IL-1 RECEPTOR MEDIATED SIGNAL TRANSDUCTION

白细胞介素1(IL-1)受体是 介导IL-1的高度炎症反应，这是 几乎影响到所有类型的细胞。我们最近展示了 转录因子NF-kappaB的激活依赖于 不仅在之前描述的伊拉克途径上，而且 IL-1受体酪氨酸参与的一种新的独立通路 磷酸化、募集和催化激活 磷脂酰肌醇3-激酶(PI3K)。我们建议进一步 研究该通路参与核因子-kappaB的激活和 IL-1诱导的其他转录因子的激活。 此外，我们建议调查不同的信号 由IL-1受体系统介导的通路汇聚在一起 或者是两条不同路径中的另一条。 提出了五个具体目标：第一个目标是理解 PI3K激活核因子-kappaB的详细机制 受体胞质必需区域的鉴定 结构域，所需关键酪氨酸激酶的身份，以及 激活所需的NF-kappaB和/或IkappaB上的靶点。这个 第二个目的是探索PI3K与其他IL-1的关系 诱导信号如MAPK和PI3K的直接靶标。第三 AIM将研究相互作用的分子要求 IL-1受体成分包括受体异构体、P13K和IRAK。 第四个特定目标是识别受体的区域。 参与激活的细胞质结构域及其相关分子 其他IL-1诱导的转录因子，如C/EBPβ，Stat3， 和我们最近发现的新的内毒素/IL-1/IL-6应答的LIL-Stat因子 描述。统计因素招聘点的确定 C/EBPbeta上的激活和目标磷酸化位点将是 下定决心。第五个目标将研究信号之间的相互作用 转导途径及其与IL-1配体的关系 IL-1配体突变所定义的受体胞外区 之前被描述为能够引发不同的信号 事件。一种新的IL-1突变扩展了早期的数据，证明 信号转导通路之间的相互作用及其相互关系 IL-1与受体的配基。

The interleukin (IL-1) receptor is a critical component in mediating the highly inflammatory responses of IL-1, which affects nearly every cell type. We have recently demonstrated that the activation of the transcription factor NF-kappaB depends not only upon the previously characterized IRAK pathway, but also a novel independent pathway involving IL-1 receptor tyrosine phosphorylation and recruitment and catalytic activation of phosphatidylinositol 3-kinase (PI3K). We propose to further study the involvement of this pathway in NF-kappaB activation and the activation of other transcription factors induced by IL-1. Additionally, we propose to investigate whether various signaling pathways mediated by the IL-1 receptor system converge with one or the other of the two distinct pathways. Five specific aims are proposed: The first is designed to understand the detailed mechanism of NF-kappaB activation by PI3K focusing on the identification of the essential regions of the receptor cytoplasmic domain, the identity of the required critical tyrosine kinase, and the target sites on NF-kappaB and/or IkappaB required for activation. The second aim will explore the relationship between PI3K and other IL-1 induced signals such as MAPK and the direct target of PI3K. The third aim will investigate the molecular requirements for interactions among IL-1 receptor components including receptor heteromers, P13K, and IRAK. The fourth specific aim will identify regions of the receptor cytoplasmic domain and associated molecules involved in the activation of other IL-1-inducible transcription factors such as C/EBPbeta, Stat3, and the novel LPS/IL-1/IL-6 responsive LIL-Stat factor that we recently described. The identification of the recruitment sites for STAT factor activation and the target phosphorylation site on C/EBPbeta will be determined. The fifth aim will investigate the interplay between signal transduction pathways and the association of the IL-1 ligand with the receptor ectodomains as defined by IL-1 ligand mutations which we previously described as being capable of eliciting distinct signaling events. A new IL-1 mutation extends the earlier data arguing for an interplay between signal transduction pathways and the association of the IL-1 ligand with the receptor.