IL-1 RECEPTOR MEDIATED SIGNAL TRANSDUCTION

白细胞介素（IL-1）受体是一个关键的组成部分， 介导IL-1的高度炎症反应， 几乎影响所有细胞类型。 我们最近展示了 转录因子NF-κ B的激活依赖于 不仅对先前表征的IRAK途径，而且 IL-1受体酪氨酸参与的新的独立途径 磷酸化和募集以及催化活化 磷脂酰肌醇3-激酶（PI 3 K）。 我们建议进一步 研究该通路参与NF-κ B活化， IL-1诱导的其他转录因子的激活。 此外，我们建议调查各种信号是否 由IL-1受体系统介导的途径与一个 或两种不同途径中的另一种。 提出了五个具体目标：第一个是旨在了解 PI 3 K激活NF-κ B的详细机制集中在 识别受体胞质的关键区域 结构域，所需的关键酪氨酸激酶的身份，和 NF-κ B和/或IkappaB上活化所需的靶向位点。 的 第二个目的是探讨PI 3 K与其他IL-1的关系 诱导信号如MAPK和PI 3 K的直接靶点。 第三 目的是研究分子间相互作用的要求， IL-1受体组分，包括受体异聚体、P13 K和IRAK。 第四个具体目标将确定受体的区域 参与激活的细胞质结构域和相关分子 其他IL-1诱导型转录因子如C/EBP β，Stat 3， 以及我们最近发现的新型LPS/IL-1/IL-6应答性LIL-Stat因子， 介绍了 STAT因子募集位点的鉴定 活化和C/EBP β上的靶磷酸化位点将被 测定 第五个目标是研究信号之间的相互作用 转导途径和IL-1配体与 受体胞外域定义为IL-1配体突变， 先前描述为能够引发不同的信号传导 事件 一种新的IL-1突变扩展了早期的数据， 信号转导通路之间的相互作用和 IL-1配体与受体的结合

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.