Tumor Necrosis Factor- Inhibits Growth Factor–Mediated Cell Proliferation Through SHP-1 Activation in Endothelial Cells

Src homology 2–containing protein-tyrosine phosphatase 1 (SHP-1) is known to regulate signal transduction through the dephosphorylation of tyrosine kinases. In this study, we addressed the role of SHP-1 under tumor necrosis factor(TNF) stimulation in endothelial cells. The addition of recombinant vascular endothelial growth factor (50 ng/mL) or epidermal growth factor (50 ng/mL) significantly increased thymidine incorporation and c-fos promoter activity, whereas TNF(5 ng/mL) attenuated these effects in human or bovine aortic endothelial cells. In bovine aortic endothelial cells, we confirmed endogenous SHP-1 expression and that TNFactivated SHP-1. Importantly, overexpression of dominant-negative SHP-1 attenuated the effect of TNFon thymidine incorporation and c-fos promoter activity. In addition, TNFattenuated vascular endothelial growth factor– and epidermal growth factor– induced extracellular signal–regulated kinase phosphorylation, whereas overexpression of dominant-negative SHP-1 prevented this inhibitory effect of TNF. Taken together, our results suggested that TNFinhibited growth factor–mediated cell proliferation through SHP-1 activation. (Arterioscler Thromb Vasc Biol. 2002;22:238-242.)