HEPATOCYTE GROWTH-FACTOR AND ITS RECEPTOR, THE TYROSINE KINASE ENCODED BY THE C-MET PROTOONCOGENE

HGF is secreted by mesenchymal cells and regulates motogenesis, mitoge nesis, and morphogenesis of epithelial and endothelial cells. HGF is a heterodimer of two glycosylated chains, alpha and beta, bound togethe r by a disulfide bond. The molecule is synthesized as single chain pre cursor devoid of biological activity (pro-HGF). The critical step in p ro-HGF activation is a proteolytic cleavage generating the two chain f orm. This step occurs in the extracellular enviroment, and is catalyze d by urokinase. Two alternative transcripts originate two HGF variants . One bears a deletion of five aminoacids in the alpha chain, and has the same properties of the full-size protein. The other one contains o nly the first portion of the alpha chain (two kringle HGF). Two kringl e HGF binds the HGF receptor, triggers its tyrosine kinase activity an d behaves as a partial agonist, inducing motogenesis but not mitogenes is in target cells. The HGF receptor is the tyrosine kinase encoded by the c-MET proto-oncogene, a tyrosine kinase receptor. This molecule i s an heterodimer of an extracellular alpha chain disulfide linked to a transmembrane beta chain. The cytoplasmic portion of the beta chain c ontains the catalytic domain and critical sites for the regulation of its kinase activity. In the C-terminal tail, a bidentate motif contain ing two tyrosines associates the transducers responsible for HGF signa lling.