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A Novel Mechanism for Integrin-Mediated Ras Activation in Breast Carcinoma Cells: The ₆ß₄ Integrin Regulates ErbB2 Translation and Transactivates Epidermal Growth Factor Receptor/ErbB2 Signaling

¹ Department of Cell Biology, Harvard Medical School and ² Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Sang-Oh Yoon, Department of Cell Biology, Harvard Medical School, Boston, MA 02115. Phone: 617-432-1281; Fax: 617-432-1144; E-mail: sang-oh_yoon{at}hms.harvard.edu.

ErbB2 (HER2, Neu) and Ras play key roles in tumor invasion and metastasis. We identified a novel mechanism by which integrin ₆ß₄ regulates ErbB2 expression, Ras activation, and the invasion of breast carcinoma cells. Here we show that integrin ₆ß₄ regulates Ras activity especially in serum-depleted condition. Down-regulation of ß₄ integrin by ß₄ short hairpin RNA (shRNA) decreased Ras activity and carcinoma invasion whereas reexpression of this integrin restored Ras activity. ErbB2, a binding partner of epidermal growth factor receptor (EGFR), and EGFR modulated Ras activity, and integrin ₆ß₄ regulated phospho-EGFR level without affecting EGFR expression. We also found that integrin ₆ß₄ is involved in ErbB2 expression. Depletion of ß₄ by shRNA reduced ErbB2 protein level without affecting ErbB2 mRNA level and reexpression of ß₄ increased ErbB2 protein level. Reduction of eukaryotic initiation factor 4E, a rate-limiting factor for cap-dependent translation, decreased ErbB2 protein level, and ß₄ shRNA cells exhibited a shift in ErbB2 mRNA to light polysomes compared with control cells. These results show that integrin ₆ß₄ regulates ErbB2 through translational control. In summary, we propose a novel mechanism for ErbB2 up-regulation and Ras activation in serum-depleted breast cancer cells; integrin ₆ß₄ regulates the expression of ErbB2 and the subsequent phosphorylation of EGFR and activation of Ras. These findings provide a mechanism that substantiates the reported role of ₆ß₄ in carcinoma invasion. (Cancer Res 2006; 66(5): 2732-9)

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