Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PP1.
Despite rapid progress in elucidating the molecular mechanisms of activation of the kinase IKK, the processes that regulate IKK deactivation are still unknown. Here we demonstrate that CUE domain-containing 2 (CUEDC2) interacted with IKKalpha and IKKbeta and repressed activation of the transcription factor NF-kappaB by decreasing phosphorylation and activation of IKK. Notably, CUEDC2 also interacted with GADD34, a regulatory subunit of protein phosphatase 1 (PP1). We found that IKK, CUEDC2 and PP1 existed in a complex and that IKK was released from the complex in response to inflammatory stimuli such as tumor necrosis factor. CUEDC2 deactivated IKK by recruiting PP1 to the complex. Therefore, CUEDC2 acts as an adaptor protein to target IKK for dephosphorylation and inactivation by recruiting PP1.
Li
Hui-Yan
HY
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
Liu
Hui
H
Wang
Chen-Hui
CH
Zhang
Ji-Yan
JY
Man
Jiang-Hong
JH
Gao
Yan-Fei
YF
Zhang
Pei-Jing
PJ
Li
Wei-Hua
WH
Zhao
Jie
J
Pan
Xin
X
Zhou
Tao
T
Gong
Wei-Li
WL
Li
Ai-Ling
AL
Zhang
Xue-Min
XM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; C519556:CUEDC2 protein, human; C576361:CUEDC2 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D015850:Interleukin-6; D008565:Membrane Proteins; D016328:NF-kappa B; D012097:Repressor Proteins; D051550:I-kappa B Kinase; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1