Vascular Endothelial Growth Factor Up-regulation via p21-activated Kinase-1 Signaling Regulates Heregulin- beta 1- mediated Angiogenesis

• Published in: The Journal of biological chemistry 2000-12, Vol.275 (50), p.39451-39457
• Main Authors: Bagheri-Yarmand, R, Vadlamudi, R K, Wang, R A, Mendelsohn, J, Kumar, R
• Format: Article
• Language: English
• Subjects: heregulin-^b1; HRG gene; Pak1 protein
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M006150200

Heregulin- beta 1 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- beta 1. The stimulation by heregulin- beta 1 of breast cancer epithelial cells induced the expression of the VEGF mRNA and protein and its promoter activity. Heregulin- beta 1 also stimulated angiogenesis in a VEGF-dependent manner. Herceptin, an anti-HER2 antibody inhibited heregulin- beta 1-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- beta 1, 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- beta 1 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- beta 1 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.