title: Necrosis- and apoptosis-related Met cleavages have divergent functional consequences.
abstract: Upon activation by its ligand hepatocyte growth factor/scatter factor, the receptor tyrosine kinase Met promotes survival, proliferation, and migration of epithelial cells during embryogenesis. Deregulated Met signaling can also promote cancer progression and metastasis. Met belongs to the functional family of dependence receptors whose activity switches from pro-survival to pro-apoptotic during apoptosis upon caspase cleavage. Although apoptosis resistance is a hallmark of cancer cells, some remain sensitive to other cell death processes, including necrosis induced by calcium stress. The role and fate of Met during necrotic cell death are unknown. Following treatment with calcium ionophores, cell lines and primary cells undergo necrosis, and the full-length Met receptor is efficiently degraded. This degradation is achieved by double cleavage of Met in its extracellular domain by a metalloprotease of the A disintegrin and metalloproteinase (ADAM) family and in its intracellular domain by calpains (calcium-dependent proteases). These cleavages separate the Met extracellular region from its kinase domain, thus preventing Met activity and its potential pro-survival activity. Although the intracellular fragment is very similar to the fragment generated by caspases, it displays no pro-apoptotic property, likely because of the presence of the last few amino acids of Met, known to inhibit this pro-apoptotic function. The fragments identified here are observed in lung tumors overexpressing the Met receptor, along with fragments previously identified, suggesting that proteolytic cleavages of Met are involved in its degradation in tumor tissues. Thus, Met is a modulator of necrosis, able to protect cells when activated by its ligand but efficiently degraded by proteolysis when this process is engaged.
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: R
authors.initials: R
authors.lastname: Montagne
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: M
authors.initials: M
authors.lastname: Berbon
authors.affiliation: 1] CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France [2] Département de Cancérologie Générale, CLCC Oscar Lambret, Université de Lille, 3 rue Fréderic Combemale, Lille 59020, France.
authors.forename: L
authors.initials: L
authors.lastname: Doublet
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: N
authors.initials: N
authors.lastname: Debreuck
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: A
authors.initials: A
authors.lastname: Baranzelli
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: H
authors.initials: H
authors.lastname: Drobecq
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: C
authors.initials: C
authors.lastname: Leroy
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: N
authors.initials: N
authors.lastname: Delhem
authors.affiliation: Service de Chirurgie Thoracique, Centre Hospitalier Régional Universitaire de Lille, Université de Lille, Lille, France.
authors.forename: H
authors.initials: H
authors.lastname: Porte
authors.affiliation: 1] CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France [2] Institut de Pathologie, Centre Hospitalier Régional Universitaire de Lille, Université de Lille, Avenue Oscar Lambret, Lille 59037, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Copin
authors.affiliation: Département de Cancérologie Générale, CLCC Oscar Lambret, Université de Lille, 3 rue Fréderic Combemale, Lille 59020, France.
authors.forename: E
authors.initials: E
authors.lastname: Dansin
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: A
authors.initials: A
authors.lastname: Furlan
authors.affiliation: CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille, Université de Lille, SIRIC ONCOLille, Lille 59021, France.
authors.forename: D
authors.initials: D
authors.lastname: Tulasne
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D009336:Necrosis / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction
chemical_list: C066855:HGF protein, human; D034741:RNA, Small Interfering; D015759:Ionomycin; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D002154:Calpain; D020169:Caspases; D051722:ADAM Proteins; D002118:Calcium