Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-β1-mediated angiogenesis

Rozita Bagheri-Yarmand, Ratna K. Vadlamudi, Rui An Wang, John Mendelsohn, Rakesh Kumar

Resultado de la investigación: Articlerevisión exhaustiva

113 Citas (Scopus)

Resumen

Heregulin-β1 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-β1. The stimulation by heregulin-β1 of breast cancer epithelial cells induced the expression of the VEGF mRNA and protein and its promoter activity. Heregulin-β1 also stimulated angiogenesis in a VEGF-dependent manner. Herceptin, an anti-HER2 antibody inhibited heregulin-β1-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-β1, 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-β1 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-β1 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.

Idioma originalEnglish (US)
Páginas (desde-hasta)39451-39457
Número de páginas7
PublicaciónJournal of Biological Chemistry
Volumen275
N.º50
DOI
EstadoPublished - dic. 15 2000
Publicado de forma externa

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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