Protein redistribution in TCR-directed NF-kB activation

TCR 介导的 NF-kB 激活中的蛋白质重新分布

• 批准号: 7173305
• 负责人: Brian Schaefer
• 金额: $ 33.1万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7173305
• 关键词: Affect; Ally; Antigen Receptors; Antigens; Basic Science; Biochemical; Cell division; Cells; Collection; Complex; Coupled; Data; Development; Evaluation; Event; Family; Foundations; Gene Expression; Goals; Imaging Techniques; Individual; Lead; Life; Ligation; Localized; Lymphocyte antigen; Mediating; Modification; Molecular; Mus; NF-kappa B; Numbers; Outcome; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Play; Process; Proteins; Proteolysis; Receptor Activation; Regulation; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; T Cell Receptor Signaling Pathway; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Transducers; Work; functional outcomes; insight; novel; protein distribution; protein protein interaction; research study; response; transcription factor

DESCRIPTION (provided by applicant): Antigen-stimulated T cell division and acquisition of effector functions are dependent upon signal transduction directed by the T cell receptor (TCR), and the consequent activation of a number of transcription factors that affect changes in gene expression. Transcription factors of the NF-?B family are of central importance in this process. The TCR-regulated NF-?B activation pathway will be investigated through a combination of molecular, biochemical, and highly advanced imaging techniques. The goal is to establish mechanistic relationships between 1) protein-protein interactions, 2) subcellular protein organization and 3) biochemical modification of cytoplasmic signal transducers in the TCR-directed NF-?B pathway. This goal will be accomplished via the execution of three specific aims: Aim1. To determine the mechanistic significance of localized protein-protein associations of signaling intermediates in TCR-directed activation of NF-?B. We will test the hypothesis that TCR-directed NF-?B signaling involves the orchestrated assembly and disassembly of defined protein complexes into discrete subcellular domains, with specific protein complexes playing a critical mechanistic role. Aim 2. To investigate, in individual cells, the mechanistic relationship between antigen signal strength, assembly of signal transduction complexes, and successful activation of the TCR-directed NF-?B signal transduction pathway. Experiments will be directed towards the evaluation of the hypothesis that antigen signals through the TCR are converted into "binary" outcomes of either no activation or full activation of effector functions. Furthermore, these functional outcomes are dependent on signal transduction decision events made at the single-cell level. Aim 3. To define the roles of phosphorylation and the MALT1 interaction domain in the TCR- mediated degradation and activation of BcHO. We will perform experiments to test the hypothesis that activation and proteolytic destruction of BcHO are mechanistically coupled, and that both processes are regulated by BcHO interaction with MALT1 and by PKC-dependent phosphorylation of BcHO. These studies will help establish the basic research foundation that could lead to the development of novel immuno-modulatory drugs, which would function via highly specific inhibition of antigen-receptor mediated activation of the NF-?B signaling cascade.

描述(申请人提供)：抗原刺激的T细胞分裂和效应器功能的获得依赖于T细胞受体(TCR)指导的信号转导，以及随后影响基因表达变化的一些转录因子的激活。核因子-βB家族的转录因子在这一过程中起着核心作用。我们将结合分子、生物化学和高级成像技术来研究TCR调节的核因子？B激活途径。其目的是建立1)蛋白质-蛋白质相互作用，2)亚细胞蛋白质组织和3)TCR-？B途径中胞质信号转导的生化修饰之间的机制关系。这一目标将通过执行三个具体目标来实现：目标1。为了确定信号中间产物的局部蛋白质-蛋白质结合在TCR诱导的NF-B活化中的机制意义，我们将检验这样一个假设，即TCR指导的NF-？B信号涉及到特定蛋白质复合体被协调地组装和分解成离散的亚细胞域，而特定的蛋白质复合体起着关键的机制作用。目的2.在单个细胞中，研究抗原信号强度、信号转导复合体的组装和TCR导向的核因子-β信号转导通路成功激活之间的机制关系。实验将针对通过TCR将抗原信号转换为不激活或完全激活效应器功能的“二元”结果的假设进行评估。此外，这些功能结果取决于在单细胞水平上做出的信号转导决定事件。目的3.明确磷酸化和MALT1相互作用结构域在TCR介导的BcHO降解和激活中的作用。我们将通过实验来验证这样的假设，即BcHO的激活和蛋白水解性破坏是机械耦合的，这两个过程都受到BcHO与MALT1的相互作用和依赖于PKC的BcHO磷酸化的调控。这些研究将有助于为开发新型免疫调节药物奠定基础，这些药物将通过高度特异性地抑制抗原受体介导的核因子-B信号级联反应而发挥作用。