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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.

Pubmed ID: 12356734

Authors

  • Pomerantz JL
  • Denny EM
  • Baltimore D

Journal

The EMBO journal

Publication Data

October 1, 2002

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI 42549-04

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • DNA
  • Female
  • Gene Expression Regulation
  • Gene Library
  • Guanylate Cyclase
  • Guanylate Kinase
  • Humans
  • Membrane Proteins
  • Mice
  • Molecular Sequence Data
  • NF-kappa B
  • Placenta
  • Pregnancy
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • Sequence Homology, Amino Acid
  • Thymoma
  • Thymus Neoplasms
  • Tumor Cells, Cultured