The Tyrosine Phosphatase SHP-2 Is Required for Sustained Activation of Extracellular Signal-Regulated Kinase and Epithelial Morphogenesis Downstream from the Met Receptor Tyrosine Kinase

doi:10.1128/MCB.20.22.8513-8525.2000

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Molecular and Cellular Biology, November 2000, p. 8513-8525, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Tyrosine Phosphatase SHP-2 Is Required for Sustained Activation of Extracellular Signal-Regulated Kinase and Epithelial Morphogenesis Downstream from the Met Receptor Tyrosine Kinase

Christiane R. Maroun,¹^,² Monica A. Naujokas,¹^,² Marina Holgado-Madruga,³ Albert J. Wong,³^,⁴ and Morag Park¹^,²^,⁵^,⁶^,^*

Molecular Oncology Group, Royal Victoria Hospital,¹ and Departments of Medicine,² Oncology,⁵ and Biochemistry,⁶ McGill University, Montreal, Quebec, Canada H3A 1A1, and Departments of Microbiology and Immunology³ and Pharmacology,⁴ Kimmel Cancer Institute, Philadelphia, Pennsylvania 19107

Received 6 March 2000/Returned for modification 28 April 2000/Accepted 21 August 2000

Epithelial morphogenesis is critical during development and wound healing, and alterations in this program contribute to neoplasia.Met, the hepatocyte growth factor (HGF) receptor, promotes a morphogenicprogram in epithelial cell lines in matrix cultures. Previousstudies have identified Gab1, the major phosphorylated proteinfollowing Met activation, as important for the morphogenic response.Gab1 is a docking protein that couples the Met receptor with multiplesignaling proteins, including phosphatidylinositol-3 kinase, phospholipaseC $gamma$ , the adapter protein Crk, and the tyrosine specific phosphataseSHP-2. HGF induces sustained phosphorylation of Gab1 and sustainedactivation of extracellular signal-regulated kinase (Erk) in epithelialMadin-Darby canine kidney cells. In contrast, epidermal growthfactor fails to promote a morphogenic program and induces transientGab1 phosphorylation and Erk activation. To elucidate the Gab1-dependentsignals required for epithelial morphogenesis, we undertook astructure-function approach and demonstrate that association ofGab1 with the tyrosine phosphatase SHP-2 is required for sustainedErk activation and for epithelial morphogenesis downstream fromthe Met receptor. Epithelial cells expressing a Gab1 mutant proteinunable to recruit SHP-2 elicit a transient activation of Erk inresponse to HGF. Moreover, SHP-2 catalytic activity is required,since the expression of a catalytically inactive SHP-2 mutant,C/S, abrogates sustained activation of Erk and epithelial morphogenesisby the Met receptor. These data identify SHP-2 as a positive modulatorof Erk activity and epithelial morphogenesis downstream from theMetreceptor.

^* Corresponding author. Mailing address: Molecular Oncology Group, Royal Victoria Hospital, 687 Pine Ave. West, Rm. H5.10, Montreal,Quebec, Canada H3A 1A1. Phone: (514) 842-1231, ext. 5845. Fax:(514) 843-1478. E-mail: morag{at}lan1.molonc.mcgill.ca.

Molecular and Cellular Biology, November 2000, p. 8513-8525, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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Holgado-Madruga, M., Wong, A. J. (2003). Gab1 Is an Integrator of Cell Death versus Cell Survival Signals in Oxidative Stress. Mol. Cell. Biol. 23: 4471-4484 [Abstract] [Full Text]
Gu, H., Botelho, R. J., Yu, M., Grinstein, S., Neel, B. G. (2003). Critical role for scaffolding adapter Gab2 in Fc{gamma}R-mediated phagocytosis. J. Cell Biol. 161: 1151-1161 [Abstract] [Full Text]
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Long, I. S., Han, K., Li, M., Shirasawa, S., Sasazuki, T., Johnston, M., Tsao, M.-S. (2003). Met Receptor Overexpression and Oncogenic Ki-ras Mutation Cooperate to Enhance Tumorigenicity of Colon Cancer Cells in Vivo. Mol Cancer Res 1: 393-401 [Abstract] [Full Text]
Palka, H. L., Park, M., Tonks, N. K. (2003). Hepatocyte Growth Factor Receptor Tyrosine Kinase Met Is a Substrate of the Receptor Protein-tyrosine Phosphatase DEP-1. J. Biol. Chem. 278: 5728-5735 [Abstract] [Full Text]
Kong, M., Mounier, C., Dumas, V., Posner, B. I. (2003). Epidermal Growth Factor-induced DNA Synthesis. KEY ROLE FOR Src PHOSPHORYLATION OF THE DOCKING PROTEIN Gab2. J. Biol. Chem. 278: 5837-5844 [Abstract] [Full Text]
Lamorte, L., Rodrigues, S., Naujokas, M., Park, M. (2002). Crk Synergizes with Epidermal Growth Factor for Epithelial Invasion and Morphogenesis and Is Required for the Met Morphogenic Program. J. Biol. Chem. 277: 37904-37911 [Abstract] [Full Text]
Huang, Q., Lerner-Marmarosh, N., Che, W., Ohta, S., Osawa, M., Yoshizumi, M., Glassman, M., Yan, C., Berk, B. C., Abe, J.-i. (2002). The Novel Role of the C-terminal Region of SHP-2. INVOLVEMENT OF Gab1 AND SHP-2 PHOSPHATASE ACTIVITY IN Elk-1 ACTIVATION. J. Biol. Chem. 277: 29330-29341 [Abstract] [Full Text]
Saenger, P. (2002). Noonan Syndrome--Certitude Replaces Conjecture. J. Clin. Endocrinol. Metab. 87: 3527-3528 [Full Text]
Saito, Y., Hojo, Y., Tanimoto, T., Abe, J.-i., Berk, B. C. (2002). Protein Kinase C-alpha and Protein Kinase C-epsilon Are Required for Grb2-associated Binder-1 Tyrosine Phosphorylation in Response to Platelet-derived Growth Factor. J. Biol. Chem. 277: 23216-23222 [Abstract] [Full Text]
Zhang, S. Q., Tsiaras, W. G., Araki, T., Wen, G., Minichiello, L., Klein, R., Neel, B. G. (2002). Receptor-Specific Regulation of Phosphatidylinositol 3'-Kinase Activation by the Protein Tyrosine Phosphatase Shp2. Mol. Cell. Biol. 22: 4062-4072 [Abstract] [Full Text]
Lock, L. S., Maroun, C. R., Naujokas, M. A., Park, M. (2002). Distinct Recruitment and Function of Gab1 and Gab2 in Met Receptor-mediated Epithelial Morphogenesis. Mol. Biol. Cell 13: 2132-2146 [Abstract] [Full Text]
Yamaguchi, H., Miki, H., Takenawa, T. (2002). Neural Wiskott-Aldrich Syndrome Protein Is Involved in Hepatocyte Growth Factor-induced Migration, Invasion, and Tubulogenesis of Epithelial Cells. Cancer Res. 62: 2503-2509 [Abstract] [Full Text]
Dorsey, J. F., Cunnick, J. M., Mane, S. M., Wu, J. (2002). Regulation of the Erk2-Elk1 signaling pathway and megakaryocytic differentiation of Bcr-Abl+ K562 leukemic cells by Gab2. Blood 99: 1388-1397 [Abstract] [Full Text]
Liang, C.-C., Chen, H.-C. (2001). Sustained Activation of Extracellular Signal-regulated Kinase Stimulated by Hepatocyte Growth Factor Leads to Integrin alpha 2 Expression That Is Involved in Cell Scattering. J. Biol. Chem. 276: 21146-21152 [Abstract] [Full Text]
Ong, S. H., Hadari, Y. R., Gotoh, N., Guy, G. R., Schlessinger, J., Lax, I. (2001). Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc. Natl. Acad. Sci. USA 98: 6074-6079 [Abstract] [Full Text]

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