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

J Biol Chem. 2005 Dec 30;280(52):43056-63. doi: 10.1074/jbc.M507807200. Epub 2005 Oct 31.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Blotting, Western
  • Cell Line
  • Cell Nucleus / metabolism
  • Humans
  • Immunoprecipitation
  • Jurkat Cells
  • Luciferases / metabolism
  • MAP Kinase Kinase Kinase 3 / metabolism*
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Kinase Kinases / physiology*
  • Microscopy, Confocal
  • NF-kappa B / metabolism*
  • Peptides / chemistry
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Structure, Tertiary
  • RNA, Small Interfering / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Signal Transduction
  • Transfection
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism*
  • Two-Hybrid System Techniques

Substances

  • NF-kappa B
  • Peptides
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Luciferases
  • Protein Serine-Threonine Kinases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • MAP Kinase Kinase Kinase 3
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7