The Dependence Receptor TrkC Triggers Mitochondria-Dependent Apoptosis upon Cobra-1 Recruitment
Open accessAbstract
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.
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In absence of ligands, UNC5D and NTRK3 are subjected to CASP3 cleavage generating intracellular fragments that translocate either into nucleus to trigger E2F1-driven expression of pro-apoptotic genes (UNC5D) or at mitochondria to activate CASP9 upon MOMP (NTRK3).
“(4) UNC5D and NTRK3 are subjected to CASP3 cleavage generating intracellular fragments that translocate either into the nucleus to trigger the E2F transcription factor 1 (E2F1)-driven expression of pro-apoptotic genes (as in the case of UNC5D) or at mitochondria to activate CASP9 upon MOMP (as in the case of NTRK3) [358, 359].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [359]
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Research works printed but not linked: 1
- Bouzas-Rodriguez, J., Cabrera, J.R., Delloye-Bourgeois, C., Ichim, G., Delcros, J.G., Raquin, M.A., Rousseau, R., Combaret, V., Be ´nard, J., (D and E) Cobra1 silencing impairs TrkC KF mitochondrial localization. TrkC KF GFP was transfected in HEK 293T cells with or without shCobra1, and cell fractionation was performed. GFP immunoblot is shown. The intensity of the bands has been quantified and is represented as a ratio (M/C, mitochondrial fraction over cytosolic fraction) in (E). Data represent mean ± SEM. (F) The silencing of Cobra1 in COS-7 cells reduces the colocalization index (Pearson's coefficient) between TrkC KF GFP and the MitoTracker. Data represent mean ± SEM. ***p < 0.001 (ns, nonsignificant; two-sided Mann-Whitney test) in comparison to control. (G) A model of Cobra1's involvement in TrkC-induced apoptosis via the mitochondrial intrinsic pathway. The unliganded TrkC is cleaved by caspases, releasing TrkC KF, which localizes at the mitochondria. This shuttling seems to require Cobra1. Furthermore, TrkC KF is able to release cytochrome c and, thus, initiates the classical cascade of the intrinsic apoptosis.
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- Authors
- Ichim, G., Genevois, A.-L., Ménard, M., Yu, L.-Y., Coelho-Aguiar, J. M., Llambi, F., Jarrosson-Wuilleme, L., Lefebvre, J., Tulasne, D., Dupin, E., Le Douarin, N., Arumäe, U., Tauszig-Delamasure, S., & Mehlen, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- University of Helsinki (FI)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Mehlen, Patrick
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 51
- Issue
- 5
- Pages
- 632-646
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2082648259
- Cited by
- 28
- References
- 49
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 1
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- Agence Nationale de la Recherche (ANR-10-LABX-0061)
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Université de Lyon
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Keywords
- TrkC, dependence receptors, neurotrophin-3, mitochondrial apoptosis, Bax activation, cytochrome c release, apoptosome, neural tube development, chick embryo
- MeSH terms
- Animals, Chick Embryo, Cytosol, Ganglia, Spinal, Humans, Mice, Inbred C57BL, Mitochondria, Neurons, Nuclear Proteins, Peptide Fragments, RNA-Binding Proteins, Apoptosis, Receptor, trkC, Gene Silencing, Neurotrophin 3, Cytochromes c, bcl-2-Associated X Protein, Mice
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