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J. Biol. Chem., Vol. 279, Issue 50, 52479-52486, December 10, 2004

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The C-terminal Tails of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) and Fas Receptors Have Opposing Functions in Fas-associated Death Domain (FADD) Recruitment and Can Regulate Agonist-specific Mechanisms of Receptor Activation^*

Lance R. Thomas, Ronald L. Johnson¶||, John C. Reed**, and Andrew Thorburn

From the Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, ^¶Human Genome Sciences Inc., Rockville, Maryland 20850, the ^**Burnham Institute, La Jolla, California 92037, and the Department of Pharmacology, University of Colorado Health Sciences Center at Fitzsimmons, Aurora, Colorado 80045-0508

Members of the tumor necrosis factor (TNF) superfamily of receptors such as Fas/CD95 and the TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5 induce apoptosis by recruiting adaptor molecules and caspases. The central adaptor molecule for these receptors is a death domain-containing protein, FADD, which binds to the activated receptor via death domain-death domain interactions. Here, we show that in addition to the death domain, the C-terminal tails of DR4 and DR5 positively regulate FADD binding, caspase activation and apoptosis. In contrast, the corresponding region in the Fas receptor has the opposite effect and inhibits binding to the receptor death domain. Replacement of wild-type or mutant DR5 molecules into DR5-deficient BJAB cells indicates that some agonistic antibodies display an absolute requirement for the C-terminal tail for FADD binding and signaling while other antibodies can function in the absence of this mechanism. These data demonstrate that regions outside the death domains of DR4 and DR5 have opposite effects to that of Fas in regulating FADD recruitment and show that different death receptor agonists can use distinct molecular mechanisms to activate signaling from the same receptor.

Received for publication, August 20, 2004 , and in revised form, September 24, 2004.

^* This work was supported by grants from the Susan G. Komen Breast Cancer Foundation (to L. R. T.), the United States Army Breast Cancer Research Program (to L. R. T. and A. T.), and National Institutes of Health Grant GM61694 (to J. C. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: Dept. of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.

^|| Current address: National Institutes of Health Chemical Genomics Center, Bethesda, MD 20892.

To whom correspondence should be addressed: Dept. of Pharmacology, University of Colorado Health Sciences Ctr., UCHSC at Fitzsimmons, P. O. Box 6508, Mail Stop 8303, Aurora CO 80045-0508. E-mail: Andrew.Thorburn{at}uchsc.edu.

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