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

Ken Blackwell; Laiqun Zhang; Gregory S Thomas; Shujie Sun; Hiroyasu Nakano; Hasem Habelhah

doi:10.1128/MCB.00699-08

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

Journal article

Peer reviewed

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

Ken Blackwell, Laiqun Zhang, Gregory S Thomas, Shujie Sun, Hiroyasu Nakano and Hasem Habelhah

Molecular and cellular biology, Vol.29(2), pp.303-314

01/2009

DOI: 10.1128/MCB.00699-08

PMCID: PMC2612514

PMID: 18981220

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Abstract

TRAF2 is an adaptor protein that regulates the activation of the c-Jun N-terminal kinase (JNK) and IkappaB kinase (IKK) signaling cascades in response to tumor necrosis factor alpha (TNF-alpha) stimulation. Although the downstream events in TNF-alpha signaling are better understood, the membrane-proximal events are still elusive. Here, we demonstrate that TNF-alpha and cellular stresses induce TRAF2 phosphorylation at serine 11 and that this phosphorylation is required for the expression of a subset of NF-kappaB target genes. Although TRAF2 phosphorylation had a minimal effect on the TNF-alpha-induced rapid and transient IKK activation, it was essential for secondary and prolonged IKK activation. Consistent with this, TRAF2 phosphorylation is not required for its recruitment to the TNFR1 complex in response to TNF-alpha stimulation but is required for its association with a cytoplasmic complex containing RIP1 and IKK. In addition, TRAF2 phosphorylation was essential for the full TNF-alpha-induced activation of JNK. Notably, TRAF2 phosphorylation increased both basal and inducible c-Jun and NF-kappaB activities and rendered cells resistant to stress-induced apoptosis. Moreover, TRAF2 was found to be constitutively phosphorylated in some lymphomas. These results unveil a new, finely tuned mechanism for TNF-alpha-induced IKK activation modulated by TRAF2 phosphorylation and suggest that TRAF2 phosphorylation contributes to elevated levels of basal NF-kappaB activity in certain human cancers.

Phosphorylation

Oxidative Stress

Apoptosis

Tumor Necrosis Factor-alpha - metabolism

Cell Line

NIH 3T3 Cells

Humans

TNF Receptor-Associated Factor 2 - genetics

Gene Expression Regulation

TNF Receptor-Associated Factor 2 - metabolism

Cytoplasm - metabolism

Electrophoresis, Gel, Two-Dimensional

JNK Mitogen-Activated Protein Kinases - metabolism

NF-kappa B - metabolism

Receptors, Tumor Necrosis Factor, Type I - metabolism

Lymphoma

Serine - metabolism

Animals

I-kappa B Kinase - metabolism

Mice

HeLa Cells

Details

Title: Subtitle: TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis
Creators: Ken Blackwell - Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA
Laiqun Zhang
Gregory S Thomas
Shujie Sun
Hiroyasu Nakano
Hasem Habelhah
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.29(2), pp.303-314
Publisher: United States
DOI: 10.1128/MCB.00699-08
PMID: 18981220
PMCID: PMC2612514
ISSN: 0270-7306
eISSN: 1098-5549
Grant note: R01 CA107185-01A2 / NCI NIH HHS R01 CA107185 / NCI NIH HHS R01 CA078419 / NCI NIH HHS CA78419 / NCI NIH HHS
Language: English
Date published: 01/2009
Academic Unit: Pathology; Medicine Administration
Record Identifier: 9984047642102771

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