期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 7, 页码 5210-5222出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.424804
关键词
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资金
- Association for International Cancer Research [11-0204]
- Canadian Cancer Society Research Institute [2011-700790]
- Research Institute of the McGill University Health Centre
- Department of Medicine, McGill University
- Fonds de recherche en sante du Quebec
- United States Army Department of Defense Breast Cancer Research Program [W81XWH-11-1-0008]
- Worldwide Cancer Research [11-0204] Funding Source: researchfish
The ErbB2 and TGF beta signaling pathways cooperate to promote the migratory, invasive, and metastatic behavior of breast cancer cells. Wepreviously demonstrated that ShcA is necessary for these synergistic interactions. Through a structure/function approach, we now show that the phosphotyrosine-binding, but not the Src homology 2, domain of ShcA is required for TGF beta-induced migration and invasion of ErbB2-expressing breast cancer cells. We further demonstrate that the tyrosine phosphorylation sites within ShcA (Tyr(239)/Tyr(240) and Tyr(313)) transduce distinct and non-redundant signals that promote these TGF beta-mediated effects. We demonstrate that Grb2 is required specifically downstream of Tyr(313), whereas the Tyr(239)/Tyr(240) phosphorylation sites require the Crk adaptor proteins to augment TGF beta-induced migration and invasion. Furthermore, ShcA Tyr(313) phosphorylation enhances tumor cell survival, and ShcA Tyr(239)/Tyr(240) signaling promotes endothelial cell recruitment into ErbB2-expressing breast tumors in vivo, whereas all three ShcA tyrosine residues are required for efficient breast cancer metastasis to the lungs. Our data uncover a novel ShcA-dependent signaling axis downstream of TGF beta and ErbB2 that requires both the Grb2 and Crk adaptor proteins to increase the migratory and invasive properties of breast cancer cells. In addition, signaling downstream of specific ShcA tyrosine residues facilitates the survival, vascularization, and metastatic spread of breast tumors.
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