TRAF2-MLK3 interaction is essential for TNF-alpha-induced MLK3 activation.

Cell Research
Gautam SondarvaAjay Rana

Abstract

Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that is activated by tumor necrosis factor-alpha (TNF-alpha) and specifically activates c-Jun N-terminal kinase (JNK) on TNF-alpha stimulation. The mechanism by which TNF-alpha 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-alpha 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-alpha treatment. Furthermore the downstream target of MLK3, JNK was activated by TNF-alpha in a TRAF2-dependent manner. Hence, our data show that the direct interaction between TRAF2 and MLK3 is required ...Continue Reading

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Citations

Mar 22, 2014·Seminars in Immunology·Guadalupe Sabio, Roger J Davis
May 1, 2013·Canadian Journal of Physiology and Pharmacology·Deborah N Chadee
Sep 2, 2011·The Journal of Biological Chemistry·Ramesh P ThylurBasabi Rana
Oct 8, 2011·Genes & Development·Shashi KantRoger J Davis
Dec 21, 2010·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Agnieszka Pindel, Anthony Sadler
Sep 22, 2015·Biochemistry·Arianna CeccarelliGiampiero Mei
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Aug 10, 2018·Molecular Biology of the Cell·Elad PrinzAmi Aronheim
Sep 11, 2014·The Journal of Biological Chemistry·Rohan K HumphreyUlupi S Jhala
Dec 22, 2019·Pharmacology & Therapeutics·Kathleen A GalloSusan E Conrad
Jun 3, 2021·International Journal of Molecular Sciences·Andy RuizLeslie Chavez-Galan

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