RIP2 kinase's function in Innate Immunity

RIP2 激酶在先天免疫中的功能

• 批准号: 7356796
• 负责人: Derek W Abbott
• 金额: $ 6.86万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356796
• 关键词: JUN kinase; RNA interference; SDS polyacrylamide gel electrophoresis; binding proteins; biological signal transduction; cell membrane; cytokine receptors; enzyme activity; immune response; immunoprecipitation; mass spectrometry; mitogen activated protein kinase; nuclear factor kappa beta; phosphorylation; polymerase chain reaction; protein kinase; serine threonine protein kinase; tissue /cell culture; toll like receptor; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): The human body has evolved mechanisms to detect pathogenic organisms and to initiate an appropriate initial immune response against these organisms. Given the diversity of pathogens, a remarkable feature of these innate immunity-signaling pathways is their ability to tailor a response to a particular pathogen. Innate immune responses are initiated at the cell membrane by a family of receptors collectively termed the Toll-like Receptors (TLRs). Downstream signaling pathways activated by the TLRs include the ERK, JNK, p38 and NF- Kappabeta signaling modules. Activation of these signaling pathways then causes cytokine and chemokine release. There is a remarkable specificity to this immune response such that the cytokines released are tailored to the pathogen destined to be eradicated. Although critical, this specificity in signal transduction is poorly understood. The adapter protein kinase RIP2 may mediate a portion of this specificity. RIP2 has been shown to be involved in the proximal TLR signaling pathway as RIP2-null mice show defects in ERK, JNK, p38 and NF-kappaB signaling and subsequent deficiencies in cytokine release in response to LPS from gram-negative bacteria and PGN from gram-positive bacteria. Although RIP2 contains a serine-threonine kinase domain and it readily autophosphorylates, no in vivo RIP2 substrates have been identified. In preliminary studies, we have began to identify the preferred peptide phosphorylation sequence of RIP2. This initial data was used to help identify the adapter protein, TRAF6, as a phosphorylation substrate of RIP2. The central hypothesis of this grant is that as an essential component of the TLR pathway, RIP2's kinase activity may underly the specificity seen in innate immune signaling pathways. This grant application aims to define the preferred peptide phosphorylation sites of RIP2, to map the phosphorylation site of TRAF6 and to identify the physiologic significance of RIP2's phosphorylation of TRAF6.

描述（由申请人提供）： 人体已经进化出检测病原微生物并针对这些微生物启动适当的初始免疫反应的机制。鉴于病原体的多样性，这些先天免疫信号通路的一个显着特征是它们能够针对特定病原体定制反应。先天免疫反应是由统称为 Toll 样受体 (TLR) 的受体家族在细胞膜上启动的。 TLR 激活的下游信号通路包括 ERK、JNK、p38 和 NF-Kappabeta 信号模块。这些信号通路的激活随后导致细胞因子和趋化因子的释放。这种免疫反应具有显着的特异性，因此释放的细胞因子是针对注定要根除的病原体而定制的。尽管很重要，但人们对信号转导的这种特异性知之甚少。衔接蛋白激酶 RIP2 可能介导这种特异性的一部分。 RIP2 已被证明参与近端 TLR 信号通路，因为 RIP2 缺失小鼠表现出 ERK、JNK、p38 和 NF-kappaB 信号传导缺陷，以及随后响应革兰氏阴性菌 LPS 和革兰氏阴性细菌 PGN 的细胞因子释放缺陷。 - 阳性细菌。尽管 RIP2 含有丝氨酸-苏氨酸激酶结构域并且很容易自磷酸化，但尚未鉴定出体内 RIP2 底物。在初步研究中，我们已经开始鉴定RIP2的优选肽磷酸化序列。 该初始数据用于帮助识别衔接蛋白 TRAF6，作为 RIP2 的磷酸化底物。这项资助的核心假设是，作为 TLR 通路的重要组成部分，RIP2 的激酶活性可能是先天免疫信号通路中所见特异性的基础。 该资助申请旨在定义 RIP2 的首选肽磷酸化位点、绘制 TRAF6 磷酸化位点图谱并确定 RIP2 磷酸化 TRAF6 的生理意义。