Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha

EMBO J. 2003 Nov 3;22(21):5793-805. doi: 10.1093/emboj/cdg552.

Abstract

TAB1, a subunit of the kinase TAK1, was phosphorylated by SAPK2a/p38alpha at Ser423, Thr431 and Ser438 in vitro. TAB1 became phosphorylated at all three sites when cells were exposed to cellular stresses, or stimulated with tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) or lipopolysaccharide (LPS). The phosphorylation of Ser423 and Thr431 was prevented if cells were pre-incubated with SB 203580, while the phosphorylation of Ser438 was partially inhibited by PD 184352. Ser423 is the first residue phosphorylated by SAPK2a/p38alpha that is not followed by proline. The activation of TAK1 was enhanced by SB 203580 in LPS-stimulated macrophages, and by proinflammatory cytokines or osmotic shock in epithelial KB cells or embryonic fibroblasts. The activation of TAK1 by TNF-alpha, IL-1 or osmotic shock was also enhanced in embryonic fibroblasts from SAPK2a/p38alpha-deficient mice, while incubation of these cells with SB 203580 had no effect. Our results suggest that TAB1 participates in a SAPK2a/p38alpha-mediated feedback control of TAK1, which not only limits the activation of SAPK2a/p38alpha but synchronizes its activity with other signalling pathways that lie downstream of TAK1 (JNK and IKK).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Benzamides / pharmacology
  • Binding Sites
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Cell Line
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Feedback
  • Humans
  • Imidazoles / pharmacology
  • Intracellular Signaling Peptides and Proteins*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / chemistry
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • Phosphorylation
  • Protein Subunits
  • Pyridines / pharmacology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Two-Hybrid System Techniques
  • p38 Mitogen-Activated Protein Kinases

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • Adaptor Proteins, Signal Transducing
  • Benzamides
  • Carrier Proteins
  • Enzyme Inhibitors
  • Imidazoles
  • Intracellular Signaling Peptides and Proteins
  • Protein Subunits
  • Pyridines
  • Recombinant Proteins
  • TAB1 protein, MAPKKK activator, vertebrate
  • TAB1 protein, human
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • SB 203580