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

Wang SE, Shin I, Wu FY, Friedman DB, Arteaga CL
Cancer Res. 2006 66 (19): 9591-600

PMID: 17018616 · DOI:10.1158/0008-5472.CAN-06-2071

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

MeSH Terms (24)

Actinin Actins Adenocarcinoma Animals Breast Neoplasms Cell Line, Tumor Female Humans Mammary Neoplasms, Experimental Mice Mice, Transgenic Neoplasm Metastasis Neuropeptides p21-Activated Kinases Phosphatidylinositol 3-Kinases Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-vav Pseudopodia rac1 GTP-Binding Protein rac GTP-Binding Proteins Receptor, ErbB-2 Recombinant Fusion Proteins Signal Transduction Transforming Growth Factor beta1

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