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Transforming Growth Factor β Induces Clustering of HER2 and Integrins by Activating Src-Focal Adhesion Kinase and Receptor Association to the Cytoskeleton

¹ Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, Duarte, California; Departments of ² Medicine and ³ Cancer Biology, and ⁴ Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Shizhen Emily Wang, Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, KCRB Room 2007, 1500 East Duarte Road, Duarte, CA 91010. Phone: 626-256-4673, ext. 63118; Fax: 626-301-8972; E-mail: ewang{at}coh.org or Carlos L. Arteaga, Division of Oncology, Vanderbilt University School of Medicine, 2200 Pierce Avenue, 777 PRB, Nashville, TN 37232-6307. Phone: 615-936-3524; Fax: 615-936-1790; E-mail: carlos.arteaga{at}vanderbilt.edu.

Key Words: TGF-β • HER2 (ErbB2) • integrin • FAK • Src

It has been proposed that cross talk between integrin and growth factor receptor signaling such as ErbB2 (HER2) is required for activation of downstream effectors and ErbB2-mediated mammary tumorigenesis. Here we show that transforming growth factor β (TGF-β) induced focal adhesion kinase (FAK)–dependent clustering of HER2 and integrins ₆, β₁, and β₄ in HER2-overexpressing mammary epithelial cells without altering the total and surface levels of HER2 receptors. This effect was mediated by ligand-induced epidermal growth factor receptor (EGFR) activation and the subsequent phosphorylation of Src and FAK. We have previously reported that TGF-β up-regulates EGFR ligand shedding through a mechanism involving the phosphorylation of tumor necrosis factor-–converting enzyme (TACE/ADAM17). Knockdown of TACE, FAK, or integrin ₆ by siRNA or inhibition of EGFR or Src by specific inhibitors abrogated TGF-β–induced receptor clustering and signaling to phosphatidylinositol 3-kinase-Akt. Finally, inhibition of Src-FAK reversed TGF-β–induced resistance to the therapeutic HER2 inhibitor trastuzumab in HER2-overexpressing breast cancer cells. Taken together, these data suggest that, by activating Src-FAK, TGF-β integrates ErbB receptor and integrin signaling to induce cell migration and survival during breast cancer progression. [Cancer Res 2009;69(2):475–82]