NF-kappaB signaling in lymphocytes: a new cast of characters.
Cell-surface antigen receptors on B and T lymphocytes are complex, multisubunit assemblies that must recruit several accessory proteins and activate multiple signaling pathways in order to illicit a proper immune response. One pathway culminates in the activation of specific protein kinase C (PKC) isoforms, which is necessary for the ultimate activation of the NF-kappaB transcription factor. Since NF-kappaB plays a crucial role in the adaptive immune response (e.g. in lymphocyte proliferation and cytokine production), it is important to understand the molecular mechanisms by which NF-kappaB is regulated. Nevertheless, the connection between PKC activation and NF-kappaB has remained a mystery that has now been at least partly solved. Recent findings implicate a new scaffolding protein, Bimp3/CARMA1/CARD11, as a key factor in bridging PKC activation with the downstream activation of Bcl10 and MALT1, which ultimately stimulates NF-kappaB. Since some of these signaling components are lymphocyte specific, therapeutic agents that block this pathway could blunt the inappropriate proliferation of lymphocytes associated with certain inflammatory and neoplastic disorders. Alternatively, agents that specifically augment this pathway, thereby enhancing immune function in immunodeficiency, may be developed.
Lucas
Peter C
PC
Department of Pathology, University of Michigan Medical School, 4131 CCGC, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
McAllister-Lucas
Linda M
LM
Nunez
Gabriel
G
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001402:B-Lymphocytes / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D020169:Caspases; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D018442:Lymphoma, B-Cell, Marginal Zone / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; D011493:Protein Kinase C; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase