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Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses

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Item Type:Article
Title:Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses
Creators Name:Schaeper, U., Gehring, N.H., Fuchs, K.P., Sachs, M., Kempkes, B. and Birchmeier, W.
Abstract:Gab1 is a substrate of the receptor tyrosine kinase c-Met and involved in c-Met-specific branching morphogenesis. It associates directly with c-Met via the c-Met-binding domain, which is not related to known phosphotyrosine- binding domains. In addition, Gab1 is engaged in a constitutive complex with the adaptor protein Grb2. We have now mapped the c-Met and Grb2 interaction sites using reverse yeast two-hybrid technology. The c-Met-binding site is localized to a 13-amino acid region unique to Gab1. Insertion of this site into the Gab1-related protein p97/Gab2 was sufficient to confer c-Met-binding activity. Association with Grb2 was mapped to two sites: a classical SH3- binding site (PXXP) and a novel Grb2 SH3 consensus-binding motif (PX(V/I)(D/N)RXXKP). To detect phosphorylation-dependent interactions of Gab1 with downstream substrates, we developed a modified yeast two-hybrid assay and identified PI(3)K, Shc, Shp2, and CRKL as interaction partners of Gab1. In a trk-met-Gab1-specific branching morphogenesis assay, association of Gab1 with Shp2, but not PI(3)K, CRKL, or Shc was essential to induce a biological response in MDCK cells. Overexpression of a Gab1 mutant deficient in Shp2 interaction could also block HGF/SF-induced activation of the MAPK pathway, suggesting that Shp2 is critical for c-Met/Gab1-specific signaling.
Keywords:Gab1, c-Met-Binding Site, Morphogenesis, Shp2, Reverse Yeast Two-Hybrid Analysis
Source:Journal of Cell Biology
ISSN:0021-9525
Publisher:Rockefeller University Press
Volume:149
Number:7
Page Range:1419-1432
Date:26 June 2000
Additional Information:Copyright (c) 2000 by The Rockefeller University Press
Official Publication:http://www.jcb.org/cgi/content/abstract/149/7/1419
PubMed:View item in PubMed

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