THE CELL-DISSOCIATION AND MOTILITY TRIGGERED BY SCATTER FACTOR HEPATOCYTE GROWTH-FACTOR ARE MEDIATED THROUGH THE CYTOPLASMIC DOMAIN OF THE C-MET RECEPTOR

Scatter factor (SF), which dissociates epithelial cell colonies into i ndividual cells and stimulates the migration of epithelial cells, is i dentical to hepatocyte growth factor (HGF), a mitogen for melanocytes, endothelial cells and epithelial cells, including hepatocytes. It was previously shown by cDNA transfection that the mitogenic effect of SF /HGF is mediated by activation of the tyrosine phosphorylation of the c-Met receptor (the c-met protooncogene product). In this study, we co nstructed a cDNA encoding a chimeric receptor composed of the extracel lular domain of the epidermal growth factor (EGF) receptor and the tra nsmembrane and cytoplasmic domains of the c-Met receptor. We transfect ed the cDNA into the B16-F1 mouse melanoma cell line to investigate wh ether the cell dissociation and motility were mediated through this ch imeric receptor following ligand stimulation. The chimeric receptor cD NA was expressed in the transfected cells and the protein product was transported to the cell surface in the correct transmembrane orientati on. EGF treatment of the chimeric receptor-expressing cells markedly e nhanced tyrosine phosphorylation of the chimeric receptor and led to s cattered morphology and enhanced motility. This scattered morphology w as inhibited by a tyrosine kinase inhibitor. Based on these results, w e concluded that the cell dissociation and motility triggered by SF/HG F were mediated through the cytoplasmic domain of the c-Met receptor b y activation of its tyrosine kinase. Thus, it is likely that the diffe rent biological effects of SF/HGF are mediated by different intracellu lar signal cascades.