Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathways |
| |
Authors: | Shambharkar Prashant B Blonska Marzenna Pappu Bhanu P Li Hongxiu You Yun Sakurai Hiroaki Darnay Bryant G Hara Hiromitsu Penninger Josef Lin Xin |
| |
Institution: | Department of Molecular and Cellular Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA. |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|