The different signaling capabilities of soluble and membrane-bound TWEAK and their relevance for cellular proliferation and differentiation

可溶性和膜结合型 TWEAK 的不同信号传导能力及其与细胞增殖和分化的相关性

• 批准号: 290773190
• 负责人: Professor Dr. Harald Günther Wajant
• 金额: --
• 依托单位: Abteilung für Molekulare Innere Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290773190?language=en
• 关键词: different; signaling; capabilities; soluble; membrane

TWEAK (Tumor necrosis factor (TNF)-like weak inducer of apoptosis) and its receptor Fn14 (fibroblast growth factor (FGF)-induced 14) regulate the activity of a variety of signaling pathways and control a diverse panel of cellular functions especially in the context of tissue injury. Indeed, the TWEAK/Fn14-system has been implicated in tissue repair and regeneration but it also promotes adverse effects that can emerge from overshooting and chronic inflam-matory/regenerative responses.TWEAK occurs as a single spanning transmembrane protein but is also found in form of a soluble ligand that is released from the membrane-bound molecule by proteolytic processing. Previously, we demonstrated that soluble processed TWEAK binds with high affinity to Fn14 and strongly triggers activation of the alternative NF-kappaB pathway and enhancement of TNFR1-induced cell death but also antagonizes TRAF2-mediated signaling by other TNF re-ceptors. Intriguingly, we also noted that soluble TWEAK does not stimulate robust activation of the classical NF-kappaB pathway. In contrast, membrane TWEAK triggers all Fn14-associated pathways with high efficacy including the classical NF-kappaB pathway. Although we have some initial evidence that the different ability to transactivate TRAF2- cIAP1 and TRAF2-cIAP2 complexes plays a crucial role for the varying signaling capacities of soluble and membrane TWEAK, the underlying mechanisms have still to be considered as poorly understood. Moreover, the question whether the two TWEAK forms also differ in their ability to stimulate other Fn14 associated signaling pathways and cellular functions has not been addressed so far. We will therefore focus in the project on the following questions:1. How does the soluble TWEAK-induced Fn14 signaling complex differ from that induced by membrane TWEAK, and how affects TWEAK/Fn14-mediated depletion of cytosolic TRAF2-cIAP1 and TRAF2-cIAP2 complexes the formation, modification and stability of death recep-tor-induced RIP/caspase-8 containing complexes?2. Does Fn14 have the ability to signal independently from TRAF2?3. How do soluble and membrane TWEAK differ in their effects on cellular proliferation and differentiation and which signaling pathways are of relevance in these contexts?So far, we observed the differential responsiveness of Fn14 to soluble and membrane TWEAK in all Fn14-expressing cell lines (n>10) and primary cell types (n=3) we have investi-gated. Thus, it must be assumed that the underlying biochemical mechanisms are operative in most cells and are of general importance for Fn14 biology. Moreover, it is possible that the molecular mechanisms that define the differential responsiveness of Fn14 to soluble and membrane TWEAK also applies to other TRAF2-interacting receptors of the TNF family. The molecular mechanisms that are identified on the example of TWEAK/Fn14 signaling have therefore the potential to be of general relevance for the TNF receptor superfamily as a whole.

TWEAK（肿瘤坏死因子 (TNF) 样弱凋亡诱导剂）及其受体 Fn14（成纤维细胞生长因子 (FGF) 诱导的 14）调节多种信号通路的活性并控制多种细胞功能，尤其是在组织损伤的情况下。事实上，TWEAK/Fn14 系统与组织修复和再生有关，但它也会促进过度反应和慢性炎症/再生反应产生的不利影响。TWEAK 作为单一跨膜蛋白出现，但也以可溶性配体的形式存在，通过蛋白水解过程从膜结合分子中释放出来。此前，我们证明可溶性加工的 TWEAK 以高亲和力与 Fn14 结合，强烈触发替代 NF-kappaB 途径的激活和 TNFR1 诱导的细胞死亡的增强，但也拮抗其他 TNF 受体介导的 TRAF2 信号传导。有趣的是，我们还注意到可溶性 TWEAK 不会刺激经典 NF-kappaB 途径的强烈激活。相比之下，膜 TWEAK 可高效触发所有 Fn14 相关通路，包括经典的 NF-kappaB 通路。尽管我们有一些初步证据表明反式激活 TRAF2-cIAP1 和 TRAF2-cIAP2 复合物的不同能力对于可溶性和膜 TWEAK 的不同信号传导能力起着至关重要的作用，但其潜在机制仍被认为知之甚少。此外，两种 TWEAK 形式刺激其他 Fn14 相关信号通路和细胞功能的能力是否也存在差异的问题迄今尚未得到解决。因此，我们将在该项目中重点解决以下问题： 1． How does the soluble TWEAK-induced Fn14 signaling complex differ from that induced by membrane TWEAK, and how affects TWEAK/Fn14-mediated depletion of cytosolic TRAF2-cIAP1 and TRAF2-cIAP2 complexes the formation, modification and stability of death recep-tor-induced RIP/caspase-8 containing complexes?2. Fn14 是否具有独立于 TRAF2 发出信号的能力？3。可溶性 TWEAK 和膜 TWEAK 对细胞增殖和分化的影响有何不同，以及哪些信号通路在这些情况下相关？到目前为止，我们在我们研究的所有表达 Fn14 的细胞系 (n>10) 和原代细胞类型 (n=3) 中观察到 Fn14 对可溶性 TWEAK 和膜 TWEAK 的不同反应性。因此，必须假设潜在的生化机制在大多数细胞中都有效，并且对于 Fn14 生物学具有普遍重要性。此外，定义 Fn14 对可溶性和膜 TWEAK 差异反应性的分子机制也可能适用于 TNF 家族的其他 TRAF2 相互作用受体。因此，以 TWEAK/Fn14 信号传导为例确定的分子机制有可能与整个 TNF 受体超家族具有普遍相关性。