ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress.
Activation of the transcription factor NF-κB by multiple genotoxic stimuli modulates cancer cell survival. This response is mediated by a conserved pathway involving the nuclear ATM kinase and cytoplasmic IκB kinase (IKK); however, the molecular link between them remains incompletely understood. Here we show that ATM activates the IKK kinase ... TAK1 in a manner dependent on IKKγ/NEMO and ELKS (a protein rich in glutamate, leucine, lysine, and serine). K63-linked polyubiquitination of ELKS, dependent on the ubiquitin ligase XIAP and the conjugating enzyme UBC13, allows ELKS association with TAK1 via its ubiquitin-binding subunits TAB2/3. Although NEMO mutants defective in ubiquitin binding permit ATM-dependent TAK1 activation, they block NEMO association with ELKS and IKK activation. Thus, ATM- and NEMO-dependent ubiquitination of ELKS leads to the ubiquitin-dependent assembly of TAK1/TAB2/3 and NEMO/IKK complexes, resulting in IKK and NF-κB activation following genotoxic stimuli.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Camptothecin, Carrier Proteins, Cell Cycle Proteins, Cell Line, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Etoposide, Humans, I-kappa B Kinase, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase Kinases, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Morpholines, Mutation, NF-kappa B, Nerve Tissue Proteins, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Pyrones, RNA Interference, Signal Transduction, Time Factors, Transfection, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Ubiquitin-Conjugating Enzymes, Ubiquitination, X-Linked Inhibitor of Apoptosis Protein
Adaptor Proteins, Signal Transducing, Animals, Camptothecin, Carrier Proteins, Cell Cycle Proteins, Cell Line, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Etoposide, Humans, I-kappa B Kinase, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase Kinases, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Morpholines, Mutation, NF-kappa B, Nerve Tissue Proteins, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Pyrones, RNA Interference, Signal Transduction, Time Factors, Transfection, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Ubiquitin-Conjugating Enzymes, Ubiquitination, X-Linked Inhibitor of Apoptosis Protein
Mol. Cell
Date: Oct. 08, 2010
PubMed ID: 20932476
View in: Pubmed Google Scholar
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