title: Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathways.
abstract: The IkappaB kinase (IKK) complex serves as the master regulator for the activation of NF-kappaB by various stimuli. It contains two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKKalpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. However, the molecular mechanism by which these inducible modifications occur remains undefined. Here, we demonstrate that CARMA1, a key scaffold molecule, is essential to regulate NEMO ubiquitination upon T-cell receptor (TCR) stimulation. However, the phosphorylation of IKKalpha/beta activation loop is independent of CARMA1 or NEMO ubiquitination. Further, we provide evidence that TAK1 is activated and recruited to the synapses in a CARMA1-independent manner and mediate IKKalpha/beta phosphorylation. Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKKalpha/beta and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Prashant B
authors.initials: PB
authors.lastname: Shambharkar
authors.forename: Marzenna
authors.initials: M
authors.lastname: Blonska
authors.forename: Bhanu P
authors.initials: BP
authors.lastname: Pappu
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: You
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.forename: Josef
authors.initials: J
authors.lastname: Penninger
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000378:metabolism*; D019169:Jurkat Cells; D008239:Lysine / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018448:Models, Immunological; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology; D025801:Ubiquitin / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D051550:I-kappa B Kinase; D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D011493:Protein Kinase C; D011948:Receptors, Antigen, T-Cell; D025801:Ubiquitin; D000099151:MAP Kinase Kinase Kinase 7; C488088:Bcl10 protein, mouse; C496467:Card11 protein, mouse; C491731:IKBKG protein, human