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Papers In Press, published online ahead of print December 1, 2004
INSERM U563, IFR 30, Toulouse 31059
Corresponding Author: raynal{at}toulouse.inserm.fr
SHP2 was recently found to downregulate PI3K activation by dephosphorylating Gab1 but the mechanisms explaining the positive role of the Gab1/SHP2 pathway in EGF-induced Ras activation remain ill defined. Substrate trapping experiments now suggest that SHP2 dephosphorylates other Gab1 phosphotyrosines located within a central region displaying four YXXP motifs. Because these sites are potential docking motifs for RasGAP, we tested whether SHP2 dephosphorylates them to facilitate Ras activation. We observed that a Gab1 construct preventing SHP2 recruitment promoted membrane relocation of RasGAP. Moreover, a RasGAP inactive mutant restored the activation of Ras in cells transfected with SHP2-inactivating Gab1 mutant or in SHP2-deficient fibroblasts, supporting the hypothesis that RasGAP is a downstream target of SHP2. To define whether Gab1 was a RasGAP-binding partner, a Gab1 mutant deleted of four YXXP motifs was produced. The deletion suppressed RasGAP redistribution and restored the defective Ras activation caused by SHP2-inactivating mutations. Moreover, Gab1 was found to interact with RasGAP SH2 domains, only under conditions where SHP2 is not activated. To identify RasGAP-binding sites, Tyr to Phe mutants of Gab1 YXXP motifs were produced. Gab1 constructs mutated on Tyr 317 were severely affected in RasGAP binding and the most active in compensating for Ras defective activation and in blocking RasGAP redistribution induced by SHP2 inactivation. We have thus localized on Gab1 a Ras negative regulatory tyrosine phosphorylation site involved in RasGAP binding and showed that an important SHP2 function is to downregulate its phosphorylation to disengage RasGAP and sustain Ras activation.
J. Biol. Chem, 10.1074/jbc.M410012200
Submitted on August 31, 2004
Revised on November 26, 2004
Accepted on December 1, 2004
A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation
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