CD3/CD28 Costimulation-Induced NF-κB Activation Is Mediated by Recruitment of Protein Kinase C-θ, Bcl10, and IκB Kinase β to the Immunological Synapse through CARMA1

T-Cell Receptor-Induced NF-κB Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b

“…It has been reported that CARMA1 recruits IKKs to lipid rafts at the immunological synapse, whereas the translocation of PKC-to lipid rafts at the immunological synapse may be independent of CARMA1 (11). On the other hand, other studies indicate that CARMA1 controls the recruitment of PKC-, Bcl10, MALT1, and IKK␤ to the immunological synapse (52). Therefore, the precise role of PKC-and CARMA1 in mediating NF-B activation is still not completely elucidated, especially for primary T cells.…”

“…Recently, it has been shown that in transformed cells, PKCcan associate with and phosphorylate the CARMA1 linker region, which binds to and blocks the accessibility of the CARD motif (31,45,52). It has previously been suggested that TCR-triggered, PKC-dependent linker phosphorylation is required to release this inhibition, thereby allowing for Bcl10 recruitment and signal propagation to the IKK complex (31,45,52). Recent studies also indicate that CARMA1 links PKC-to downstream signaling components that lead to the activation of NF-B.…”

“…The signaling complex consisting of CARMA1, Bcl10, and MALT1 (CBM complex) functions as an intermediate, linking the TCR to the IKK complex, and this process is facilitated by CD28 costimulation (28,43). PKC-associates with and phosphorylates CARMA1 in Jurkat T cells (31,52), suggesting that PKCmay favor the formation of the CBM complex. Mice deficient in CBM show severe defects in antigen receptor-induced NF-B activation (6,12,21), placing CBM in the same pathway, leading to the activation of NF-B.…”

Current Status of Immunosuppression in Liver Transplantation

“…Along with signal 1, T cells activation also needs costimulatory signal 2, provided by interaction of CD80/CD86 (surface of antigen presenting cells) and CD28 (surface of T lymphocytes). [8][9][10][11] Signals 1 and 2 activate downstream signal transduction pathways, which include calcium/ calcineurin pathway (target for calcineurin inhibitors), RAS mitogen activated protein (MAP) kinase and nuclear factor kappa B (NF-kB) pathways which in turn leads to transcription of cytokines including interleukin-2 (IL-2). Interleukin-2 acts on other immune cells providing signal 3 trigger for cell proliferation.…”

Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

“…37 SH3 and GUK domains likely regulate activity by controlling subcellular localization and crucial proteineprotein interactions. 38,39 Furthermore, enhanced activation has been reported upon loss of MAGUK domains 40 raising the possibility that cSCC-specific variants may increase activity by abrogating this inhibitory action. Exactly how the mutations we identify here affect CARD11 function and impact NF-kB signaling in the epidermis currently is unclear, but because downstream activation is comparable with oncogenic coiled-coil domain mutants (also identified in cSCC), it suggests that CARD11-mediated NF-kB signaling is regulated at multiple levels in human cSCC.…”