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The Journal of Neuroscience, August 15, 2001, 21(16):5854-5863
A Prosurvival Function for the p75 Receptor Death Domain Mediated
via the Caspase Recruitment Domain Receptor-Interacting Protein 2
Gus
Khursigara1,
John
Bertin2,
Hiroko
Yano3,
Howell
Moffett3,
Peter S.
DiStefano2, and
Moses V.
Chao3
1 Weill Medical College of Cornell University, New
York, New York 10021, 2 Millennium Pharmaceuticals,
Cambridge, Massachusetts 01239, and 3 Molecular
Neurobiology Program, Skirball Institute for Biomolecular Medicine,
Departments of Cell Biology and Physiology and Neuroscience, New York
University School of Medicine, New York, New York 10016
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- B (NF-B) 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-B 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.
Key words:
neurotrophin; apoptosis; Schwann cells; p75 receptor; death domain; receptor-interacting protein
Copyright © 2001 Society for Neuroscience 0270-6474/01/21165854-10$05.00/0
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