A prosurvival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor-interacting protein 2

被引:131
作者
Khursigara, G
Bertin, J
Yano, H
Moffett, H
DiStefano, PS
Chao, MV
机构
[1] NYU, Sch Med, Skirball Inst Biomol Med, Dept Cell Biol & Physiol,Mol Neurobiol Program, New York, NY 10016 USA
[2] NYU, Sch Med, Skirball Inst Biomol Med, Dept Neurosci, New York, NY 10016 USA
[3] Cornell Univ, Weill Med Coll, New York, NY 10021 USA
[4] Millennium Pharmaceut Inc, Cambridge, MA 01239 USA
关键词
neurotrophin; apoptosis; Schwann cells; p75; receptor; death domain; receptor-interacting protein;
D O I
10.1523/JNEUROSCI.21-16-05854.2001
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In addition to promoting cell survival, neurotrophins also can elicit apoptosis in restricted cell types. Recent results indicate that nerve growth factor (NGF) can induce Schwann cell death via engagement of the p75 neurotrophin receptor. Here we describe a novel interaction between the p75 receptor and receptor-interacting protein 2, RIP2 (RICK/CARDIAK), that accounts for the ability of neurotrophins to choose between a survival-versus-death pathway. RIP2, an adaptor protein with a serine threonine kinase and a caspase recruitment domain (CARD), is highly expressed in dissociated Schwann cells and displays an endogenous association with p75. RIP2 binds to the death domain of p75 via its CARD domain in an NGF-dependent manner. The introduction of RIP2 into Schwann cells deficient in RIP2 conferred NGF-dependent nuclear transcription factor-kappaB (NF-kappaB) activity and decreased the cell death induced by NGF. Conversely, the expression of a dominant-negative version of RIP2 protein resulted in a loss of NGF-induced NF-kappaB induction and increased NGF-mediated cell death. These results indicate that adaptor proteins like RIP2 can provide a bifunctional switch for cell survival or cell death decisions mediated by the p75 neurotrophin receptor.
引用
收藏
页码:5854 / 5863
页数:10
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