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

 描述(申请人提供)：本申请是一个正在进行的计划项目的更新，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努力，以了解TCR信号的两个基本重要水平：1)TCR如何调节控制关键下游酪氨酸磷酸化的酪氨酸激酶(SFK、Syk激酶和Tec激酶)；以及，2)RAS激活，一个关键的下游信号通路，如何由RAS鸟嘌呤核苷酸交换因子(GEF)调节，其本身的活性通过TCR控制的一组激酶的底物与TCR信号耦合。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，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。在项目1中，我们将研究T细胞表达的SFK、Syk和 与B细胞中的相应蛋白相比，Tec蛋白激酶更适合于T细胞中的抗原受体信号传递。我们假设Lck和Fyn、ZAP-70和ITK的特性及其信号调节因子在T细胞中已经被优化，以建立 用来维持基本的信号状态，抵抗非激动剂多肽的干扰，并为激动剂pMHC的最佳识别和反应建立一个敏感的阈值。在项目2中，我们希望了解基础和TCR诱导的Rasgef信号如何调节外周T细胞的启动但受控状态，同时允许有效的T细胞激活。我们假设SOS1和RASGRP1 RasGEF已经进化成以不同的方式被调节，以允许T细胞中建立动态平衡/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.