The Dependence Receptor TrkC Triggers Mitochondria-Dependent Apoptosis upon Cobra-1 Recruitment

• The dependence receptor TrkC interacts with Cobra1
• Upon NT-3 withdrawal, TrkC triggers mitochondria-dependent apoptosis
• Upon NT-3 withdrawal, TrkC is cleaved and generates a proapoptotic killer fragment
• TrkC killer fragment shuttles with Cobra1 to the mitochondria to engage apoptosis

SummaryThe 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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