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 beta (TGF-beta) induced focal adhesion kinase (FAK)-dependent clustering of HER2 and integrins alpha(6), beta(1), and beta(4) 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-beta up-regulates EGFR ligand shedding through a mechanism involving the phosphorylation of tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17). Knockdown of TACE, FAK, or integrin alpha(6) by siRNA or inhibition of EGFR or Src by specific inhibitors abrogated TGF-beta-induced receptor clustering and signaling to phosphatidylinositol 3-kinase-Akt. Finally, inhibition of Src-FAK reversed TGF-beta-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-beta integrates ErbB receptor and integrin signaling to induce cell migration and survival during breast cancer progression.