CARD11 mediates factor-specific activation of NF-kappaB by the T cell receptor complex.
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 Bcl10 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.
D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D015723:Gene Library; D006162:Guanylate Cyclase / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051528:Guanylate Kinases; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics*; D010920:Placenta / Q000502:physiology; D011247:Pregnancy; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013945:Thymoma; D013953:Thymus Neoplasms; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D004247:DNA; D051528:Guanylate Kinases; C426242:CARD11 protein, human; D006162:Guanylate Cyclase