Defining the Unique Properties of the Distinct Signaling Machinery Used by the TCR

 描述（由申请人提供）：本申请是一项正在进行的计划项目的延续，在该项目中，五名具有不同但互补专业知识的研究人员共同研究了TCR信号传导的两个基本重要水平：1）TCR如何调节酪氨酸激酶（SFK、Syk激酶和Tec激酶），其控制关键的下游酪氨酸磷酸化;以及2）Ras激活（一种关键的下游信号传导途径）如何被Ras鸟嘌呤核苷酸交换因子（GEF）调节，所述Ras鸟嘌呤核苷酸交换因子（GEF）的活性本身通过由TCR控制的激酶的一组底物与TCR信号传导偶联。我们的合作研究取得了相当大的进展。在这次更新中，我们的总体目标是利用我们目前的进展，并将结构生物学，蛋白质组学，免疫学和计算生物学的方法结合起来，以了解TCR信号传导。在项目#1中，我们将研究T细胞表达的SFKs，Syk和 Tec激酶，使它们比B细胞中的对应物更适合T细胞中的抗原受体信号传导。我们假设Lck和Fyn、ZAP-70和Itk及其信号调节因子的特征在T细胞中已经被优化，以建立信号通路， 用于维持抵抗非激动剂肽干扰的基础信号传导状态，并且还建立了对激动剂pMHC的最佳识别和应答的敏感阈值。在项目#2中，我们希望了解基础和TCR诱导的RasGEF信号传导如何调节外周T细胞的启动但受控状态，同时允许有效的T细胞活化。我们假设，SOS 1和RasGRP 1 RasGEFs已经进化到以不同的方式进行调节，以允许T细胞中建立稳态/激活平衡的非冗余Ras信号。

 DESCRIPTION (provided by applicant): This application is a renewal of an ongoing Program Project in which five investigators with different but complementary expertise have worked together to understand two fundamentally important levels of TCR signaling: 1) how the TCR regulates the tyrosine kinases (SFKs, Syk kinases and Tec kinases) that control critical downstream tyrosine phosphorylation; and, 2) how Ras activation, a critical downstream signaling pathway, is regulated by Ras guanine nucleotide exchange factors (GEFs) whose activities themselves are coupled to TCR signaling via the set of substrates of the kinases controlled by the TCR. Our collaborative studies have resulted in considerable progress. In this renewal, our overall goal is to capitalize on our current progress and bring together approaches from structural biology, proteomics, immunology, and computational biology to understand TCR signaling. In project #1, we will study the distinct features of the T cell-expressed SFKs, Syk and Tec kinases that make these more suitable for antigen receptor signaling in T cells than their counterparts in B cells. We hypothesize that the characteristics of Lck and Fyn, ZAP-70 and Itk and their signaling regulators have been optimized in T cells to establish signaling circuitry that serves to maintain a basal signaling state that is resistant to perturbations by non-agonist peptides and also establishes a sensitive threshold for optimal recognition and response to agonist pMHC. In project #2, we hope to understand how basal and TCR-induced RasGEF signaling regulates the primed but controlled state of peripheral T cells while allowing for efficient T cell activation. We hypothesize that the SOS1 and RasGRP1 RasGEFs have evolved to be regulated in distinct manners to allow for non-redundant Ras signals in T cells that establish the homeostasis/activation balance.