HER2/Neu (ErbB2) Signaling to Rac1-Pak1 Is Temporally and Spatially Modulated by Transforming Growth Factor B
نویسندگان
چکیده
In HER2 (ErbB2)-overexpressing cells, transforming growth factor B (TGF-B), 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 dnPak1, suggesting that the reciprocal interplay of PI3K, HER2 kinase, and Rac GTPases with the actin cytoskeleton is necessary for TGF-B action in oncogene-overexpressing cells. Thus, by recruiting the actin skeleton, TGF-B ‘‘cross-links’’ this signaling complex at cell lamellipodia; this prolongs Rac1 activation and increases metastatic properties and survival of HER2-overexpressing cells. (Cancer Res 2006; 66(19): 9591-600)
منابع مشابه
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 surv...
متن کاملI. the Importance of Her2 in Breast Cancer
The human epidermal growth factor receptors (HER), also known as ERBB receptors, are a family of signal transduction proteins. There are 4 family members in humans—HER1, HER2, HER3, and HER4—each of which is composed of an extracellular (ligandbinding) domain, a transmembrane domain, and an intracellular tyrosine kinase, except for HER3, which lacks a tyrosine kinase domain (Figure 1). HER-fami...
متن کاملTransforming Growth Factor B Induces Clustering of HER2 and Integrins by Activating Src-Focal Adhesion Kinase and Receptor Association to the Cytoskeleton
It has been proposed that cross talk between integrin and growth factor receptor signaling such as ErbB2 (HER2) is required for activation of downstream effectors and ErbB2mediated mammary tumorigenesis. Here we show that transforming growth factor B (TGF-B) induced focal adhesion kinase (FAK)–dependent clustering of HER2 and integrins A6, B1, and B4 in HER2-overexpressing mammary epithelial ce...
متن کاملConcurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer.
PURPOSE The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer. PATIENTS AND METHODS Twenty-two patients with stage IV HER2/neu-positive breast cancer r...
متن کاملTGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells.
Increased intraglomerular pressure is an important pathogenic determinant of kidney fibrosis in the progression of chronic kidney disease, and can be modeled by exposing glomerular mesangial cells (MC) to mechanical stretch. MC produce extracellular matrix and profibrotic cytokines, including connective tissue growth factor (CTGF) when stretched. We show that p21-activated kinase 1 (Pak1) is ac...
متن کامل