Volume 20, No 1, Jan 2010
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 20 Issue 1, January 2010: 89-98
ORIGINAL ARTICLES
TRAF2-MLK3 interaction is essential for TNF-α-induced MLK3 activation
Gautam Sondarva1,*, Chanakya N Kundu2,*, Suneet Mehrotra1, Rajakishore Mishra1, Velusamy Rangasamy1, Pradeep Sathyanarayana2, Rajarshi S Ray1, Basabi Rana3,4 and Ajay Rana1,2,4
1Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
2Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, Temple, TX 76504, USA
3Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
4Hines Veterans Affairs Medical Center, Hines, IL 60141, USA
Correspondence: Ajay Rana,(arana@lumc.edu)
Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that is activated by tumor necrosis factor-α (TNF-α) and specifically activates c-Jun N-terminal kinase (JNK) on TNF-α stimulation. The mechanism by which TNF-α activates MLK3 is still not known. TNF receptor-associated factors (TRAFs) are adapter molecules that are recruited to cytoplasmic end of TNF receptor and mediate the downstream signaling, including activation of JNK. Here, we report that MLK3 associates with TRAF2, TRAF5 and TRAF6; however only TRAF2 can significantly induce the kinase activity of MLK3. The interaction domain of TRAF2 maps to the TRAF domain and for MLK3 to its C-terminal half (amino acids 511-847). Endogenous TRAF2 and MLK3 associate with each other in response to TNF-α treatment in a time-dependent manner. The association between MLK3 and TRAF2 mediates MLK3 activation and competition with the TRAF2 deletion mutant that binds to MLK3 attenuates MLK3 kinase activity in a dose-dependent manner, on TNF-α treatment. Furthermore the downstream target of MLK3, JNK was activated by TNF-α in a TRAF2-dependent manner. Hence, our data show that the direct interaction between TRAF2 and MLK3 is required for TNF-α-induced activation of MLK3 and its downstream target, JNK.
Cell Research (2010) 20:89-98. doi: 10.1038/cr.2009.125; published online 17 November 2009
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