TAK1 is a ubiquitin-dependent kinase of MKK and IKK

Nature. 2001 Jul 19;412(6844):346-51. doi: 10.1038/35085597.

Abstract

TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS). IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enzyme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms2). This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism. Here we report the purification and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism. We find that the TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13-Uev1A. Moreover, the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p38 kinase pathway, is directly regulated by K63-linked polyubiquitination. We also provide evidence that TRAF6 is conjugated by the K63 polyubiquitin chains. These results indicate that ubiquitination has an important regulatory role in stress response pathways, including those of IKK and JNK.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Carrier Proteins / metabolism
  • Cell Line
  • Cloning, Molecular
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • I-kappa B Kinase
  • Interleukin-1 / metabolism
  • Intracellular Signaling Peptides and Proteins*
  • JNK Mitogen-Activated Protein Kinases*
  • Ligases / metabolism
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase 6
  • MAP Kinase Kinase Kinases*
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Multienzyme Complexes / metabolism
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Recombinant Proteins / metabolism
  • Transcription Factors*
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Interleukin-1
  • Intracellular Signaling Peptides and Proteins
  • Multienzyme Complexes
  • Recombinant Proteins
  • TAB1 protein, MAPKKK activator, vertebrate
  • TAB1 protein, human
  • TAB2 protein, human
  • Transcription Factors
  • Ubiquitins
  • UBE2V1 protein, human
  • Ubiquitin-Conjugating Enzymes
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase 6
  • MAP2K6 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • Ligases