Lee, Ho H. and Dempsey, Paul W. and Parks, Thomas P. and Zhu, Xiaoqing and Baltimore, David and Cheng, Genhong (1999) Specificities of CD40 signaling: Involvement of TRAF2 in CD40-induced NF-kappa B activation and intercellular adhesion molecule-1 up-regulation. Proceedings of the National Academy of Sciences of the United States of America, 96 (4). pp. 1421-1426. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:LEEpnas99
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Several tumor necrosis factor receptor-associated factor (TRAF) family proteins including TRAF2, TRAF3, TRAF5, and TRAF6, as well as Jak3, have been implicated as potential mediators of CD40 signaling. An extensive in vitro binding study indicated that TRAF2 and TRAF3 bind to the CD40 cytoplasmic tail (CD40ct) with much higher affinity than TRAF5 and TRAF6 and that TRAF2 and TRAF3 bind to different residues of the CD40ct. Using CD40 mutants incapable of binding TRAF2, TRAF3, or Jak3, we found that the TRAF2-binding site of the CD40ct is critical for NF-kappa B and stress-activated protein kinase activation, as well as the up-regulation of the intercellular adhesion molecule-1 (ICAM-1) gene, whereas binding of TRAF3 and Jak3 is dispensable for all of these functions. Overexpression of a dominantly active I kappa B alpha strongly inhibited CD40-induced NF-kappa B activation, ICAM-1 promoter activity, and cell-surface ICAM-1 up regulation. These studies suggest a potential signal transduction pathway from the CD40 receptor to the transcriptional activation of the ICAM-1 gene.
|Additional Information:||Copyright © 1999 by The National Academy of Sciences. Contributed by David Baltimore, December 22, 1998. We thank Drs. Jun-ichiro Inoue, Owen Witte, and Carrie Miceli for providing mouse TRAF5 cDNA, WEHI 231 cells, and BI-141 cells. We also thank Leejee Suh, Ben Wong, and Drs. Sean Doyle and Anahid Jewett for their technical assistance. This project was supported by the University of California at Los Angeles (UCLA) Jonsson Comprehensive Cancer Center Development Fund. H.H.L. is a recipient of a UCLA Medical Scientist Training Program training grant (GM 08042). P.W.D. is a recipient of Microbiology Pathogenesis Training Grant PMS AI107323. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.|
|Subject Keywords:||NECROSIS-FACTOR RECEPTOR, CROSS-LINKING CD40, CYTOPLASMIC DOMAIN, IMMUNE-RESPONSES, FINGER PROTEIN, FAMILY, CELLS, INDUCTION, GENE, MICE|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Tony Diaz|
|Deposited On:||02 Nov 2005|
|Last Modified:||26 Dec 2012 08:41|
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