TAK1 is recruited to the tumor necrosis factor-alpha (TNF-alpha) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-kappaB activation.
Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor-alpha (TNF-alpha)-induced IkappaB kinase (IKK) activation and subsequent activation of transcription factor NF-kappaB. However, the molecular mechanism by which RIP mediates TNF-alpha-induced NF-kappaB activation is not completely defined. In this study, we have found that TAK1 is recruited to the ... TNF-alpha receptor complex in a RIP-dependent manner following the stimulation of TNF-alpha receptor 1 (TNF-R1). Moreover, a forced recruitment of TAK1 to TNF-R1 in the absence of RIP is sufficient to mediate TNF-alpha-induced NF-kappaB activation, indicating that the major function of RIP is to recruit its downstream kinases to the TNF-R1 complex. Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates autophosphorylation of MEKK3. The TAK1-mediated regulation of MEKK3 phosphorylation is dependent on the kinase activity of TAK1. Although TAK1-MEKK3 interaction is not affected by overexpressed TAB1, TAB1 is required for TAK1 activation and subsequent MEKK3 phosphorylation. Together, we conclude that TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-kappaB in TNF-alpha signaling.
Mesh Terms:
Blotting, Western, Cell Line, Cell Nucleus, Humans, Immunoprecipitation, Jurkat Cells, Luciferases, MAP Kinase Kinase Kinase 3, MAP Kinase Kinase Kinases, Microscopy, Confocal, NF-kappa B, Peptides, Phosphorylation, Plasmids, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Transfection, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Two-Hybrid System Techniques
Blotting, Western, Cell Line, Cell Nucleus, Humans, Immunoprecipitation, Jurkat Cells, Luciferases, MAP Kinase Kinase Kinase 3, MAP Kinase Kinase Kinases, Microscopy, Confocal, NF-kappa B, Peptides, Phosphorylation, Plasmids, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Transfection, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Two-Hybrid System Techniques
J. Biol. Chem.
Date: Dec. 30, 2005
PubMed ID: 16260783
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