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Phosphorylation of TRAF2 within its RING domain inhibits stress-induced cell death by promoting IKK and suppressing

Gregory S Thomas1, Laiqun Zhang, Ken Blackwell

  • 1Pathology Graduate Program and Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

Cancer Research
|April 2, 2009
PubMed

Insights

Protein kinase Czeta phosphorylates TRAF2, impacting tumor necrosis factor (TNF) signaling. This TRAF2 phosphorylation promotes prolonged IKK activation, elevates NF-kappaB activity, and confers resistance to apoptosis in cancer cells.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Biology

Background:

  • Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is crucial for TNFalpha-induced signaling pathways.
  • Activation of c-Jun NH(2) terminal kinase (JNK) and IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) cascades are key responses to TNFalpha.
  • The precise mechanisms regulating prolonged IKK activation and NF-kappaB activity remain incompletely understood.

Purpose of the Study:

  • To investigate the role of protein kinase Czeta (PKCzeta) in TRAF2-mediated TNFalpha signaling.
  • To elucidate the impact of TRAF2 phosphorylation on IKK and JNK activation dynamics.
  • To determine the functional consequences of TRAF2 phosphorylation in cellular responses, including apoptosis and NF-kappaB activity.

Main Methods:

  • Utilized TNFalpha stimulation in cellular models.
  • Investigated the phosphorylation status of TRAF2 at Ser(55) using biochemical assays.
  • Assessed the activation kinetics of IKK and JNK signaling pathways.
  • Evaluated NF-kappaB activation and apoptosis resistance in cells with modified TRAF2 phosphorylation.

Main Results:

  • PKCzeta phosphorylates TRAF2 at Ser(55) following TNFalpha stimulation.
  • TRAF2 phosphorylation minimally affects immediate IKK/JNK activation but promotes prolonged IKK activation and inhibits JNK activation.
  • Constitutive TRAF2 phosphorylation enhances basal and inducible NF-kappaB activation.
  • TRAF2 phosphorylation confers resistance to stress-induced apoptosis in transformed cells.
  • Elevated TRAF2 phosphorylation is observed in certain cancer cell lines and Hodgkin's lymphoma.

Conclusions:

  • TRAF2 phosphorylation by PKCzeta represents a novel regulatory mechanism in TNFalpha-induced IKK activation.
  • This phosphorylation event contributes to sustained NF-kappaB activity, a hallmark of some human cancers.
  • TRAF2 phosphorylation plays a significant role in promoting cancer cell survival by inhibiting apoptosis.

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