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Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways
Author(s) -
Shambharkar Prashant B,
Blonska Marzenna,
Pappu Bhanu P,
Li Hongxiu,
You Yun,
Sakurai Hiroaki,
Darnay Bryant G,
Hara Hiromitsu,
Penninger Josef,
Lin Xin
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601622
Subject(s) - biology , phosphorylation , signal transduction , ubiquitin , microbiology and biotechnology , kinase , protein serine threonine kinases , ubiquitin protein ligases , protein kinase a , biochemistry , genetics , ubiquitin ligase , gene
The IκB kinase (IKK) complex serves as the master regulator for the activation of NF‐κB by various stimuli. It contains two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKKα/β 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 IKKα/β 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 IKKα/β phosphorylation. Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKKα/β and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation.