HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor beta.
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.
Wang
Shizhen Emily
SE
Department of Cancer Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA.
Shin
Incheol
I
Wu
Frederick Y
FY
Friedman
David B
DB
Arteaga
Carlos L
CL
D000185:Actinin / Q000502:physiology; D000199:Actins / Q000502:physiology; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology; D011554:Pseudopodia / Q000502:physiology* / Q000648:ultrastructure; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000502:physiology*; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
D000185:Actinin; D000199:Actins; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051567:Proto-Oncogene Proteins c-vav; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D053773:Transforming Growth Factor beta1; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; C508961:Tgfb1 protein, mouse; C093651:VAV2 protein, human; C490565:Vav2 protein, mouse; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse