Signal transduction through the T cell receptor (TCR) and a costimulatory molecule, CD28, results in the stimulation of multiple
signaling pathways, leading to the activation of several transcription factors including activator protein–1 (AP-1), nuclear
factor of activated T cells (NF-AT), and nuclear factor kappa B (NF-κB). The molecular mechanisms by which NF-κB is activated
by TCR–CD28 have only recently become known. New findings indicate that the adaptor molecules CARMA1 and Bcl10 are essential
to the process. Additionally, a critical role for MALT1/paracaspase has been identified. MALT1, CARMA1, and Bcl10 form a tripartite
protein complex, in which Bcl10 is thought to facilitate the oligomerization of MALT1 monomers. Overexpression of MALT1, as
observed in a subset of lymphoma patients, leads to the potent activation of NF-κB, suggesting that MALT1 might stimulate
(directly or indirectly) the kinase complex [IKK, inhibitor of NF-κB (IκB) kinase] responsible for activating cytoplasmic
NF-κB for translocation into the nucleus. Moreover, the MALT1–CARMA1–Bcl10 complex is responsible for ubiquitination of NEMO,
a step that appears to be critical for TCR-induced NF-κB activation but not for induction mediated by other stimuli such as
TNF or IL-1.
