Tumor-derived mutations in the TRAIL receptor DR5 inhibit TRAIL signaling through the DR4 receptor by competing for ligand binding

被引:60
作者
Bin, Lianghua
Thorburn, Jacqueline
Thomas, Lance R.
Clark, Peter E.
Humphreys, Robin
Thorburn, Andrew
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Aurora, CO 80045 USA
[2] Vanderbilt Univ, Dept Microbiol & Immunol, Nashville, TN 37212 USA
[3] Vanderbilt Univ, Sch Med, Dept Urol, Nashville, TN 37232 USA
[4] Human Genome Sci, Oncol Res Dept, Rockville, MD 20850 USA
关键词
D O I
10.1074/jbc.M704210200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 DRS 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.
引用
收藏
页码:28189 / 28194
页数:6
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