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Molecular and Cellular Biology, January 2009, p. 303-314, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.00699-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

TRAF2 Phosphorylation Modulates Tumor Necrosis Factor Alpha-Induced Gene Expression and Cell Resistance to Apoptosis ^,

Ken Blackwell,^1, Laiqun Zhang,^1, Gregory S. Thomas,¹ Shujie Sun,¹ Hiroyasu Nakano,² and Hasem Habelhah^1*

Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242,¹ Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan²

Received 29 April 2008/ Returned for modification 23 June 2008/ Accepted 23 October 2008

TRAF2 is an adaptor protein that regulates the activation of the c-Jun N-terminal kinase (JNK) and IB kinase (IKK) signaling cascades in response to tumor necrosis factor alpha (TNF-) stimulation. Although the downstream events in TNF- signaling are better understood, the membrane-proximal events are still elusive. Here, we demonstrate that TNF- and cellular stresses induce TRAF2 phosphorylation at serine 11 and that this phosphorylation is required for the expression of a subset of NF-B target genes. Although TRAF2 phosphorylation had a minimal effect on the TNF--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- 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--induced activation of JNK. Notably, TRAF2 phosphorylation increased both basal and inducible c-Jun and NF-B 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--induced IKK activation modulated by TRAF2 phosphorylation and suggest that TRAF2 phosphorylation contributes to elevated levels of basal NF-B activity in certain human cancers.

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* Corresponding author. Mailing address: Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242. Phone: (319) 335-6517. Fax: (319) 335-8453. E-mail: hasem-habelhah{at}uiowa.edu

Published ahead of print on 3 November 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

K.B. and L.Z. contributed equally to this work.

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Molecular and Cellular Biology, January 2009, p. 303-314, Vol. 29, No. 2
0270-7306/09/$08.00+0     doi:10.1128/MCB.00699-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Thomas, G. S., Zhang, L., Blackwell, K., Habelhah, H. (2009). Phosphorylation of TRAF2 within Its RING Domain Inhibits Stress-Induced Cell Death by Promoting IKK and Suppressing JNK Activation. Cancer Res. 69: 3665-3672 [Abstract] [Full Text]