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EGF-induced Grb7 Recruits and Promotes Ras Activity.pdf

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EGF-induced Grb7 Recruits and Promotes Ras Activity

EGF-induced Grb7 Recruits and Promotes Ras Activity Essential for the Tumorigenicity of Sk-Br3 Breast Cancer Cells* Received for publication, February 14, 2010, and in revised form, July 2, 2010 Published, JBC Papers in Press, July 9, 2010, DOI 10.1074/jbc.C110.114124 Pei-Yu Chu?, Tsai-Kun Li§?, Shih-Torng Ding?, I-Rue Lai**, and Tang-Long Shen??1 From the ?Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, the §Graduate Institute of Microbiology, National Taiwan University Medical College, Taipei 10051, the ?Center for Biotechnology and the Department of Animal Science and Technology, National Taiwan University, Taipei 10617, and the **Graduate Institute of Anatomy and Cell Biology, National Taiwan University Medical College, Taipei 10051, Taiwan Co-amplification and co-overexpression of ErbB2 and Grb7 are frequently found in various cancers, including breast cancer. Biochemical and functional correlations of the two molecules have identified Grb7 to be a pivotal mediator downstream of ErbB2-mediated oncogenesis. However, it remains largely unknown how Grb7 is involve in the ErbB2-mediated tumori- genesis. In this study, we show that Grb7-mediated cell prolifer- ation and growth are essential for the tumorigenesis that occurs in ErbB2-Grb7-overexpressing breast cancer cells. Intrinsically, EGF-inducedde novoGrb7 tyrosine phosphorylation/activation recruits and activates Ras-GTPases and subsequently promotes the phosphorylation of ERK1/2, thereby stimulating tumor growth. Furthermore, we also found the anti-tumor effect could be synergized by co-treatment withHerceptin plusGrb7 knock- down in Sk-Br3 breast cancer cells. Our findings illustrate an underlying mechanism by which Grb7 promotes tumorigenesis through the formation of a novel EGFR-Grb7-Ras signaling complex, therebyhighlighting the potential strategy of targeting Grb7 as an anti-breast cancer therapy. Growth factor receptor-bound protein-7 (Grb7)2 is the pro- totype