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[Cancer Research 66, 9591-9600, October 1, 2006]
© 2006 American Association for Cancer Research

Cell, Tumor, and Stem Cell Biology

HER2/Neu (ErbB2) Signaling to Rac1-Pak1 Is Temporally and Spatially Modulated by Transforming Growth Factor ß

Shizhen Emily Wang1,5, Incheol Shin6, Frederick Y. Wu2, David B. Friedman3,4 and Carlos L. Arteaga1,2,5

Departments of 1 Cancer Biology, 2 Medicine, and 3 Biochemistry; 4 Mass Spectrometry Research Center; 5 Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; and 6 Department of Life Sciences, Hanyang University, Seoul, Korea

Requests for reprints: Carlos L. Arteaga, Division of Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 PRB, Nashville, TN 37232-6307. Phone: 615-936-3524; Fax: 615-936-1790; E-mail: carlos.arteaga{at}vanderbilt.edu.

In HER2 (ErbB2)-overexpressing cells, transforming growth factor ß (TGF-ß), via activation of phosphoinositide-3 kinase (PI3K), recruits actin and actinin to HER2, which then colocalizes with Vav2, activated Rac1, and Pak1 at cell protrusions. This results in prolonged Rac1 activation, enhanced motility and invasiveness, Bad phosphorylation, uncoupling of Bad/Bcl-2, and enhanced cell survival. The recruitment of the HER2/Vav2/Rac1/Pak1/actin/actinin complex to lamellipodia was abrogated by actinin siRNAs, dominant-negative (dn) p85, gefitinib, and dn-Rac1 or dn-Pak1, suggesting that the reciprocal interplay of PI3K, HER2 kinase, and Rac GTPases with the actin cytoskeleton is necessary for TGF-ß action in oncogene-overexpressing cells. Thus, by recruiting the actin skeleton, TGF-ß "cross-links" this signaling complex at cell lamellipodia; this prolongs Rac1 activation and increases metastatic properties and survival of HER2-overexpressing cells. (Cancer Res 2006; 66(19): 9591-600)




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Copyright © 2006 by the American Association for Cancer Research.