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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 morphogenic program in epithelial cell lines in matrix cultures. Previous studies have identified Gab1, the major phosphorylated protein following Met activation, as important for the morphogenic response. Gab1 is a docking protein that couples the Met receptor with multiple signaling proteins, including phosphatidylinositol-3 kinase, phospholipase Cgamma , the adapter protein Crk, and the tyrosine specific phosphatase SHP-2. HGF induces sustained phosphorylation of Gab1 and sustained activation of extracellular signal-regulated kinase (Erk) in epithelial Madin-Darby canine kidney cells. In contrast, epidermal growth factor fails to promote a morphogenic program and induces transient Gab1 phosphorylation and Erk activation. To elucidate the Gab1-dependent signals required for epithelial morphogenesis, we undertook a structure-function approach and demonstrate that association of Gab1 with the tyrosine phosphatase SHP-2 is required for sustained Erk activation and for epithelial morphogenesis downstream from the Met receptor. Epithelial cells expressing a Gab1 mutant protein unable to recruit SHP-2 elicit a transient activation of Erk in response 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 morphogenesis by the Met receptor. These data identify SHP-2 as a positive modulator of Erk activity and epithelial morphogenesis downstream from the Met receptor.

* 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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