Article
- The EMBO Journal (2006) 25, 97 - 107
- doi:10.1038/sj.emboj.7600913
Published online: 15 December 2005
Subject Categories:
Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor and stress pathways
Dongyu Zhang1,a, Valeria Facchinetti1,a, Xiaofang Wang1, Qiaojia Huang1,b, Jun Qin2 and Bing Su1
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Biochemistry, The Baylor College of Medicine, Houston, TX, USA
Correspondence to:
Bing Su, Department of Immunology, MD Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Box 178, Houston, TX 77030-1903, USA. Tel.: +1 713 563 3218; Fax: +1 713 563 3357; E-mail: bingsu@odin.mdacc.tmc.edu
aThese authors contributed equally to this work
bPresent address: Department of Laboratory Medicine, Fuzhou General Hospital, Fuzhou, Fujian, China
Received 22 July 2005; Accepted 22 November 2005
Abstract
Members of the mitogen-activated protein kinase kinase kinase (MAP3K) family are crucial for the Toll-like receptor (TLR) signaling and cellular stress responses. However, the molecular mechanisms underlying the TLR- and cellular stress-mediated MAP3K activation remain largely unknown. In this study, we identified a key regulatory phosphorylation site, serine 519 and serine 526, in MAP3K MEKK2 and MEKK3, respectively. Mutation of this serine to an alanine severely impaired MEKK2/3 activation. We generated an anti-p-MEKK2/3 antibody and used this antibody to demonstrate that lipopolysaccharide induced MEKK2 and MEKK3 phosphorylation on their regulatory serine. We found that the serine phosphorylation was crucial for TLR-induced interleukin 6 production and this process is regulated by TRAF6, a key adaptor molecule for the TLR pathway. We further demonstrated that many, but not all, MAPK agonists induced the regulatory serine phosphorylation, suggesting an involvement of different MAP3Ks in activation of the MAPK cascades leading to different cellular responses. In conclusion, this study reveals a novel molecular mechanism for MEKK2/3 activation by the TLR and cellular stress pathways.
Keywords:
- anti-phospho-MEKK2/3 antibody,
- cellular stress,
- cytokine,
- MAP3K,
- mitogen-activated protein kinase
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