title: The dependence receptor TrkC triggers mitochondria-dependent apoptosis upon Cobra-1 recruitment.
abstract: The neurotrophin receptor TrkC was recently identified as a dependence receptor, and, as such, it triggers apoptosis in the absence of its ligand, NT-3. The molecular mechanism for apoptotic engagement involves the double cleavage of the receptor's intracellular domain, leading to the formation of a proapoptotic "killer" fragment (TrkC KF). Here, we show that TrkC KF interacts with Cobra1, a putative cofactor of BRCA1, and that Cobra1 is required for TrkC-induced apoptosis. We also show that, in the developing chick neural tube, NT-3 silencing is associated with neuroepithelial cell death that is rescued by Cobra1 silencing. Cobra1 shuttles TrkC KF to the mitochondria, where it promotes Bax activation, cytochrome c release, and apoptosome-dependent apoptosis. Thus, we propose that, in the absence of NT-3, the proteolytic cleavage of TrkC leads to the release of a killer fragment that triggers mitochondria-dependent apoptosis via the recruitment of Cobra1.
authors.affiliation: Apoptosis, Cancer and Development Laboratory, Equipe Labellisée La Ligue, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ichim
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Genevois
authors.forename: Marie
authors.initials: M
authors.lastname: Ménard
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Yu
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Coelho-Aguiar
authors.forename: Fabien
authors.initials: F
authors.lastname: Llambi
authors.forename: Loraine
authors.initials: L
authors.lastname: Jarrosson-Wuilleme
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lefebvre
authors.forename: David
authors.initials: D
authors.lastname: Tulasne
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dupin
authors.forename: Nicole
authors.initials: N
authors.lastname: Le Douarin
authors.forename: Urmas
authors.initials: U
authors.lastname: Arumäe
authors.forename: Servane
authors.initials: S
authors.lastname: Tauszig-Delamasure
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002642:Chick Embryo / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D016601:RNA-Binding Proteins; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C541978:Cobra1 protein, mouse; D020933:Neurotrophin 3; D009687:Nuclear Proteins; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020812:Receptor, trkC