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J Biol Chem, Vol. 275, Issue 20, 15392-15398, May 19, 2000
From the Departments of Signals delivered to antigen-presenting cells
through CD40 are critical for the activation of immune responses.
Intracellular tumor necrosis factor (TNF) receptor-associated factors
(TRAFs) are key elements of the signal transduction pathways of many
TNF receptor family members, including CD40. We show for the first time
that engagement of CD40 in intact B cells induces the rapid translocation of TRAF2 from the cytoplasm to the plasma membrane. We
found that CD40 engagement also results in its recruitment, together
with TRAF2 and TRAF3, to membrane microdomains, regions of the plasma
membrane enriched in signaling molecules such as the Src family
kinases. Using a membrane-permeable chelator of zinc or a mutant TRAF2
molecule, we show that the putative zinc-binding domains of TRAFs
contribute to their recruitment to microdomains and to the downstream
activation of c-Jun N-terminal kinase. We suggest that the zinc RING
and zinc finger domains of TRAFs are required for communication between
CD40 and microdomain-associated signaling molecules and may serve a
similar role in the signal transduction pathways of other TNF receptor
family members.
Recruitment of CD40 and Tumor Necrosis Factor
Receptor-associated Factors 2 and 3 to Membrane Microdomains during
CD40 Signaling*
,, and§¶
Microbiology and
§ Internal Medicine, University of Iowa, and the
¶ Veterans Affairs Medical Center, Iowa City, Iowa 52242
*
This work was supported by an Arthritis Foundation
postdoctoral fellowship (to B. S. H.) and by National Institutes of
Health Grants AI28847 and CA66570 and Veterans Affairs Medical Center Merit Review 383 (to G. A. B.). Core support was provided by National Institutes of Health Grant DK25295 (to the University of Iowa Diabetes
and Endocrinology Research Center).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.
To whom correspondence should be addressed: 3-570 BSB,
University of Iowa, Iowa City, IA 52242. Tel.: 319-335-7945; Fax:
319-335-9006; E-mail: gail-bishop@uiowa.edu.
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