Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation

Vascular endothelial cell growth factor (VEGF) binds to and promotes the ac tivation of one of its receptors, KDR, Once activated, KDR induces the tyro sine phosphorylation of cytoplasmic signaling proteins that are important t o endothelial cell proliferation. In human umbilical vein endothelial cells (HUVECs), tumor necrosis factor (TNF) inhibits the phosphorylation and act ivation of KDR, The ability of TNF to diminish VEGF-stimulated KDR activity was impaired by sodium orthovanadate, suggesting that the inhibitory activ ity of TNF was mediated by a protein-tyrosine phosphatase, KDR-initiated re sponses specifically associated with endothelial cell proliferation, mitoge n-activated protein kinase activation and DNA synthesis, were also inhibite d by TNF, and this was reversed by sodium orthovanadate. Stimulation of HUV ECs with TNF induced association of the SHP-1 protein-tyrosine phosphatase with KDR, identifying this phosphatase as a candidate negative regulator of VEGF signal transduction. Heterologous receptor inactivation mediated by a protein-tyrosine phosphatase provides insight into how TNF may inhibit end othelial cell proliferative responses and modulate angiogenesis in patholog ical settings.