Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis.
Heregulin-beta1 promotes the activation of p21-activated kinase 1 (Pak1) and the motility and invasiveness of breast cancer cells. In this study, we identified vascular endothelial growth factor (VEGF) as a gene product induced by heregulin-beta1. The stimulation by heregulin-beta1 of breast cancer epithelial cells induced the expression of the VEGF mRNA and protein and its promoter activity. Heregulin-beta1 also stimulated angiogenesis in a VEGF-dependent manner. Herceptin, an anti-HER2 antibody inhibited heregulin-beta1-mediated stimulation of both VEGF expression in epithelial cells and angiogenesis in endothelial cells. Because the activation of Pak1 and VEGF expression are positively regulated by heregulin-beta1, we hypothesized that Pak1 regulates VEGF expression, and hence explored the role of Pak1 in angiogenesis. We provide new evidence to implicate Pak1 signaling in VEGF expression. Overexpression of a kinase-dead K299R Pak1 leads to suppression of VEGF promoter activity, as well as VEGF mRNA expression and secretion of VEGF protein. Conversely, kinase-active T423E Pak1 promotes the expression and secretion of VEGF. Furthermore, expression of the heregulin-beta1 transgene, HRG, in harderian tumors in mice enhances the activation of Pak1 as well as expression of VEGF and angiogenic marker CD34 antigen. These results suggest that heregulin-beta1 regulates angiogenesis via up-regulation of VEGF expression and that Pak1 plays an important role in controlling VEGF expression and, consequently, VEGF secretion and function.
Bagheri-Yarmand
R
R
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Vadlamudi
R K
RK
Wang
R A
RA
Mendelsohn
J
J
Kumar
R
R
D016475:3T3 Cells; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000378:metabolism; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism*; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D018919:Neovascularization, Physiologic; D020890:Neuregulin-1 / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D054462:p21-Activated Kinases
D018952:Antigens, CD34; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D007797:Laminin; D008222:Lymphokines; D020890:Neuregulin-1; D011509:Proteoglycans; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; C087230:heregulin beta1; D003094:Collagen; D010770:Phosphotransferases; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases