Association of the p75 Neurotrophin Receptor with TRAF6*
- From the Molecular Neurobiology Program, Skirball Institute, New York University Medical Center, 540 New York, New York 10016
Abstract
In addition to the Trk tyrosine kinase receptors, neurotrophins also bind to a second receptor, p75, a member of the tumor necrosis factor receptor superfamily. Several signaling pathways have been implicated for p75 in the absence of Trk receptors, including induction of NF-κB and c-Jun kinase activities and increased production of ceramide. However, to date, the mechanisms by which the p75 receptor initiates intracellular signal transduction have not been defined. Here we report a specific interaction between p75 and TRAF6 (tumor necrosis factorreceptor-associated factor-6) after transient transfection in HEK293T cells. The interaction was ligand-dependent and maximal at 100 ng/ml of nerve growth factor (NGF). Other neurotrophins also promoted the association of TRAF6 with p75 but to a lesser extent. The binding of TRAF6 was localized to the juxtamembrane region of p75 by co-immunoprecipitation and Western blotting. To assess the functional significance of this interaction, we have tested responses in cultured Schwann cells that express p75 and TRAF6. An NGF-mediated increase in the nuclear localization of the p65 subunit of NF-κB could be blocked by the introduction of a dominant negative form of TRAF6 in Schwann cells. These results indicate that TRAF6 can potentially function as a signal transducer for NGF actions through the p75 receptor.
Footnotes
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↵* This work was supported by the National Institutes of Health and the American Heart Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: Molecular Neurobiology Program, Skirball Inst., New York University Medical Center, 540 First Ave., New York, NY 10016.
- Abbreviations:
- NGF
-
nerve growth factor
- TNF
-
tumor necrosis factor
- TRAF
-
tumor necrosis factor receptor-associated factor
- BDNF
-
brain-derived neurotrophin factor
- NT
-
neurotrophin
- IL
-
interleukin
- HA
-
hemagglutinin
- JNK
-
c-Jun N-terminal kinase
- PCR
-
polymerase chain reaction
- DN
-
dominant negative.
-
- Received September 17, 1998.
- Revision received November 6, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
