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TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis

Ken Blackwell1, Laiqun Zhang, Gregory S Thomas

  • 1Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.

Molecular and Cellular Biology
|November 5, 2008
PubMed

Insights

Tumor necrosis factor alpha (TNF-alpha) signaling involves TRAF2 phosphorylation, crucial for sustained IKK activation and JNK signaling. This modification enhances NF-kappaB activity, impacting gene expression and cellular survival in certain cancers.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Cancer research

Background:

  • Tumor necrosis factor alpha (TNF-alpha) initiates signaling cascades, including JNK and IKK pathways, but early membrane-proximal events remain unclear.
  • TRAF2 is a key adaptor protein in TNF-alpha signaling, mediating downstream responses.

Purpose of the Study:

  • To investigate the role of TRAF2 phosphorylation in TNF-alpha signaling and cellular responses.
  • To elucidate the impact of TRAF2 phosphorylation on IKK and JNK activation, NF-kappaB activity, and apoptosis.

Main Methods:

  • Analysis of TRAF2 phosphorylation at serine 11 induced by TNF-alpha and cellular stress.
  • Assessment of TRAF2 phosphorylation's effect on IKK and JNK activation kinetics and protein complex formation.
  • Evaluation of NF-kappaB and c-Jun activity, gene expression, and stress-induced apoptosis resistance.

Main Results:

  • TNF-alpha and stress induce TRAF2 phosphorylation at serine 11, essential for a subset of NF-kappaB target genes.
  • TRAF2 phosphorylation is critical for sustained IKK activation and full JNK activation, but not for rapid IKK activation or TNFR1 recruitment.
  • TRAF2 phosphorylation enhances basal and inducible NF-kappaB and c-Jun activity, conferring resistance to apoptosis and is constitutively present in some lymphomas.

Conclusions:

  • TRAF2 phosphorylation represents a novel regulatory mechanism for TNF-alpha-induced IKK activation, influencing signaling duration and intensity.
  • TRAF2 phosphorylation contributes to elevated basal NF-kappaB activity, potentially playing a role in the pathogenesis of certain human cancers.

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