Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis.

Abstract

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.

• Authors: R Bagheri-Yarmand, R K Vadlamudi, R A Wang, J Mendelsohn, R Kumar
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 275 Issue 50 Pg. 39451-7 (Dec 15 2000) ISSN: 0021-9258 [Print] United States
• PMID: 10967114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, CD34
• Drug Combinations
• Endothelial Growth Factors
• Laminin
• Lymphokines
• Neuregulin-1
• Proteoglycans
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• matrigel
• heregulin beta1
• Collagen
• Phosphotransferases
• PAK1 protein, human
• Pak1 protein, mouse
• Protein Serine-Threonine Kinases
• p21-Activated Kinases

Topics

• 3T3 Cells
• Animals
• Antigens, CD34 (metabolism)
• Blotting, Northern
• Breast Neoplasms (metabolism)
• Cell Movement
• Collagen (metabolism)
• Drug Combinations
• Endothelial Growth Factors (genetics, metabolism)
• Genes, Dominant
• Genes, Reporter
• Humans
• Laminin (metabolism)
• Lymphokines (genetics, metabolism)
• Mice
• Mice, Transgenic
• Mutagenesis
• Neovascularization, Physiologic
• Neuregulin-1 (metabolism)
• Phosphotransferases (metabolism)
• Precipitin Tests
• Promoter Regions, Genetic
• Protein Serine-Threonine Kinases (metabolism)
• Proteoglycans (metabolism)
• RNA, Messenger (metabolism)
• Signal Transduction
• Transgenes
• Tumor Cells, Cultured
• Up-Regulation
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• p21-Activated Kinases