c-Src mediates mitogenic signals and associates with cytoskeletal proteinsupon vascular endothelial growth factor stimulation in Kaposi's sarcoma cells

Vascular endothelial growth factor (VEGF) appears to be a critical cytokine modulating the growth and spread of Kaposi's sarcoma (KS), Furthermore, in fection with the KS herpes virus results in up-regulation of VEGF and trigg ering of VEGF receptor activation. The molecular mechanisms regulating such cytokine-driven proliferation of KS cells are not well characterized. We i nvestigated the role of Src-related tyrosine kinases in VEGF-mediated signa ling in model KS 38 tumor cells. VEGF stimulation specifically activated c- Src kinase activity but not that of other related Src kinases such as Lyn, Fyn, or Hck in KS cells. Pyrazolopyrimidine, a selective inhibitor of Src f amily tyrosine kinases, significantly blocked the VEGF-induced growth of KS cells. Further studies using mutants of c-Src kinase revealed that Src med iates mitogen-activated protein kinase activation induced by VEGF, We also observed that VEGF stimulation resulted in increased tyrosine phosphorylati on of the focal adhesion components paxillin and p130(cas). Furthermore, VE GF induction enhanced the complex formation between Src kinase and paxillin . Src kinase appears to play an important functional role in VEGF-induced s ignaling in KS cells and may act to link pathways from the VEGF receptor to mitogen-activated protein kinase and cytoskeletal components, thereby effe cting tumor proliferation and migration.