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Roles for the protein tyrosine phosphatase SHP-2 in cytoskeletal organization, cell adhesion and cell migration revealed by overexpression of a dominant negative mutant

Oncogene volume 19, pages 75–84 (2000)Cite this article

Abstract

SHP-2, a SRC homology 2 domain-containing protein tyrosine phosphatase, mediates activation of Ras and mitogen-activated protein kinase by various mitogens and cell adhesion. Inhibition of endogenous SHP-2 by overexpression of a catalytically inactive (dominant negative) mutant in Chinese hamster ovary cells or Rat-1 fibroblasts has now been shown to induce a marked change in cell morphology (from elongated to less polarized) that is accompanied by substantial increases in the numbers of actin stress fibers and focal adhesion contacts. Overexpression of the SHP-2 mutant also increased the strength of cell-substratum adhesion and resulted in hyperphosphorylation of SHPS-1, a substrate of SHP-2 that contributes to cell adhesion-induced signaling. Inhibition of SHP-2 also markedly increased the rate of cell attachment to and cell spreading on extracellular matrix proteins such as fibronectin and vitronectin, effects that were accompanied by enhancement of adhesion-induced tyrosine phosphorylation of paxillin and p130Cas. In addition, cell migration mediated by fibronectin or vitronectin, but not that induced by insulin, was impaired by overexpression of the SHP-2 mutant. These results suggest that SHP-2 plays an important role in the control of cell shape by contributing to cytoskeletal organization, and that it is an important regulator of integrin-mediated cell adhesion, spreading, and migration as well as of tyrosine phosphorylation of focal adhesion contact-associated proteins.

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References

  • Adachi M, Fischer EH, Ihle J, Imai K, Jirik F, Neel B, Pawson T, Shen SH, Thomas M, Ullrich A and Zhao Z . 1996 Cell 85: 15

  • Anand-Apte B, Zetter BR, Viswanathan A, Qui R-G, Chen J, Ruggieri R and Symons M . 1997 J Biol Chem 272: 30688–30692.

  • Barry ST, Flinn HM, Humphries MJ, Critchley CR and Ridley AJ . 1997 Cell Adhes Commun 4: 387–398.

  • Bennett AM, Hausdorff SF, O'Reilly AM, Freeman RM and Neel BG . 1996 Mol Cell Biol 16: 1189–1202.

  • Clark EA and Hynes RO . 1996 J Biol Chem 271: 14814–14818.

  • Clark EA, King WG, Brugge JS, Symons M and Hynes RO . 1998 J Cell Biol 142: 573–586.

    Article  CAS  Google Scholar 

  • Drubin DG and Nelson WJ . 1996 Cell 84: 335–344.

    Article  CAS  Google Scholar 

  • Feng G-S, Hui CC and Pawson T . 1993 Science 259: 1607–1611.

    Article  CAS  Google Scholar 

  • Fujioka Y, Matozaki T, Noguchi T, Iwamatsu A, Yamao T, Takahashi N, Tsuda M, Takada T and Kasuga M . 1996 Mol Cell Biol 16: 6887–6899.

  • Hanks SK and Polte TR . 1997 BioEssays 19: 137–145.

  • Holgado-Madruga MD, Emlet R, Moscatello DK, Godwin AK and Wong AJ . 1996 Nature 379: 560–564.

    Article  CAS  Google Scholar 

  • Horikawa T, Norris DA, Yohn JJ, Zekman T, Travers JB and Morelli JG . 1995 J Invest Dermatol 104: 256–259.

  • Hughes PE, Renshaw MW, Pfaff M, Forsyth J, Keivens VM, Schwartz MA and Ginsberg MH . 1997 Cell 88: 521–530.

    Article  CAS  Google Scholar 

  • Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, Nomura S, Fujimoto J, Okada M, Yamamoto T and Aizawa T . 1995 Nature 377: 539–544.

    Article  Google Scholar 

  • Kharitonenkov A, Chen Z, Sures I, Wang H, Schilling J and Ullrich A . 1997 Nature 386: 181–186.

    Article  CAS  Google Scholar 

  • Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P and Cheresh DA . 1997 J Cell Biol 137: 481–492.

    Article  CAS  Google Scholar 

  • Kuhné MR, Pawson T, Lienhard GE and Feng G-S . 1993 J Biol Chem 268: 11479–11481.

  • Lauffenburger DA and Horwitz AF . 1996 Cell 84: 359–369.

    Article  CAS  Google Scholar 

  • Lechleider RJ, Freeman Jr RM and Neel BG . 1993 J Biol Chem 268: 13434–13438.

  • Maher PA . 1993 Proc Natl Acad Sci USA 90: 11177–11181.

  • Manes S, Mira E, Gomez-Mouton C, Zhao ZZJ, LaCalle RA and Martinez AC . 1999 Mol Cell Biol 19: 3125–3135.

  • Matozaki T and Kasuga M . 1996 Cell Signal 8: 13–19.

  • Menzel D . 1996 Curr Opin Cell Biol 8: 38–42.

  • Milarski KL and Saltiel AR . 1994 J Biol Chem 269: 21239–21243.

  • Mitchison TJ and Cramer LP . 1996 Cell 84: 371–379.

    Article  CAS  Google Scholar 

  • Nakamura I, Jimi E, Duong LT, Sasaki T, Takahashi N, Rodan GA and Suda T . 1998 J Biol Chem 273: 11144–11149.

  • Neel BG and Tonks NK . 1997 Curr Opin Cell Biol 9: 193–204.

  • Nobes CD, Hawkins P, Stephens L and Hall A . 1995 J Cell Sci 108: 225–233.

  • Noguchi T, Matozaki T, Horita K, Fujioka Y and Kasuga M . 1994 Mol Cell Biol 14: 6674–6682.

  • Noguchi T, Matozaki T, Fujioka Y, Yamao T, Tsuda M, Takada T and Kasuga M . 1996 J Biol Chem 271: 27652–27658.

  • Nojima Y, Morino N, Mimura T, Hamasaki K, Furuya H, Sakai R, Sato T, Tachibana K, Morimoto C, Yazaki Y and Hirai H . 1995 J Biol Chem 270: 15398–15402.

  • Ochi F, Matozaki T, Noguchi T, Fujioka Y, Yamao T, Takada T, Tsuda M, Takeda H, Fukunaga K, Okabayashi Y and Kasuga M . 1997 Biochem Biophys Res Commun 239: 483–487.

  • Oh ES, Gu HH, Saxton TM, Timms JF, Hausdorff S, Frevert EU, Kahn BB, Pawson T, Neel BG and Thomas SM . 1999 Mol Cell Biol 19: 3205–3215.

  • Ouwens DM, Mikkers HMM, van der Zon GCM, Stein Gerlach M, Ullrich A and Maassen JA . 1996 Biochem J 318: 609–614.

  • Qi JH, Ito N and Claesson-Welsh L . 1999 J Biol Chem 274: 14455–14463.

  • Richardson A, Malik RK, Hildebrand JD and Parsons JT . 1997 Mol Cell Biol 17: 6906–6914.

  • Roach TIA, Slater SE, White LS, Zhang X, Majerus PW, Brown EJ and Thomas ML . 1998 Curr Biol 8: 1035–1038.

  • Sano S, Ohnishi H, Omori A, Hasegawa J and Kubota M . 1997 FEBS Lett 411: 327–334.

  • Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, Shalaby F, Feng G-S and Pawson T . 1997 EMBO J 16: 2352–2364.

  • Schlaepfer DD and Hunter T . 1996 Mol Cell Biol 16: 5623–5633.

  • Schlaepfer DD and Hunter T . 1998 Trends Cell Biol 8: 151–157.

  • Schwartz MA, Schaller MD and Ginsberg MH . 1995 Annu Rev Cell Dev Biol 11: 549–599.

  • Schwarzbauer JE . 1997 Curr Biol 7: 292–294.

  • Sun XJ, Wang L-H, Zhang Y, Yenush L, Myers MG Jr, Glasheen E, Lane WS, Pierce JH and White MF . 1995 Nature 377: 173–177.

    Article  CAS  Google Scholar 

  • Takada T, Matozaki T, Takeda H, Fukunaga K, Noguchi T, Fujioka Y, Okazaki I, Tsuda M, Yamao T, Ochi F and Kasuga M . 1998 J Biol Chem 273: 9234–9242.

  • Takeda H, Matozaki T, Fujioka Y, Takada T, Noguchi T, Yamao Y, Tsuda M, Ochi F, Fukunaga K, Narumiya S, Yamamoto T and Kasuga M . 1998 Oncogene 16: 3019–3028.

    Article  CAS  Google Scholar 

  • Tang TL, Freeman RM, O'Reilly AM, Neel BG and Sokol SY . 1995 Cell 80: 473–483.

    Article  CAS  Google Scholar 

  • Tauchi T, Feng G-S, Marshall MS, Shen R, Mantel C, Pawson T and Broxmeyer HE . 1994 J Biol Chem 269: 25206–25211.

  • Tauchi T, Feng G-S, Shen R, Hoatlin M, Bagby GC Jr, Kabat D, Lu L and Broxmeyer HE . 1995 J Biol Chem 270: 5631–5635.

  • Tsuda M, Matozaki T, Fukunaga K, Fujioka Y, Imamoto A, Noguchi T, Takada T, Yamao T, Takeda H, Ochi F and Kasuga M . 1998 J Biol Chem 273: 13223–13229.

  • Tsui HW, Siminovitch KA, de Souza L and Tsui FW . 1993 Nature Genet 4: 124–129.

  • Vogel W, Lammers R, Huang J and Ullrich A . 1993 Science 259: 1611–1614.

    Article  CAS  Google Scholar 

  • Waterman-Storer CM and Salmon ED . 1999 Curr Opin Cell Biol 11: 61–67.

  • Xiao S, Rose DW, Sasaoka T, Maegawa H, Burke Jr TR, Roller PP, Schoelson SE and Olefsky JM . 1994 J Biol Chem 269: 21244–21248.

  • Yamada KM and Miyamoto S . 1995 Curr Biol 7: 681–689.

  • Yamao T, Matozaki T, Takahashi N, Amano K, Matsuda Y, Ochi F, Fujioka Y and Kasuga M . 1997 Biochem Biophys Res Commun 231: 61–67.

  • Yamauchi K, Milarski KL, Saltiel AR and Pessin JE . 1995 Proc Natl Acad Sci USA 92: 664–668.

  • Yu D-H, Qu CK, Henegariu O, Lu X and Feng G-S . 1998 J Biol Chem 273: 21125–21131.

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Acknowledgements

This work was supported by a grant-in-aid for cancer research and a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan; a grant-in-aid for the Research for the Future Program from the Japan Society for the Promotion of Science; and a grant from the Takeda Science Foundation.

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  1. Takashi Matozaki

    Present address: Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan

Authors and Affiliations

  1. Second Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan

    Kenjiro Inagaki, Tetsuya Noguchi, Takashi Matozaki, Kaoru Fukunaga, Masahiro Tsuda & Masato Kasuga

  2. Department of Dermatology, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan

    Tatsuya Horikawa & Masamitsu Ichihashi

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Inagaki, K., Noguchi, T., Matozaki, T. et al. Roles for the protein tyrosine phosphatase SHP-2 in cytoskeletal organization, cell adhesion and cell migration revealed by overexpression of a dominant negative mutant. Oncogene 19, 75–84 (2000). https://doi.org/10.1038/sj.onc.1203204

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