Hepatocyte growth factor (scatter factor) is an angiogenic growth factor that binds to its cellular transmembrane receptor, c-met. Both HGF and c-met are expressed by vascular smooth muscle and endothelial cells, where HGF may exert autocrine and paracrine effects. We have found that human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs) release a soluble, truncated form of c-met. Receptor shedding was induced by treatment of the cells with phorbol 12-myristate 13-acetate (PMA) and by the ligand, HGF. Shedding was inhibited by cycloheximide, a metalloproteinase inhibitor, and protein kinase C inhibitors. The soluble form of c-met was able to bind HGF, although with reduced affinity (Kd≈10 nmol/L) compared with the membrane bound receptor. Conditioned medium containing soluble c-met inhibited the induction of Akt phosphorylation by HGF in HUVECs. The soluble truncated form of c-met was detectable in the plasma of 5 healthy volunteers. The shedding of c-met may represent a novel mechanism for regulating the mitogenic, motogenic, and morphogenic effects of hepatocyte growth factor.