Bin Lianghua, Thorburn Jacqueline, Thomas Lance R, Clark Peter E, Humphreys Robin, Thorburn Andrew
Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, USA.
J Biol Chem. 2007 Sep 21;282(38):28189-94. doi: 10.1074/jbc.M704210200. Epub 2007 Jul 31.
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.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种细胞因子，与正常细胞相比，它通过两种受体（DR4和DR5）优先诱导肿瘤细胞凋亡。在不同类型的癌症中已发现这些受体的体细胞突变；然而，人们对这些突变如何影响信号传导了解甚少。我们发现，在人类肿瘤中鉴定出的点突变（L334F、E326K、E338K和K386N）导致DR5受体失去形成功能性死亡诱导信号复合物并诱导凋亡的能力。突变受体还具有“显性负性”作用，即它们抑制TRAIL通过功能性DR4受体诱导凋亡的能力。这种显性负性机制是通过竞争TRAIL结合来实现的，实验表明突变型DR5受体与配体结合的能力被消除，从而恢复了TRAIL通过DR4的信号传导。如果使用不受这种竞争影响的DR4激动性抗体绕过抑制机制，则可以克服对野生型DR4蛋白信号传导的抑制作用。这项研究为在肿瘤携带体细胞DR5突变的人群中使用TRAIL受体的特异性治疗激动剂提供了分子基础。
