TRAF2-MLK3 interaction is essential for TNF-α-induced MLK3 activation  

作　　者：Gautam Sondarva Chanakya N Kundu Suneet Mehrotra Rajakishore Mishra Velusamy Rangasamy Pradeep Sathyanarayana Rajarshi S Ray Basabi Rana Ajay Rana 

机构地区：[1]Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA [2]Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, Temple, TX 76504, USA [3]Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA [4]Hines Veterans Affairs Medical Center, Hines, IL 60141, USA

出　　处：《Cell Research》2010年第1期89-98,共10页细胞研究（英文版）

摘　　要：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-a stimulation. The mecha- nism 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.

关 键 词：c-Jun N-terminal kinase （JNK） tumor necrosis factor-α （TNF-α） mixed lineage kinase （MLK3） TNF receptorassociated factors （TRAFs） 

分 类 号：Q26[生物学—细胞生物学] Q786