Fn14 is a growth-factor-inducible immediate-early-response gene encoding a 102-amino-acid type I transmembrane protein. The human Fn14 protein was recently identified as a cell-surface receptor for the tumour necrosis factor (TNF) superfamily member named TWEAK (TNF-like weak inducer of apoptosis). In the present paper, we report that the human TWEAK extracellular domain can also bind the murine Fn14 protein. Furthermore, site-specific mutagenesis and directed yeast two-hybrid interaction assays revealed that the TNFR-associated factor (TRAF) 1, 2, 3 and 5 adaptor molecules bind the murine Fn14 cytoplasmic tail at an overlapping, but non-identical, amino acid sequence motif. We also found that TWEAK treatment of quiescent NIH 3T3 cells stimulates inhibitory κBα phosphorylation and transcriptional activation of a nuclear factor-κB (NF-κB) enhancer/luciferase reporter construct. Fn14 overexpression in transiently transfected NIH 3T3 cells also promotes NF-κB activation, and this cellular response requires an intact TRAF binding site. These results indicate that Fn14 is a functional TWEAK receptor that can associate with four distinct TRAF family members and stimulate the NF-κB transcription factor signalling pathway.
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April 2003
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Research Article|
April 15 2003
The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation
Sharron A.N. BROWN;
Sharron A.N. BROWN
∗Vascular Biology Department, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, U.S.A.
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Christine M. RICHARDS;
Christine M. RICHARDS
∗Vascular Biology Department, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, U.S.A.
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Heather N. HANSCOM;
Heather N. HANSCOM
∗Vascular Biology Department, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, U.S.A.
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Sheau-Line Y. FENG;
Sheau-Line Y. FENG
∗Vascular Biology Department, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, U.S.A.
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Jeffrey A. WINKLES
Jeffrey A. WINKLES
1
∗Vascular Biology Department, Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, U.S.A.
†Department of Biochemistry and Molecular Biology, and the Institute for Biomedical Sciences, George Washington University Medical Center, Washington, DC 20037, U.S.A.
1To whom all correspondence should be addressed (e-mail winkles@usa.redcross.org).
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Publisher: Portland Press Ltd
Received:
November 05 2002
Revision Received:
January 13 2003
Accepted:
January 15 2003
Accepted Manuscript online:
January 15 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 371 (2): 395–403.
Article history
Received:
November 05 2002
Revision Received:
January 13 2003
Accepted:
January 15 2003
Accepted Manuscript online:
January 15 2003
Citation
Sharron A.N. BROWN, Christine M. RICHARDS, Heather N. HANSCOM, Sheau-Line Y. FENG, Jeffrey A. WINKLES; The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation. Biochem J 15 April 2003; 371 (2): 395–403. doi: https://doi.org/10.1042/bj20021730
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