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

Epithelial morphogenesis is critical during development and wound healing, and alterations in this program contribute to neoplasia. Met, the hepatocyt e growth factor (HGF) receptor, promotes a morphogenic program in epithelia l cell lines in matrix cultures. Previous studies have identified Gab1, the major phosphorylated protein following Met activation, as important for th e morphogenic response. Gab1 is a docking protein that couples the Met rece ptor with multiple signaling proteins, including phosphatidylinositol-3 kin ase, phospholipase C gamma, the adapter protein Crk, and the tyrosine speci fic phosphatase SHP-2. HGF induces sustained phosphorylation of Gab1 and su stained activation of extracellular signal-regulated kinase (Erk) in epithe lial Madin-Darby canine kidney cells. In contrast, epidermal growth factor fails to promote a morphogenic program and induces transient Gab1 phosphory lation and Erk activation. To elucidate the Gab1-dependent signals required for epithelial morphogenesis, we undertook a structure-function approach a nd 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 re sponse to HGF. Moreover, SHP-2 catalytic activity is required, since the ex pression 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.