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

78 Citations (Scopus)

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

Fingerprint

Transforming Growth Factors
Actinin
Actins
Pseudopodia
1-Phosphatidylinositol 4-Kinase
GTP Phosphohydrolases
Actin Cytoskeleton
Oncogenes
Skeleton
Cell Survival
Phosphotransferases
Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor β. / Wang, Shizhen Emily; Shin, Incheol; Wu, Frederick Y.; Friedman, David B.; Arteaga, Carlos L.

In: Cancer Research, Vol. 66, No. 19, 01.10.2006, p. 9591-9600.

Research output: Contribution to journalArticle

Wang, Shizhen Emily ; Shin, Incheol ; Wu, Frederick Y. ; Friedman, David B. ; Arteaga, Carlos L. / HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor β. In: Cancer Research. 2006 ; Vol. 66, No. 19. pp. 9591-9600.
@article{14b77eee4b99456081ba920c8b1c78ca,
title = "HER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor β",
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.",
author = "Wang, {Shizhen Emily} and Incheol Shin and Wu, {Frederick Y.} and Friedman, {David B.} and Arteaga, {Carlos L.}",
year = "2006",
month = "10",
day = "1",
doi = "10.1158/0008-5472.CAN-06-2071",
language = "English (US)",
volume = "66",
pages = "9591--9600",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "19",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=33750324597&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750324597&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-2071

DO - 10.1158/0008-5472.CAN-06-2071

M3 - Article

C2 - 17018616

AN - SCOPUS:33750324597

VL - 66

SP - 9591

EP - 9600

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 19

ER -