This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yoon, S.-O. Articles by Lipscomb, E. A. Search for Related Content PubMed PubMed Citation Articles by Yoon, S.-O. Articles by Lipscomb, E. A.

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)

This article has been cited by other articles:

				P. Dentelli, A. Rosso, A. Zeoli, R. Gambino, L. Pegoraro, G. Pagano, R. Falcioni, and M. F. Brizzi Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and beta4 Integrin Expression J. Biol. Chem., September 7, 2007; 282(36): 26101 - 26110. [Abstract] [Full Text] [PDF]