The Receptor for the Hepatocyte Growth Factor-Scatter Factor: Ligand-Dependent and Phosphorylation-Dependent Regulation of Kinase Activity

Hepatocyte Growth Factor (HGF) and Scatter Factor (SF) are identical molecules produced by the stromal fibroblats and non-parenchimal cells of many organs and also present in serum. HGF exerts an array of activities on epitelial cells, i.e. mitogenesis, dissociation of epithelial sheets, stimulation of cell motility, and promotion of matrix invasion. The receptor for HGF is the tyrosine kinase encoded by the MET proto-oncogene. It is widely expressed in normal epithelial tissues as a 190 kDa heterodimer of two disulfide-linked protein subunits. HGF binding triggers tyrosine autophosphorylation of the receptor β subunit in intact cultured cells. Autophosphorylation upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. The major phosphorylation site has been mapped to Tyr 1235. Negative regulation of the receptor kinase activity occurs through distinguishable pathways involving protein kinase C activation or increase in the intracellular Ca2+ concentration. Both lead to the phosphorylation of serine residue(s) in a unique tryptic phosphopeptide of the receptor and to a decrease in its tyrosine phosphorylation and kinase activity. Receptor autophosphorylation also triggers the signal transduction pathways inside the target cells. The phosphorylated receptor associates phosphatidylinositol 3-kinase, indicating that the generation of the D-3 phosphorylated inositol lipids is involved in effecting the motility and/or growth response to HGF.