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. 1994 Oct;14(10):6674–6682. doi: 10.1128/mcb.14.10.6674

Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation.

T Noguchi 1, T Matozaki 1, K Horita 1, Y Fujioka 1, M Kasuga 1
PMCID: PMC359197  PMID: 7935386

Abstract

SH-PTP2 is a nontransmembrane human protein-tyrosine phosphatase that contains two Src homology 2 (SH2) domains and binds to insulin receptor substrate 1 (IRS-1) via these domains in response to insulin. The expression of a catalytically inactive mutant of SH-PTP2 (containing the mutation Cys-459-->Ser) in Chinese hamster ovary cells that overexpress human insulin receptors (CHO-IR cells) markedly attenuated insulin-stimulated Ras activation. Expression of mutant SH-PTP2 also inhibited MAP kinase activation in response to insulin but not in response to 12-O-tetradecanoyl phorbol-13-acetate. In contrast, the insulin-induced association of phosphoinositide 3-kinase activity with IRS-1 was not affected by the expression of inactive SH-PTP2. Furthermore, the expression of mutant SH-PTP2 had no effect on the binding of Grb2 to IRS-1, on the tyrosine phosphorylation of Shc, or on the formation of the complex between Shc and Grb2 in response to insulin. However, the amount of SH-PTP2 bound to IRS-1 in insulin-treated CHO-IR cells expressing mutant SH-PTP2 was greater than that observed in CHO-IR cells overexpressing wild-type SH-PTP2. Recombinant SH-PTP2 specifically dephosphorylated a synthetic phosphopeptide corresponding to the sequence surrounding Tyr-1172 of IRS-1, a putative binding site for SH-PTP2. Additionally, phenylarsine oxide, an inhibitor of protein-tyrosine phosphatases, inactivated SH-PTP2 in vitro and increased the insulin-induced association of SH-PTP2 with IRS-1. These results suggest that SH-PTP2 may regulate an upstream element necessary for Ras activation in response to insulin and that this upstream element may be required for the Grb2- or Shc-dependent pathway. Furthermore, these results are consistent with the notion that SH-PTP2 may bind to IRS-1 through its SH2 domains in response to insulin and dephosphorylate the phosphotyrosine residue to which it binds, thereby regulating its association with IRS-1.

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Selected References

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

  1. Adachi M., Sekiya M., Miyachi T., Matsuno K., Hinoda Y., Imai K., Yachi A. Molecular cloning of a novel protein-tyrosine phosphatase SH-PTP3 with sequence similarity to the src-homology region 2. FEBS Lett. 1992 Dec 21;314(3):335–339. doi: 10.1016/0014-5793(92)81500-l. [DOI] [PubMed] [Google Scholar]
  2. Ahmad S., Banville D., Zhao Z., Fischer E. H., Shen S. H. A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2197–2201. doi: 10.1073/pnas.90.6.2197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ahn N. G., Seger R., Krebs E. G. The mitogen-activated protein kinase activator. Curr Opin Cell Biol. 1992 Dec;4(6):992–999. doi: 10.1016/0955-0674(92)90131-u. [DOI] [PubMed] [Google Scholar]
  4. Backer J. M., Myers M. G., Jr, Shoelson S. E., Chin D. J., Sun X. J., Miralpeix M., Hu P., Margolis B., Skolnik E. Y., Schlessinger J. Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 1992 Sep;11(9):3469–3479. doi: 10.1002/j.1460-2075.1992.tb05426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barford D., Flint A. J., Tonks N. K. Crystal structure of human protein tyrosine phosphatase 1B. Science. 1994 Mar 11;263(5152):1397–1404. [PubMed] [Google Scholar]
  6. Boguski M. S., McCormick F. Proteins regulating Ras and its relatives. Nature. 1993 Dec 16;366(6456):643–654. doi: 10.1038/366643a0. [DOI] [PubMed] [Google Scholar]
  7. Chou C. K., Dull T. J., Russell D. S., Gherzi R., Lebwohl D., Ullrich A., Rosen O. M. Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin. J Biol Chem. 1987 Feb 5;262(4):1842–1847. [PubMed] [Google Scholar]
  8. Dechert U., Adam M., Harder K. W., Clark-Lewis I., Jirik F. Characterization of protein tyrosine phosphatase SH-PTP2. Study of phosphopeptide substrates and possible regulatory role of SH2 domains. J Biol Chem. 1994 Feb 25;269(8):5602–5611. [PubMed] [Google Scholar]
  9. Ebina Y., Araki E., Taira M., Shimada F., Mori M., Craik C. S., Siddle K., Pierce S. B., Roth R. A., Rutter W. J. Replacement of lysine residue 1030 in the putative ATP-binding region of the insulin receptor abolishes insulin- and antibody-stimulated glucose uptake and receptor kinase activity. Proc Natl Acad Sci U S A. 1987 Feb;84(3):704–708. doi: 10.1073/pnas.84.3.704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feng G. S., Hui C. C., Pawson T. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science. 1993 Mar 12;259(5101):1607–1611. doi: 10.1126/science.8096088. [DOI] [PubMed] [Google Scholar]
  11. Fischer E. H., Charbonneau H., Tonks N. K. Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science. 1991 Jul 26;253(5018):401–406. doi: 10.1126/science.1650499. [DOI] [PubMed] [Google Scholar]
  12. Freeman R. M., Jr, Plutzky J., Neel B. G. Identification of a human src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11239–11243. doi: 10.1073/pnas.89.23.11239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Izumi T., Saeki Y., Akanuma Y., Takaku F., Kasuga M. Requirement for receptor-intrinsic tyrosine kinase activities during ligand-induced membrane ruffling of KB cells. Essential sites of src-related growth factor receptor kinases. J Biol Chem. 1988 Jul 25;263(21):10386–10393. [PubMed] [Google Scholar]
  14. Kasuga M., Fujita-Yamaguchi Y., Blithe D. L., Kahn C. R. Tyrosine-specific protein kinase activity is associated with the purified insulin receptor. Proc Natl Acad Sci U S A. 1983 Apr;80(8):2137–2141. doi: 10.1073/pnas.80.8.2137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kasuga M., Izumi T., Tobe K., Shiba T., Momomura K., Tashiro-Hashimoto Y., Kadowaki T. Substrates for insulin-receptor kinase. Diabetes Care. 1990 Mar;13(3):317–326. doi: 10.2337/diacare.13.3.317. [DOI] [PubMed] [Google Scholar]
  16. Kazlauskas A., Feng G. S., Pawson T., Valius M. The 64-kDa protein that associates with the platelet-derived growth factor receptor beta subunit via Tyr-1009 is the SH2-containing phosphotyrosine phosphatase Syp. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6939–6943. doi: 10.1073/pnas.90.15.6939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kuhné M. R., Pawson T., Lienhard G. E., Feng G. S. The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp. J Biol Chem. 1993 Jun 5;268(16):11479–11481. [PubMed] [Google Scholar]
  18. Lechleider R. J., Freeman R. M., Jr, Neel B. G. Tyrosyl phosphorylation and growth factor receptor association of the human corkscrew homologue, SH-PTP2. J Biol Chem. 1993 Jun 25;268(18):13434–13438. [PubMed] [Google Scholar]
  19. Lee C. H., Li W., Nishimura R., Zhou M., Batzer A. G., Myers M. G., Jr, White M. F., Schlessinger J., Skolnik E. Y. Nck associates with the SH2 domain-docking protein IRS-1 in insulin-stimulated cells. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11713–11717. doi: 10.1073/pnas.90.24.11713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Li W., Nishimura R., Kashishian A., Batzer A. G., Kim W. J., Cooper J. A., Schlessinger J. A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Mol Cell Biol. 1994 Jan;14(1):509–517. doi: 10.1128/mcb.14.1.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lu X., Chou T. B., Williams N. G., Roberts T., Perrimon N. Control of cell fate determination by p21ras/Ras1, an essential component of torso signaling in Drosophila. Genes Dev. 1993 Apr;7(4):621–632. doi: 10.1101/gad.7.4.621. [DOI] [PubMed] [Google Scholar]
  22. Matozaki T., Suzuki T., Uchida T., Inazawa J., Ariyama T., Matsuda K., Horita K., Noguchi H., Mizuno H., 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):2075–2081. [PubMed] [Google Scholar]
  23. Medema R. H., Burgering B. M., Bos J. L. Insulin-induced p21ras activation does not require protein kinase C, but a protein sensitive to phenylarsine oxide. J Biol Chem. 1991 Nov 5;266(31):21186–21189. [PubMed] [Google Scholar]
  24. Morgan D. O., Roth R. A. Acute insulin action requires insulin receptor kinase activity: introduction of an inhibitory monoclonal antibody into mammalian cells blocks the rapid effects of insulin. Proc Natl Acad Sci U S A. 1987 Jan;84(1):41–45. doi: 10.1073/pnas.84.1.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pawson T., Schlessingert J. SH2 and SH3 domains. Curr Biol. 1993 Jul 1;3(7):434–442. doi: 10.1016/0960-9822(93)90350-w. [DOI] [PubMed] [Google Scholar]
  26. Pelicci G., Lanfrancone L., Grignani F., McGlade J., Cavallo F., Forni G., Nicoletti I., Grignani F., Pawson T., Pelicci P. G. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell. 1992 Jul 10;70(1):93–104. doi: 10.1016/0092-8674(92)90536-l. [DOI] [PubMed] [Google Scholar]
  27. Perkins L. A., Larsen I., Perrimon N. corkscrew encodes a putative protein tyrosine phosphatase that functions to transduce the terminal signal from the receptor tyrosine kinase torso. Cell. 1992 Jul 24;70(2):225–236. doi: 10.1016/0092-8674(92)90098-w. [DOI] [PubMed] [Google Scholar]
  28. Perrimon N. The torso receptor protein-tyrosine kinase signaling pathway: an endless story. Cell. 1993 Jul 30;74(2):219–222. doi: 10.1016/0092-8674(93)90412-j. [DOI] [PubMed] [Google Scholar]
  29. Porras A., Nebreda A. R., Benito M., Santos E. Activation of Ras by insulin in 3T3 L1 cells does not involve GTPase-activating protein phosphorylation. J Biol Chem. 1992 Oct 15;267(29):21124–21131. [PubMed] [Google Scholar]
  30. Pronk G. J., McGlade J., Pelicci G., Pawson T., Bos J. L. Insulin-induced phosphorylation of the 46- and 52-kDa Shc proteins. J Biol Chem. 1993 Mar 15;268(8):5748–5753. [PubMed] [Google Scholar]
  31. Pronk G. J., de Vries-Smits A. M., Buday L., Downward J., Maassen J. A., Medema R. H., Bos J. L. Involvement of Shc in insulin- and epidermal growth factor-induced activation of p21ras. Mol Cell Biol. 1994 Mar;14(3):1575–1581. doi: 10.1128/mcb.14.3.1575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rose D. W., Saltiel A. R., Majumdar M., Decker S. J., Olefsky J. M. Insulin receptor substrate 1 is required for insulin-mediated mitogenic signal transduction. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):797–801. doi: 10.1073/pnas.91.2.797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rosen O. M. After insulin binds. Science. 1987 Sep 18;237(4821):1452–1458. doi: 10.1126/science.2442814. [DOI] [PubMed] [Google Scholar]
  34. Roth R. A., Cassell D. J. Insulin receptor: evidence that it is a protein kinase. Science. 1983 Jan 21;219(4582):299–301. doi: 10.1126/science.6849137. [DOI] [PubMed] [Google Scholar]
  35. Skolnik E. Y., Batzer A., Li N., Lee C. H., Lowenstein E., Mohammadi M., Margolis B., Schlessinger J. The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science. 1993 Jun 25;260(5116):1953–1955. doi: 10.1126/science.8316835. [DOI] [PubMed] [Google Scholar]
  36. Skolnik E. Y., Lee C. H., Batzer A., Vicentini L. M., Zhou M., Daly R., Myers M. J., Jr, Backer J. M., Ullrich A., White M. F. The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. EMBO J. 1993 May;12(5):1929–1936. doi: 10.1002/j.1460-2075.1993.tb05842.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Streuli M., Krueger N. X., Thai T., Tang M., Saito H. Distinct functional roles of the two intracellular phosphatase like domains of the receptor-linked protein tyrosine phosphatases LCA and LAR. EMBO J. 1990 Aug;9(8):2399–2407. doi: 10.1002/j.1460-2075.1990.tb07415.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sugimoto S., Lechleider R. J., Shoelson S. E., Neel B. G., Walsh C. T. Expression, purification, and characterization of SH2-containing protein tyrosine phosphatase, SH-PTP2. J Biol Chem. 1993 Oct 25;268(30):22771–22776. [PubMed] [Google Scholar]
  39. Sun X. J., Crimmins D. L., Myers M. G., Jr, Miralpeix M., White M. F. Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. Mol Cell Biol. 1993 Dec;13(12):7418–7428. doi: 10.1128/mcb.13.12.7418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sun X. J., Rothenberg P., Kahn C. R., Backer J. M., Araki E., Wilden P. A., Cahill D. A., Goldstein B. J., White M. F. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991 Jul 4;352(6330):73–77. doi: 10.1038/352073a0. [DOI] [PubMed] [Google Scholar]
  41. Tobe K., Matuoka K., Tamemoto H., Ueki K., Kaburagi Y., Asai S., Noguchi T., Matsuda M., Tanaka S., Hattori S. Insulin stimulates association of insulin receptor substrate-1 with the protein abundant Src homology/growth factor receptor-bound protein 2. J Biol Chem. 1993 May 25;268(15):11167–11171. [PubMed] [Google Scholar]
  42. Trowbridge I. S. CD45. A prototype for transmembrane protein tyrosine phosphatases. J Biol Chem. 1991 Dec 15;266(35):23517–23520. [PubMed] [Google Scholar]
  43. Uchida T., Matozaki T., Matsuda K., Suzuki T., Matozaki S., Nakano O., Wada K., Konda Y., Sakamoto C., Kasuga M. Phorbol ester stimulates the activity of a protein tyrosine phosphatase containing SH2 domains (PTP1C) in HL-60 leukemia cells by increasing gene expression. J Biol Chem. 1993 Jun 5;268(16):11845–11850. [PubMed] [Google Scholar]
  44. Uchida T., Matozaki T., Noguchi T., Yamao T., Horita K., Suzuki T., Fujioka Y., Sakamoto C., Kasuga M. Insulin stimulates the phosphorylation of Tyr538 and the catalytic activity of PTP1C, a protein tyrosine phosphatase with Src homology-2 domains. J Biol Chem. 1994 Apr 22;269(16):12220–12228. [PubMed] [Google Scholar]
  45. Valius M., Kazlauskas A. Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal. Cell. 1993 Apr 23;73(2):321–334. doi: 10.1016/0092-8674(93)90232-f. [DOI] [PubMed] [Google Scholar]
  46. Vogel W., Lammers R., Huang J., Ullrich A. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science. 1993 Mar 12;259(5101):1611–1614. doi: 10.1126/science.7681217. [DOI] [PubMed] [Google Scholar]
  47. Yonezawa K., Ando A., Kaburagi Y., Yamamoto-Honda R., Kitamura T., Hara K., Nakafuku M., Okabayashi Y., Kadowaki T., Kaziro Y. Signal transduction pathways from insulin receptors to Ras. Analysis by mutant insulin receptors. J Biol Chem. 1994 Feb 11;269(6):4634–4640. [PubMed] [Google Scholar]
  48. Yonezawa K., Ueda H., Hara K., Nishida K., Ando A., Chavanieu A., Matsuba H., Shii K., Yokono K., Fukui Y. Insulin-dependent formation of a complex containing an 85-kDa subunit of phosphatidylinositol 3-kinase and tyrosine-phosphorylated insulin receptor substrate 1. J Biol Chem. 1992 Dec 25;267(36):25958–25965. [PubMed] [Google Scholar]

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