TY - JOUR
T1 - HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor β
AU - Wang, Shizhen Emily
AU - Shin, Incheol
AU - Wu, Frederick Y.
AU - Friedman, David B.
AU - Arteaga, Carlos L.
PY - 2006/10/1
Y1 - 2006/10/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-06-2071
DO - 10.1158/0008-5472.CAN-06-2071
M3 - Article
C2 - 17018616
AN - SCOPUS:33750324597
SN - 0008-5472
VL - 66
SP - 9591
EP - 9600
JO - Cancer research
JF - Cancer research
IS - 19
ER -