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PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitination

Shitao Li1, Lingyan Wang, Martin E Dorf

  • 1Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.

Molecular Cell
|January 20, 2009
PubMed

Insights

Protein kinase C (PKC) kinases phosphorylate tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), initiating TNF signaling. This phosphorylation drives TRAF2 ubiquitination and recruits key kinases for NF-kappaB and JNK pathway activation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Immunology

Background:

  • Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a critical adaptor protein in TNF-mediated signaling pathways.
  • Previous research indicated TRAF2's role in NF-kappaB and AP-1 activation, but the precise signaling mechanisms remained unclear.
  • TRAF2 phosphorylation upon TNF stimulation was previously observed, but the responsible kinases were unidentified.

Purpose of the Study:

  • To identify the specific protein kinase C (PKC) kinases responsible for TRAF2 phosphorylation.
  • To elucidate the molecular mechanisms by which TRAF2 relays signals downstream of the TNF receptor.
  • To understand the role of TRAF2 phosphorylation and ubiquitination in activating NF-kappaB and JNK signaling.

Main Methods:

  • Identification of PKC kinases mediating TRAF2 phosphorylation following TNF stimulation.
  • Analysis of TRAF2 recruitment of IKKalpha and IKKbeta to the TNF receptor.
  • Investigation of K63-linked polyubiquitination of TRAF2 at lysine 31 and its association with TAB2/3.

Main Results:

  • Protein kinase C (PKC) kinases were identified as responsible for TRAF2 phosphorylation after TNF stimulation.
  • Phosphorylated TRAF2 facilitates the recruitment of IKKalpha and IKKbeta to the TNF receptor.
  • TRAF2 phosphorylation promotes its K63-linked polyubiquitination at lysine 31, enabling association with TAB2/3 and activation of IKK and JNK kinases.

Conclusions:

  • TRAF2 phosphorylation is a critical regulatory step in TNF signaling.
  • Phosphorylation directs the IKK complex to the membrane and promotes TRAF2 ubiquitination.
  • This mechanism positions IKKalpha and IKKbeta with the TAK1/TAB kinase complex, facilitating downstream signaling.

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