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J. Biol. Chem., Vol. 278, Issue 45, 44075-44082, November 7, 2003

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Src Phosphorylates Grb2-associated Binder 1 upon Hepatocyte Growth Factor Stimulation^*

Po-Chao Chan, Yen-Ling Chen, Chi-Hung Cheng, Kuo-Ching Yu¶, Leslie A. Cary||, Kuo-Hsiung Shu, William L. Ho¶, and Hong-Chen Chen**

From the Department of Life Sciences and the Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan, the Section of Nephrology and the ^¶Department of Pathology, Taichung Veterans General Hospital, Taichung 40705, Taiwan, and the ^||Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109

Grb2-associated binder 1 (Gab1) is known to play an important role in hepatocyte growth factor (HGF) signaling, which rapidly becomes tyrosine-phosphorylated upon HGF stimulation. In this study, we found that the tyrosine phosphorylation of Gab1 in the cells derived from Src/Yes/Fyn null mouse embryos was 40% lower than that in their wild type counterparts upon HGF stimulation. Increased expression of wild-type Src enhanced HGF-induced phosphorylation of Gab1, and, in contrast, expression of the Src kinase-deficient mutant or treatment of the specific Src inhibitor PP1 suppressed it. Expression of a constitutively active Src mutant (Y527F) or oncogenic v-Src led to a prominent increase in Gab1 phosphorylation independent of HGF stimulation. Moreover, Src interacted with Gab1 via both its Src homology 2 and 3 domains and was capable of phosphorylating purified Gab1 in vitro. Finally, the increased phosphorylation of Gab1 by Src selectively potentiated HGF-induced activation of ERK and AKT. Taken together, our results establish a new role for Src in HGF-induced Gab1 phosphorylation.

Received for publication, June 2, 2003 , and in revised form, August 19, 2003.

^* This work was supported by National Science Council, Taiwan, Grants NSC-91-2311-B-005-044 and NSC-92-2311-B-005-012, Taichung Veterans General Hospital, and National Chung Hsing University, Grants TCVGH-91910C, TCVGH-925804A, 91VH-13, and 92VH-18. 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.: 886-4-22854922; Fax: 886-4-22853469; E-mail: hcchen{at}nchu.edu.tw.

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