Regulation of NF-κB activation in T cells via association of the adapter proteins ADAP and CARMA1

Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Science (Impact Factor: 33.61). 06/2007; 316(5825):754-8. DOI: 10.1126/science.1137895
Source: PubMed


The adapter protein ADAP regulates T lymphocyte adhesion and activation. We present evidence for a previously unrecognized function for ADAP in regulating T cell receptor (TCR)-mediated activation of the transcription factor NF-kappaB. Stimulation of ADAP-deficient mouse T cells with antibodies to CD3 and CD28 resulted in impaired nuclear translocation of NF-kappaB, a reduced DNA binding, and delayed degradation and decreased phosphorylation of IkappaB (inhibitor of NF-kappaB). TCR-stimulated assembly of the CARMA1-BCL-10-MALT1 complex was substantially impaired in the absence of ADAP. We further identified a region of ADAP that is required for association with the CARMA1 adapter and NF-kappaB activation but is not required for ADAP-dependent regulation of adhesion. These findings provide new insights into ADAP function and the mechanism by which CARMA1 regulates NF-kappaB activation in T cells.

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Available from: Ricardo De Medeiros, May 07, 2015
    • ") whereas RIAM activates NFAT by controlling the activation of PLC1 (Patsoukis et al., 2009). Along the same line, ADAP has been shown to activate NF-B signaling, an event not directly required for ADAP-SKAP55-dependent regulation of cell adhesion (Medeiros et al., 2007), emphasizing the fact that components of inside-out signaling pathways can influence distinct TCR signaling events beyond their adhesion function. "
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    • "3.3. The adaptor ADAP is not needed for direct CD28 activation of NF-ÄB Previous reports have shown a role of ADAP-CARMA1-Bcl10- Malt1 complex in the regulation of NF-␬B in T-cells in response to co-ligation by TCR/CD28 [47] [48] [49]. However, the role of ADAP in anti-CD28 stimulation alone of NF-␬B had not been examined. "
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    ABSTRACT: The transcription factor NF-κB is needed for the induction of inflammatory responses in T-cells. Whether its activation by the antigen-receptor and CD28 is mediated by the same or different intracellular signaling pathways has been unclear. Here, using T-cells from various knock-out (Cd28−/−, adap−/−) and knock-in (i.e. Cd28 Y-170F) mice in conjunction with transfected Jurkat T-cells, we show that the TCR and CD28 use distinct pathways to activate NF-κB in T-cells. Anti-CD28 ligation alone activated NF-κB in primary and Jurkat T-cells as measured by NF-κB reporter and EMSA assays. Anti-CD28 also activated NF-κB normally in primary T-cells from adap−/− mice, while anti-CD3 stimulation required the adaptor ADAP. Over-expression of ADAP or its binding partner SKAP1 failed to enhance anti-CD28 activation of NF-κB, while ADAP greatly increased anti-CD3 induced NF-κB activity. By contrast, CD28 activation of NF-κB depended on GRB-2 binding to CD28 as seen in CD28 deficient Jurkat T-cells reconstituted with the CD28 YMN-FM mutant, and in primary T-cells from CD28 Y170F mutant knock-in mice. CD28 associated with GRB-2, and GRB-2 siRNA impaired CD28 NF-κB activation. GRB-2 binding partner and guanine nucleotide exchange factor, VAV1, greatly enhanced anti-CD28 driven activation of NF-κB. Further, unlike in the case of anti-CD28, NF-κB activation by anti-CD3 and its cooperation with ADAP was strictly dependent on LAT expression. Overall, we provide evidence that CD28 and the TCR complex regulate NF-κB via different signaling modules of GRB-2/VAV1 and LAT/ADAP pathways respectively.
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    • "The kinase TAK1 is another component involved in the signaling pathways downstream of TLR4 [28]. ADAP has been shown to be involved in the regulation of NF-κB activation in T cells via an association with CARMA1 [10]. More recently, it has been reported that ADAP associates with TAK1, and that this interaction is critical for the recruitment of TAK1 to the CBM complex in T cells [29]. "
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    ABSTRACT: The cytosolic adaptor protein ADAP (adhesion and degranulation promoting adapter protein) is expressed by T cells, natural killer cells, myeloid cells and platelets. ADAP is involved in T-cell-receptor-mediated inside-out signaling, which leads to integrin activation, adhesion and reorganization of the actin cytoskeleton. However, little is known about the role of ADAP in myeloid cells. In the present study, we analyzed the function of ADAP in bone-marrow-derived dendritic cells (BMDCs) from ADAP-deficient mice. ADAP-deficient BMDCs showed almost normal levels of antigen uptake, adhesion, maturation, migration from the periphery to the draining lymph nodes, antigen-specific T-cell activation, and production of the proinflammatory cytokines IL-6 and TNF-∝. Furthermore, we provide evidence that the activation of signaling pathways after lipopolysaccharide (LPS) stimulation are not affected by the loss of ADAP. In contrast, ADAP-deficient BMDCs showed defects in CD11c-mediated cellular responses, with significantly diminished production of IL-6, TNF-∝ and IL-10. Actin polymerization was enhanced after CD11c integrin stimulation. In summary, we propose that the adapter molecule ADAP is critical for selected CD11c integrin-mediated functions of dendritic cells.
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