title: Caspase-generated fragment of the Met receptor favors apoptosis via the intrinsic pathway independently of its tyrosine kinase activity.
abstract: The receptor tyrosine kinase Met and its ligand, the hepatocyte growth factor, are essential to embryonic development, whereas the deregulation of Met signaling is associated with tumorigenesis. While ligand-activated Met promotes survival, caspase-dependent generation of the p40 Met fragment leads to apoptosis induction - hallmark of the dependence receptor. Although the survival signaling pathways induced by Met are well described, the pro-apoptotic signaling pathways are unknown. We show that, although p40 Met contains the entire kinase domain, it accelerates apoptosis independently of kinase activity. In cell cultures undergoing apoptosis, the fragment shows a mitochondrial localization, required for p40 Met-induced cell death. Fulminant hepatic failure induced in mice leads to the generation of p40 Met localized also in the mitochondria, demonstrating caspase cleavage of Met in vivo. According to its localization, the fragment induces mitochondrial permeabilization, which is inhibited by Bak silencing and Bcl-xL overexpression. Moreover, Met silencing delays mitochondrial permeabilization induced by an apoptotic treatment. Thus, the Met-dependence receptor in addition to its well-known role in survival signaling mediated by its kinase activity, also participates in the intrinsic apoptosis pathway through the generation of p40 Met - a caspase-dependent fragment of Met implicated in the mitochondrial permeabilization process.
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille - Institut Pasteur de Lille-IFR 142 - Université de Lille 1-Université de Lille 2, Lille, France.
authors.forename: J
authors.initials: J
authors.lastname: Lefebvre
authors.forename: G
authors.initials: G
authors.lastname: Muharram
authors.forename: C
authors.initials: C
authors.lastname: Leroy
authors.forename: Z
authors.initials: Z
authors.lastname: Kherrouche
authors.forename: R
authors.initials: R
authors.lastname: Montagne
authors.forename: G
authors.initials: G
authors.lastname: Ichim
authors.forename: S
authors.initials: S
authors.lastname: Tauszig-Delamasure
authors.forename: A
authors.initials: A
authors.lastname: Chotteau-Lelievre
authors.forename: C
authors.initials: C
authors.lastname: Brenner
authors.forename: P
authors.initials: P
authors.lastname: Mehlen
authors.forename: D
authors.initials: D
authors.lastname: Tulasne
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000201:enzymology; D020868:Gene Silencing; D006801:Humans; D008024:Ligands; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010539:Permeability; D021381:Protein Transport; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D008024:Ligands; D010446:Peptide Fragments; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D019859:Proto-Oncogene Proteins c-met; D020169:Caspases