Proapoptotic Function of the MET Tyrosine Kinase Receptor through Caspase Cleavage

Abstract

The MET tyrosine kinase, the receptor of hepatocyte growth factor-scatter factor (HGF/SF), is known to be essential for normal development and cell survival. We report that stress stimuli induce the caspase-mediated cleavage of MET in physiological cellular targets, such as epithelial cells, embryonic hepatocytes, and cortical neurons. Cleavage occurs at aspartic residue 1000 within the SVD site of the juxtamembrane region, independently of the crucial docking tyrosine residues Y1001 or Y1347 and Y1354. This cleavage generates an intracellular 40-kDa MET fragment containing the kinase domain. The p40 MET fragment itself causes apoptosis of MDCK epithelial cells and embryonic cortical neurons, whereas its kinase-dead version is impaired in proapoptotic activity. Finally, HGF/SF treatment does not favor MET cleavage and apoptosis, confirming the known survival role of ligand-activated MET. Our results show that stress stimuli convert the MET survival receptor into a proapoptotic factor.

This work was supported by the Institut Pasteur de Lille, the CNRS, and INSERM, and by grants from the Association Régionale pour l'Enseignement et la Recherche Scientifique et Technologique, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer, the Fondation de France, the Ligue Nationale contre le Cancer, the Association Française contre le Myopathies, the Fondation pour la Recherche Médicale, the Association pour la Recherche sur le Cancer, the Shlumberger Fundation, and NIH. A.M was supported by a Ligue contre le Cancer fellowship.