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J. Biol. Chem., Vol. 280, Issue 7, 5350-5360, February 18, 2005

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A Novel Role for Gab1 and SHP2 in Epidermal Growth Factor-induced Ras Activation^*

Alexandra Montagner, Armelle Yart, Marie Dance, Bertrand Perret, Jean-Pierre Salles, and Patrick Raynal

From the Département Lipoprotéines et Médiateurs Lipidiques, INSERM U563, Hôpital Purpan, 31300 Toulouse, France

SHP2 was recently found to down-regulate 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 Ras-GAP, 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 determine whether Gab1 is 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 Ras-GAP-binding sites, Tyr to Phe mutants of Gab1 YXXP motifs were produced. Gab1 constructs mutated on Tyr³¹⁷ were severely affected in RasGAP binding and were the most active in compensating for Ras-defective activation and 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 down-regulate its phosphorylation to disengage RasGAP and sustain Ras activation.

Received for publication, August 31, 2004 , and in revised form, November 26, 2004.

^* This work was supported by grants from Association pour la Recherche sur le Cancer, Ligue Nationale Contre le Cancer (comités de Haute-Garonne et Tarn) and from the Alliance des Recherches sur le Cancer (ARECA) network "Proteomics and Cancer." The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 33-561-77-94-12; Fax: 33-561-77-94-01; E-mail: raynal{at}toulouse.inserm.fr.

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