Article
- The EMBO Journal (2007) 26, 1794 - 1805
- doi:10.1038/sj.emboj.7601622
Published online: 15 March 2007
Subject Category:
Phosphorylation and ubiquitination of the I
B kinase complex by two distinct signaling pathways
Prashant B Shambharkar1,2, Marzenna Blonska1, Bhanu P Pappu1, Hongxiu Li1, Yun You1, Hiroaki Sakurai3, Bryant G Darnay4, Hiromitsu Hara5, Josef Penninger6 and Xin Lin1
- Department of Molecular and Cellular Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
- Graduate Program in Microbiology and Immunology, State University of New York, Buffalo, NY, USA
- Division of Pathogenic Biochemistry, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan
- Department of Experimental Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA
- Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan
- IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
Correspondence to:
Xin Lin, Department of Molecular and Cellular Oncology, Department of Experimental Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA. Tel.: +1 171 379 289 69; Fax: +1 171 379 402 09; E-mail: xllin@mdanderson.org
Received 5 September 2006; Accepted 29 January 2007
Abstract
The I
B kinase (IKK) complex serves as the master regulator for the activation of NF-B by various stimuli. It contains two catalytic subunits, IKK
and IKK
, and a regulatory subunit, IKK
/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK/ 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 IKK/ 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 IKK/ phosphorylation. Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKK/ and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation.
Keywords:
- IB kinase,
- phosphorylation,
- ubiquitination
- I
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