TRAF4 in TGF-beta Signaling and Embryonic Development

描述(申请人提供)：肿瘤坏死因子受体相关因子，或TRAF家族的接头蛋白，将信号从细胞因子受体传递到下游的信号转导，从而影响细胞凋亡、炎症、免疫和细胞分化。TRAF家族由6个不同的蛋白质组成，即TRAF 1-6，主要参与肿瘤坏死因子(TNF)和白介素1/Toll相关(IL/TLR)信号转导通路。TRAF4家族中有一个成员在肿瘤坏死因子和IL/TLR信号通路中不起作用。TRAF4的生物学和生化在很大程度上是一个谜，然而我们最近发现TRAF4通过转化生长因子-β超家族的两个主要分支，即BMP和转化生长因子-β/结节通路来增强信号转导。TRAF4可能通过调节SMurf泛素连接酶或R-SMADs在信号转导水平发挥作用。在非洲爪哇两栖动物胚胎的发育中，TRAF4的错误表达或抑制会扰乱头部、背部中胚层和神经脊的发育，揭示了TRAF4在这些组织的发育中的关键作用。最近的蛋白质相互作用筛选显示，TRAF4与TGFbeta信号无关，但这些因子如何在TRAF4信号转导和发育中发挥作用尚不清楚。这项资助的主要目的是了解TRAF4如何在脊椎动物发育中增强转化生长因子-β或其他信号通路。目的1通过检测TRAF4和转化生长因子-β信号转导分子是否相互作用，并分析这些相互作用的生化效应，探讨TRAF4在骨形态发生蛋白和结节信号转导中的作用机制。目的2将测试TRAF4如何通过异位表达TRAF4或阻断内源性TRAF4来调节非洲爪哇胚胎发育。重点将放在确定TRAF4如何调节中胚层、外胚层和神经脊的分化。TRAF4还与非TGFbeta途径中涉及的几种蛋白质相互作用。AIM 3将研究这些蛋白质是否将TRAF4连接到上游信号，或者在非洲爪哇发育过程中作为下游效应器发挥作用。转化生长因子β途径调控细胞的生长、分化、免疫和发育。了解TRAF4如何调节脊椎动物发育中的转化生长因子-β信号或其他途径，将影响信号转导和胚胎学领域，并为理解免疫和炎症性疾病、癌症和出生缺陷如何由转化生长因子-β和转化生长因子信号异常引起提供重要信息。

DESCRIPTION (provided by applicant): The Tumor Necrosis Factor Receptor Associated Factor, or TRAF family of adaptor proteins relays signals from cytokine receptors to downstream signal transducers to affect apoptosis, inflammation, immunity and cell differentiation. The TRAF family consists of six distinct proteins, TRAFs 1-6, and most function in Tumor Necrosis Factor (TNF) and lnterleukin-1/Toll-related (IL/TLR) signal transduction pathways. One member of the family named TRAF4 does not function in TNF and IL/TLR signaling. TRAF4 biology and biochemistry is largely a mystery, however we have recently discovered that TRAF4 enhances signaling by the two major branches of the Transforming Growth Factor-beta superfamily, the BMP and TGF-beta/nodal pathways. TRAF4 appears to act at the signal transduction level, possibly by regulating the Smurf ubiquitin ligases or R-Smads. In developing embryos of the amphibian Xenopus laevis, misexpression or inhibition of TRAF4 disrupts development of the head, dorsal mesoderm and neural crest, revealing a critical function for TRAF4 in the development of these tissues. Recent protein interaction screens have yielded TRAF4 partners not implicated in TGFbeta signaling, but how these factors function in TRAF4 signal transduction and development is barely understood. The main objective of this grant is to understand how TRAF4 enhances TGF-beta or other signaling pathways in vertebrate development. Aim 1 will tackle the mechanism of TRAF4 in BMP and nodal signaling by testing whether TRAF4 and TGF-beta signal transduction molecules interact, and by analyzing the biochemical effects of those interactions. Aim 2 will test how TRAF4 regulates Xenopus embryonic development by ectopically expressing TRAF4 or blocking endogenous TRAF4. Emphasis will be on determining how TRAF4 regulates differentiation of the mesoderm, ectoderm and neural crest. TRAF4 also interacts with several proteins implicated in non-TGFbeta pathways. Aim 3 will examine whether these proteins connect TRAF4 to upstream signals or function as downstream effectors in Xenopus development. TGFbeta pathways govern cell growth, differentiation, immunity and development. Understanding how TRAF4 regulates TGF-beta signaling or other pathways in vertebrate development will impact the fields of signal transduction and embryology and provide vital information for understanding how immune and inflammatory diseases, cancers and birth defects might arise from abnormal TGF-beta and TRAF signaling.