Pre-association and Signaling by TNF-like Receptors

描述(申请人提供)：研究的长期目标 提出是为了了解肿瘤成员坏死的机制 肿瘤坏死因子及其受体对健康和病理的调节作用 免疫系统。肿瘤坏死因子和肿瘤坏死因子受体样细胞因子受体对至关重要 免疫功能和动态平衡的调节剂。许多基因的突变 在家庭内部会导致人类各种形式的免疫紊乱。 最近的证据表明，类TNFR分子以预先形成的复合体的形式存在 在配体结合之前的细胞表面。这种预先的联系似乎 只允许同种特定的复合体，但不允许异种的复合体。 肿瘤坏死因子样配体试验被吹捧为潜在的抗肿瘤药物 因为它对肿瘤细胞有选择性的细胞毒性。TRAIL绑定到四个 不同的细胞表面受体，其中一些是信号缺陷的， 因此被称为“诱饵”。这项提案的第一部分涉及到 TRAIL受体可以形成异源复合体作为调节其受体的一种手段 细胞毒作用。 肿瘤坏死因子可介导多种细胞反应，包括炎症、细胞 增殖、分化和凋亡/坏死。肿瘤坏死因子-RL引起这些 通过一个通用适配器招募FADD、RIP和TRAF2，从而做出不同的反应 一种叫做Tradd的蛋白质。目前还不清楚是否所有这些信号蛋白都可以 同时出现在同一受体复合体上。摄动 这些蛋白质的募集可能是许多肿瘤坏死因子相关的分子原因的基础。 疾病。本提案的第二部分试图阐明 TNFR协调这些信号的招募的机制 蛋白质。

DESCRIPTION (provided by applicant): The long-term goal of the studies proposed is to understand the mechanism by which members of the tumor necrosis factor (TNF) and their receptors (TNFRs) regulate the healthy and pathological immune systems. TNF- and TNFR-like cytokine-receptor pairs are critical mediators for immune functions and homeostasis. Mutations in many of the genes within the family can lead to various forms of immune disorders in humans. Recent evidence shows that TNFR-like molecules exist as pre-formed complexes on the cell surface prior to ligand binding. This pre-association appears to allow only homo-specific complexes but not hetero-complexes. The TNF-like ligand TRAIL has been vaunted as a potential anti-tumor agent because of its selective cytotoxicity to tumor cells. TRAIL binds to four different cell surface receptors, some of which are signal-deficient and are therefore termed "decoys". The first part of this proposal concerns whether the TRAIL receptors can form heterocomplexes as a means to regulate their cytotoxic function. TNF can mediate multiple cellular responses including inflammation, cellular proliferation, differentiation and apoptosis/necrosis. TNF-Rl elicits these diverse responses by recruiting FADD, RIP and TRAF2 through a common adapter protein called TRADD. It is unclear if all of these signaling proteins can be present at the same receptor complex concomitantly. Perturbation of recruitment of these proteins may underlie the molecular cause for many TNFrelated diseases. The second part of this proposal attempts to elucidate the mechanism by which TNFR coordinates the recruitment of these signaling proteins.