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

Gregory S Thomas; Laiqun Zhang; Ken Blackwell; Hasem Habelhah

doi:10.1158/0008-5472.CAN-08-4867

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

Journal article

Open access

Peer reviewed

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

Gregory S Thomas, Laiqun Zhang, Ken Blackwell and Hasem Habelhah

Cancer research (Chicago, Ill.), Vol.69(8), pp.3665-3672

04/15/2009

DOI: 10.1158/0008-5472.CAN-08-4867

PMCID: PMC2669835

PMID: 19336568

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Abstract

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an adaptor protein that modulates the activation of the c-Jun NH(2) terminal kinase (JNK)/c-Jun and IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) signaling cascades in response to TNFalpha stimulation. Although many serine/threonine kinases have been implicated in TNFalpha-induced IKK activation and NF-kappaB-dependent gene expression, most of them do not directly activate IKK. Here, we report that protein kinase Czeta phosphorylates TRAF2 at Ser(55), within the RING domain of the protein, after TNFalpha stimulation. Although this phosphorylation event has a minimal effect on induction of the immediate/transient phase of IKK and JNK activation by TNFalpha, it promotes the secondary/prolonged phase of IKK activation and inhibits that of JNK. Importantly, constitutive TRAF2 phosphorylation increased both basal and inducible NF-kappaB activation and rendered Ha-Ras-V12-transformed cells resistant to stress-induced apoptosis. Moreover, TRAF2 was found to be constitutively phosphorylated in some malignant cancer cell lines and Hodgkin's lymphoma. These results reveal a new level of complexity in TNFalpha-induced IKK activation modulated by TRAF2 phosphorylation and suggest that TRAF2 phosphorylation is one of the events that are responsible for elevated basal NF-kappaB activity in certain human cancers.

Tumor Necrosis Factor-alpha - metabolism

NIH 3T3 Cells

Phosphorylation

Humans

TNF Receptor-Associated Factor 2 - metabolism

RING Finger Domains

Animals

MAP Kinase Kinase 4 - metabolism

I-kappa B Kinase - metabolism

Mice

Apoptosis - physiology

Enzyme Activation

HeLa Cells

Details

Title: Subtitle: Phosphorylation of TRAF2 within its RING domain inhibits stress-induced cell death by promoting IKK and suppressing JNK activation
Creators: Gregory S Thomas - Pathology Graduate Program and Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
Laiqun Zhang
Ken Blackwell
Hasem Habelhah
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.69(8), pp.3665-3672
Publisher: United States
DOI: 10.1158/0008-5472.CAN-08-4867
PMID: 19336568
PMCID: PMC2669835
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: R01 CA107185 / NCI NIH HHS R01 CA107185-02 / NCI NIH HHS R01 CA078419 / NCI NIH HHS CA78419 / NCI NIH HHS
Language: English
Date published: 04/15/2009
Academic Unit: Pathology; Medicine Administration
Record Identifier: 9984047614202771

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