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Cross interference with TNF-alpha-induced TAK1 activation via EGFR-mediated p38 phosphorylation of TAK1-binding

Myoung-Sook Shin1, Pattama Shinghirunnusorn, Yumiko Sugishima

  • 1Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.

Biochimica Et Biophysica Acta
|April 28, 2009
PubMed

Insights

Epidermal growth factor receptor (EGFR) activation interferes with tumor necrosis factor-alpha (TNF-alpha)-induced transforming growth factor-alpha-activated kinase 1 (TAK1) activation. This occurs through p38-mediated phosphorylation of TAB1, reducing NF-kappaB activation.

Area of Science:

  • Cellular signaling pathways
  • Kinase regulation
  • Immune receptor activation

Background:

  • Transforming growth factor-alpha-activated kinase 1 (TAK1) regulates cytokine and immune receptor signaling.
  • Previous work showed TNF-alpha triggers EGFR internalization via TAK1-p38alpha, suppressing EGFR.
  • This study explores signaling in the reverse direction: EGFR activation impacting TAK1.

Purpose of the Study:

  • To investigate the intracellular signaling pathway from EGFR activation to TAK1.
  • To elucidate the mechanism by which EGFR activation affects TNF-alpha-induced TAK1 activation.

Main Methods:

  • Investigated ligand-induced EGFR activation.
  • Utilized chemical inhibitors and siRNA for p38alpha.
  • Analyzed phosphorylation of TAK1-binding proteins TAB1 and TAB2.
  • Assessed NF-kappaB activation in response to EGF and TNF-alpha.

Main Results:

  • EGFR activation induced TAK1-independent phosphorylation of TAB1 and TAB2.
  • EGFR-mediated TAB1 phosphorylation at Ser-423 and Thr-431 was p38alpha-dependent.
  • TAB1 phosphorylation interfered with TNF-alpha-induced TAK1 activation and reduced NF-kappaB activation.
  • TAB2 phosphorylation was sustained and largely p38alpha-independent.

Conclusions:

  • EGFR activation negatively regulates TNF-alpha-induced TAK1 activation.
  • This regulation occurs via p38alpha-mediated phosphorylation of TAB1.
  • The findings reveal a feedback mechanism where EGFR signaling impacts inflammatory pathways mediated by TAK1.

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