title: Reciprocal inhibition between the transforming growth factor-β-activated kinase 1 (TAK1) and apoptosis signal-regulating kinase 1 (ASK1) mitogen-activated protein kinase kinase kinases and its suppression by TAK1-binding protein 2 (TAB2), an adapter protein for TAK1.
abstract: Mitogen-activated protein kinase kinase kinases (MAP3Ks) are activated by a wide spectrum of extracellular stimuli and are involved in various cellular events including proinflammatory and oxidative damage response through activations of two specific transcription factors, nuclear factor κB (NF-κB) and activator protein-1 (AP-1). Although members of the MAP3K family have both overlapping and distinct functions, the inter-regulatory mechanism of MAP3Ks remains largely unknown. In this study we demonstrated that transforming growth factor-β-activated kinase 1 (TAK1)-TAK1-binding protein 1 (TAB1) complex negatively regulates ASK1-mediated signaling, and TAB2 reciprocally regulates TAK1-induced NF-κB and apoptosis signal-regulating kinase 1 (ASK1)-mediated AP-1 activations through the TAK1-TAB2 interaction and the interferences of TAK1-ASK1 interaction. TAK1 interacted with the N or C terminus of ASK1 through the C-terminal TAB2 binding domain of TAK1, with resultant inhibition of ASK1-induced AP-1 activation. Interestingly, the interaction between TAK1 and TAB2 significantly attenuated the ASK1-TAK1 interaction through the competitive interaction with ASK1 to TAK1 and resulted in the activations of TAK1-induced activations of NF-κB and AP-1. More interestingly, H(2)O(2)- and TNF-α-induced apoptosis in TAK1-deficient mouse embryo fibroblast cells were dramatically enhanced by overexpression of ASK1, whereas the apoptosis was markedly inhibited by the overexpression of TAK1. Overall, these results demonstrate that TAK1 and its adapter protein, TAB2, reciprocally regulate both TAK1- and ASK1-mediated signaling pathways to direct the activations of NF-κB and AP-1.
authors.affiliation: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea.
authors.forename: So Yong
authors.initials: SY
authors.lastname: Kim
authors.forename: Jea-Hyuck
authors.initials: JH
authors.lastname: Shim
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Chun
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006861:Hydrogen Peroxide; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D016877:Oxidants; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C410585:TAB2 protein, human; C498761:Tab2 protein, mouse; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse