ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress.
Mol Cell
; 40(1): 75-86, 2010 Oct 08.
Article
em En
| MEDLINE
| ID: mdl-20932476
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Transdução de Sinais
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Proteínas de Transporte
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Proteínas Serina-Treonina Quinases
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Proteínas de Ciclo Celular
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MAP Quinase Quinase Quinases
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Proteínas Supressoras de Tumor
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Peptídeos e Proteínas de Sinalização Intracelular
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Proteínas Adaptadoras de Transdução de Sinal
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Proteínas de Ligação a DNA
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article