Hepatocyte growth factor-induced proliferation of primary hepatocytes is mediated by activation of phosphatidylinositol 3-kinase.

Primary hepatocytes respond to the proliferating signals of Hepatocyte Growth Factor (HGF) through activation of the tyrosine kinase activity of the met (p145) receptor. Addition of dHGF in hepatocyte cultures resulted in receptor phosphorylation which co-precipitated with a phosphorylated protein of 85 kDa. This protein was identified as the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase). Co-precipitation of the PI 3-kinase regulatory subunit with the met receptor was observed only with the phosphorylated receptor. Wortmanin, which specifically inhibits PI 3-kinase, was found to abolish the hepatocyte DNA synthetic response due to stimulation with dHGF. It is suggested that the D-3-phosphorylated inositol phospholipids participate as major regulators in the growth and differentiation factor-initiated cascades, this not being restricted to primary hepatocytes.