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J. Biol. Chem., Vol. 282, Issue 38, 28189-28194, September 21, 2007

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Tumor-derived Mutations in the TRAIL Receptor DR5 Inhibit TRAIL Signaling through the DR4 Receptor by Competing for Ligand Binding^*

Lianghua Bin, Jacqueline Thorburn, Lance R. Thomas, Peter E. Clark^¶, Robin Humphreys^||, and Andrew Thorburn¹

From the Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, Departments of Microbiology and Immunology and ^¶Urology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and ^||Oncology Research Department, Human Genome Sciences, Rockville, Maryland 20850

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a cytokine that preferentially induces apoptosis in tumor cells compared with normal cells through two receptors (DR4 and DR5). Somatic mutations in these receptors have been found in different kinds of cancer; however, it is poorly understood how the mutations affect signaling. We found that point mutations (L334F, E326K, E338K, and K386N) that were identified in human tumors result in the DR5 receptor losing its ability to form a functional death-inducing signaling complex and induce apoptosis. The mutant receptors also have a "dominant negative" effect whereby they inhibit the ability of TRAIL to induce apoptosis through functional DR4 receptors. This dominant negative mechanism is achieved through competition for TRAIL binding as shown by experiments where the ability of the mutant DR5 receptor to bind with the ligand was abolished, thus restoring TRAIL signaling through DR4. The inhibitory effect on signaling through the wild-type DR4 protein can be overcome if the inhibitory mechanism is bypassed by using a DR4-agonistic antibody that is not subject to this competition. This study provides a molecular basis for the use of specific therapeutic agonists of TRAIL receptors in people whose tumors harbor somatic DR5 mutations.

Received for publication, May 22, 2007 , and in revised form, July 30, 2007.

^* This work was supported by NCI, National Institutes of Health Grant CA11421. 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.

¹ To whom correspondence should be addressed: University of Colorado at Denver and Health Sciences Center, Fitzsimons Campus, Dept. of Pharmacology, Mail Stop 8303, RC1 South Tower, Rm. 6100, P. O. Box 6511, Aurora, CO 80045. Tel.: 303-724-3290; Fax: 303-724-3663; E-mail: Andrew.Thorburn{at}uchsc.edu.

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