The Journal of Experimental Medicine
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Published online 30 September 2002 doi:10.1084/jem.20020774
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© Rockefeller University Press, 0022-1007/2002/10/923/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 7, October 7, 2002 923-934

Regulation of the Subcellular Localization of Tumor Necrosis Factor Receptor–associated Factor (TRAF)2 by TRAF1 Reveals Mechanisms of TRAF2 Signaling

Joseph R. Arron1,2,3, Yael Pewzner-Jung2, Matthew C. Walsh3, Takashi Kobayashi3 and Yongwon Choi3

1 Tri-Institutional MD-PhD Program, The Rockefeller University, New York, NY 10021
2 Laboratory of Immunology, The Rockefeller University, New York, NY 10021
3 Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Address correspondence to Y. Choi, Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Phone: 215-746-6404; Fax: 215-573-0888; E-mail: ychoi3{at}mail.med.upenn.edu

Tumor necrosis factor receptor–associated factor (TRAF)2 is a critical adaptor molecule for tumor necrosis factor (TNF) receptors in inflammatory and immune signaling. Upon receptor engagement, TRAF2 is recruited to CD40 and translocates to lipid rafts in a RING finger-dependent process, which enables the activation of downstream signaling cascades including c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-{kappa}B. Although TRAF1 can displace TRAF2 and CD40 from raft fractions, it promotes the ability of TRAF2 activate signaling over a sustained period of time. Removal of the RING finger of TRAF2 prevents its translocation into detergent-insoluble complexes and renders it dominant negative for signaling. TRAF1-/- dendritic cells show attenuated responses to secondary stimulation by TRAF2-dependent factors and increased stimulus-dependent TRAF2 degradation. Replacement of the RING finger of TRAF2 with a raft-targeting signal restores JNK activation and association with the cyto-skeletal protein Filamin, but not NF-{kappa}B activation. These findings offer insights into the mechanism of TRAF2 signaling and identify a physiological role for TRAF1 as a regulator of the subcellular localization of TRAF2.

Key Words: CD40 • dendritic cell • lipid rafts • NF-{kappa}B • JNK


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