NF-kappaB activation pathways induced by T cell costimulation.
Analysis of knockout mice and of T cells deficient for individual signaling proteins allowed the identification of novel members of the costimulation-induced NF-kappaB activation pathway while biochemical approaches started to unveil their functional mechanisms. These results show that NF-kappaB activation depends on an early wave of tyrosine phosphorylation that allows the inducible formation of multiprotein complexes containing several proteins required for NF-kappaB activation: adaptor proteins including Src homology 2 domain-containing leukocyte phosphoprotein 76 (SLP-76) and proteins with enzymatic activity, such as phospholipase C (PLC) gamma and the exchange factor Vav1. While Vav1 contributes to Rac-dependent reorganization of the actin cytoskeleton, activated PLCgamma1 generates the protein kinase C (PKC) activator diacylglycerol. In T cells, the novel PKC isoform PKCtheta is indispensable for NF-kappaB activation and its enzymatic activity depends on recruitment to the immunological synapse. Downstream from PKCtheta, the caspase recruitment domain (CARD) proteins CARD11/CARMA1 and Bcl10 relay T cell receptor-derived signals to the IkappaB kinase (IKK) complex. Many members of the NF-kappaB activation cascade, including the IKKs, are either constitutively or inducibly translocated to the lipid raft fraction, showing a highly organized spatial distribution of these NF-kappaB activating proteins.
Schmitz
M Lienhard
ML
University of Bern, Department of Chemistry and Biochemistry, Switzerland. Lienhard.Schmitz@ibc.unibe.ch
Bacher
Susanne
S
Dienz
Oliver
O
D000818:Animals; D006801:Humans; D051550:I-kappa B Kinase; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018448:Models, Immunological; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*
D007527:Isoenzymes; D046911:Macromolecular Substances; D046912:Multiprotein Complexes; D016328:NF-kappa B; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; C076233:PRKCQ protein, human; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta