HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor β

Shizhen Emily Wang, Incheol Shin, Frederick Y. Wu, David B. Friedman, Carlos L. Arteaga

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

In HER2 (ErbB2)-overexpressing cells, transforming growth factor β (TGF-β), 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-β action in oncogene-overexpressing cells. Thus, by recruiting the actin skeleton, TGF-β "cross-links" this signaling complex at cell lamellipodia; this prolongs Rac1 activation and increases metastatic properties and survival of HER2-overexpressing cells.

Original languageEnglish (US)
Pages (from-to)9591-9600
Number of pages10
JournalCancer research
Volume66
Issue number19
DOIs
StatePublished - Oct 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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