期刊
EMBO JOURNAL
卷 21, 期 19, 页码 5184-5194出版社
OXFORD UNIV PRESS
DOI: 10.1093/emboj/cdf505
关键词
CARD11; expression cloning; MAGUK; NF-kappa B; RNAi
资金
- NIAID NIH HHS [R01 AI042549, AI 42549-04] Funding Source: Medline
NF-kappaB is a critical target of signaling downstream of the T cell receptor (TCR) complex, but how TCR signaling activates NF-kappaB is poorly understood. We have developed an expression cloning strategy that can identify catalytic and noncatalytic molecules that participate in different pathways of NF-kappaB activation. Screening of a mouse thymus cDNA library yielded CARD11, a membrane-associated guanylate kinase (MAGUK) family member containing CARD, PDZ, SH3 and GUK domains. Using a CARD-deleted variant of CARD11 and RNA interference (RNAi), we demonstrate that CARD11 mediates NF-kappaB activation by alphaCD3/alphaCD28 cross-linking and PMA/ionomycin treatment, but not by TNFalpha or dsRNA. CARD11 is not required for TCR-mediated induction of NFAT or AP-1. CARD11 functions upstream of the IkappaB-kinase (IKK) complex and cooperates with Bc110 in a CARD domain-dependent manner. RNAi-rescue experiments suggest that the CARD, coiled-coil, SH3 and GUK domains of CARD11 are critical for its signaling function. These results implicate CARD11 in factor-specific activation of NF-kappaB by the TCR complex and establish a role for a MAGUK family member in antigen receptor signaling.
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