TRAF4 in TGF-beta Signaling and Embryonic Development

描述（由申请人提供）：肿瘤坏死因子受体相关因子或TRAF家族衔接蛋白将信号从细胞因子受体传递至下游信号转导子，以影响细胞凋亡、炎症、免疫和细胞分化。TRAF家族由六种不同的蛋白质TRAF 1-6组成，并且大多数在肿瘤坏死因子（TNF）和白细胞介素-1/Toll相关（IL/TLR）信号转导途径中起作用。TRAF 4家族的一个成员在TNF和IL/TLR信号传导中不起作用。TRAF 4的生物学和生物化学在很大程度上是一个谜，但是我们最近发现TRAF 4通过转化生长因子-β超家族的两个主要分支，BMP和TGF-β/nodal途径增强信号传导。TRAF 4似乎在信号转导水平起作用，可能通过调节Smurf泛素连接酶或R-Smads。在两栖动物非洲爪蟾的胚胎发育中，TRAF 4的错误表达或抑制会破坏头部、背中胚层和神经嵴的发育，揭示了TRAF 4在这些组织发育中的关键功能。最近的蛋白质相互作用筛选已经产生了与TGF β信号转导无关的TRAF 4伴侣，但这些因子在TRAF 4信号转导和发育中的功能几乎不清楚。这项资助的主要目的是了解TRAF 4如何增强TGF-β或其他信号通路在脊椎动物发育。目的1将通过测试TRAF 4和TGF-β信号转导分子是否相互作用，并通过分析这些相互作用的生化效应，来解决TRAF 4在BMP和节点信号传导中的机制。目的2将测试TRAF 4如何通过异位表达TRAF 4或阻断内源性TRAF 4来调节非洲爪蟾胚胎发育。重点将是确定TRAF 4如何调节中胚层，外胚层和神经嵴的分化。TRAF 4还与涉及非TGF β途径的几种蛋白质相互作用。目的3将研究这些蛋白质是否连接TRAF 4上游信号或功能作为下游效应器在非洲爪蟾的发展。TGF β途径控制细胞生长、分化、免疫和发育。了解TRAF 4如何调节TGF-β信号传导或脊椎动物发育中的其他途径将影响信号转导和胚胎学领域，并为了解异常TGF-β和TRAF信号传导如何引起免疫和炎症性疾病，癌症和出生缺陷提供重要信息。

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.