 10.1074/jbc.M004927200. [DOI] [PubMed] [Google Scholar]
  21. Kenner K. A., Anyanwu E., Olefsky J. M., Kusari J. Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling. J Biol Chem. 1996 Aug 16;271(33):19810–19816. doi: 10.1074/jbc.271.33.19810. [DOI] [PubMed] [Google Scholar]
  22. Keyse S. M. Protein phosphatases and the regulation of MAP kinase activity. Semin Cell Dev Biol. 1998 Apr;9(2):143–152. doi: 10.1006/scdb.1997.0219. [DOI] [PubMed] [Google Scholar]
  23. Klaman L. D., Boss O., Peroni O. D., Kim J. K., Martino J. L., Zabolotny J. M., Moghal N., Lubkin M., Kim Y. B., Sharpe A. H. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol. 2000 Aug;20(15):5479–5489. doi: 10.1128/mcb.20.15.5479-5489.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kuwada S. K., Li X. Integrin alpha5/beta1 mediates fibronectin-dependent epithelial cell proliferation through epidermal growth factor receptor activation. Mol Biol Cell. 2000 Jul;11(7):2485–2496. doi: 10.1091/mbc.11.7.2485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Li J., Lin M. L., Wiepz G. J., Guadarrama A. G., Bertics P. J. Integrin-mediated migration of murine B82L fibroblasts is dependent on the expression of an intact epidermal growth factor receptor. J Biol Chem. 1999 Apr 16;274(16):11209–11219. doi: 10.1074/jbc.274.16.11209. [DOI] [PubMed] [Google Scholar]
  26. Liotta A. S., Kole H. K., Fales H. M., Roth J., Bernier M. A synthetic tris-sulfotyrosyl dodecapeptide analogue of the insulin receptor 1146-kinase domain inhibits tyrosine dephosphorylation of the insulin receptor in situ. J Biol Chem. 1994 Sep 16;269(37):22996–23001. [PubMed] [Google Scholar]
  27. Liu F., Chernoff J. Protein tyrosine phosphatase 1B interacts with and is tyrosine phosphorylated by the epidermal growth factor receptor. Biochem J. 1997 Oct 1;327(Pt 1):139–145. doi: 10.1042/bj3270139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Liu F., Hill D. E., Chernoff J. Direct binding of the proline-rich region of protein tyrosine phosphatase 1B to the Src homology 3 domain of p130(Cas). J Biol Chem. 1996 Dec 6;271(49):31290–31295. doi: 10.1074/jbc.271.49.31290. [DOI] [PubMed] [Google Scholar]
  29. Liu F., Sells M. A., Chernoff J. Protein tyrosine phosphatase 1B negatively regulates integrin signaling. Curr Biol. 1998 Jan 29;8(3):173–176. doi: 10.1016/s0960-9822(98)70066-1. [DOI] [PubMed] [Google Scholar]
  30. Liu F., Sells M. A., Chernoff J. Transformation suppression by protein tyrosine phosphatase 1B requires a functional SH3 ligand. Mol Cell Biol. 1998 Jan;18(1):250–259. doi: 10.1128/mcb.18.1.250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lu Y., Brush J., Stewart T. A. NSP1 defines a novel family of adaptor proteins linking integrin and tyrosine kinase receptors to the c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway. J Biol Chem. 1999 Apr 9;274(15):10047–10052. doi: 10.1074/jbc.274.15.10047. [DOI] [PubMed] [Google Scholar]
  32. Moro L., Venturino M., Bozzo C., Silengo L., Altruda F., Beguinot L., Tarone G., Defilippi P. Integrins induce activation of EGF receptor: role in MAP kinase induction and adhesion-dependent cell survival. EMBO J. 1998 Nov 16;17(22):6622–6632. doi: 10.1093/emboj/17.22.6622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Neel B. G. Structure and function of SH2-domain containing tyrosine phosphatases. Semin Cell Biol. 1993 Dec;4(6):419–432. doi: 10.1006/scel.1993.1050. [DOI] [PubMed] [Google Scholar]
  34. O'Neill G. M., Fashena S. J., Golemis E. A. Integrin signalling: a new Cas(t) of characters enters the stage. Trends Cell Biol. 2000 Mar;10(3):111–119. doi: 10.1016/s0962-8924(99)01714-6. [DOI] [PubMed] [Google Scholar]
  35. Parsons J. T., Parsons S. J. Src family protein tyrosine kinases: cooperating with growth factor and adhesion signaling pathways. Curr Opin Cell Biol. 1997 Apr;9(2):187–192. doi: 10.1016/s0955-0674(97)80062-2. [DOI] [PubMed] [Google Scholar]
  36. Rock M. T., Brooks W. H., Roszman T. L. Calcium-dependent signaling pathways in T cells. Potential role of calpain, protein tyrosine phosphatase 1b, and p130Cas in integrin-mediated signaling events. J Biol Chem. 1997 Dec 26;272(52):33377–33383. doi: 10.1074/jbc.272.52.33377. [DOI] [PubMed] [Google Scholar]
  37. Sakai R., Iwamatsu A., Hirano N., Ogawa S., Tanaka T., Mano H., Yazaki Y., Hirai H. A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. EMBO J. 1994 Aug 15;13(16):3748–3756. doi: 10.1002/j.1460-2075.1994.tb06684.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Salmeen A., Andersen J. N., Myers M. P., Tonks N. K., Barford D. Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Mol Cell. 2000 Dec;6(6):1401–1412. doi: 10.1016/s1097-2765(00)00137-4. [DOI] [PubMed] [Google Scholar]
  39. Seely B. L., Staubs P. A., Reichart D. R., Berhanu P., Milarski K. L., Saltiel A. R., Kusari J., Olefsky J. M. Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes. 1996 Oct;45(10):1379–1385. doi: 10.2337/diab.45.10.1379. [DOI] [PubMed] [Google Scholar]
  40. Sorokin A., Reed E. Insulin stimulates the tyrosine dephosphorylation of docking protein p130cas (Crk-associated substrate), promoting the switch of the adaptor protein crk from p130cas to newly phosphorylated insulin receptor substrate-1. Biochem J. 1998 Sep 15;334(Pt 3):595–600. doi: 10.1042/bj3340595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sun X. J., Pons S., Asano T., Myers M. G., Jr, Glasheen E., White M. F. The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation. J Biol Chem. 1996 May 3;271(18):10583–10587. doi: 10.1074/jbc.271.18.10583. [DOI] [PubMed] [Google Scholar]
  42. Tonks N. K., Cicirelli M. F., Diltz C. D., Krebs E. G., Fischer E. H. Effect of microinjection of a low-Mr human placenta protein tyrosine phosphatase on induction of meiotic cell division in Xenopus oocytes. Mol Cell Biol. 1990 Feb;10(2):458–463. doi: 10.1128/mcb.10.2.458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. You-Ten K. E., Muise E. S., Itié A., Michaliszyn E., Wagner J., Jothy S., Lapp W. S., Tremblay M. L. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J Exp Med. 1997 Aug 29;186(5):683–693. doi: 10.1084/jem.186.5.683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yu X., Miyamoto S., Mekada E. Integrin alpha 2 beta 1-dependent EGF receptor activation at cell-cell contact sites. J Cell Sci. 2000 Jun;113(Pt 12):2139–2147. doi: 10.1242/jcs.113.12.2139. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES