TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop

J Biol Chem. 2000 Mar 10;275(10):7359-64. doi: 10.1074/jbc.275.10.7359.

Abstract

TAK1, a member of the mitogen-activated kinase kinase kinase family, is activated in vivo by various cytokines, including interleukin-1 (IL-1), or when ectopically expressed together with the TAK1-binding protein TAB1. However, this molecular mechanism of activation is not yet understood. We show here that endogenous TAK1 is constitutively associated with TAB1 and phosphorylated following IL-1 stimulation. Furthermore, TAK1 is constitutively phosphorylated when ectopically overexpressed with TAB1. In both cases, dephosphorylation of TAK1 renders it inactive, but it can be reactivated by preincubation with ATP. A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cells, Cultured
  • Enzyme Activation
  • Humans
  • Interleukin-1 / pharmacology
  • MAP Kinase Kinase Kinases / chemistry
  • MAP Kinase Kinase Kinases / metabolism*
  • Molecular Sequence Data
  • NF-kappa B / physiology
  • Phosphorylation
  • Structure-Activity Relationship

Substances

  • Interleukin-1
  • NF-kappa B
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7