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

In addition to promoting cell survival, neurotrophins also can elicit apopt osis in restricted cell types. Recent results indicate that nerve growth fa ctor (NGF) can induce Schwann cell death via engagement of the p75 neurotro phin receptor. Here we describe a novel interaction between the p75 recepto r and receptor-interacting protein 2, RIP2 (RICK/CARDIAK), that accounts fo r the ability of neurotrophins to choose between a survival-versus-death pa thway. RIP2, an adaptor protein with a serine threonine kinase and a caspas e recruitment domain (CARD), is highly expressed in dissociated Schwann cel ls 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 introduc tion of RIP2 into Schwann cells deficient in RIP2 conferred NGF-dependent n uclear transcription factor-kappaB (NF-kappaB) activity and decreased the c ell death induced by NGF. Conversely, the expression of a dominant-negative version of RIP2 protein resulted in a loss of NGF-induced NF-kappaB induct ion and increased NGF-mediated cell death. These results indicate that adap tor proteins like RIP2 can provide a bifunctional switch for cell survival or cell death decisions mediated by the p75 neurotrophin receptor.