Transforming growth factor β induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton

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 tumorigenes is. Here we show that transforming growth factor β (TGF-β) induced focal adhesion kinase (FAK)-dependent clustering of HER2 and integrins α₆, 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-α-converting enzyme (TACE/ADAM17). Knockdown of TACE, FAK, or integrin α₆ 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.