SIGNAL TRANSDUCTION IN T LYMPHOCYTE ACTIVIATION

描述(改编自申请者摘要)：T细胞的订婚 静息T细胞上的抗原受体(TCR)引发 Src激活引起的细胞内蛋白酪氨酸磷酸化 和Syk家族酪氨酸激酶。这些酪氨酸磷酸化事件，在 反过来，刺激第二信使的释放，增加细胞内的 游离钙离子浓度和激活蛋白激酶C(PKC)。奥特曼医生的 实验室重点研究了Src家族激酶、Lck和 SYK家族成员Syk和ZAP-70在启动信号输出中的作用 TCR。此外，还发现了一种新的PKC亚型PKC-theta 并被发现主要在造血细胞和骨骼中表达 肌肉。初步证据表明，这种PKC亚型可能 特异性地介导细胞表面受体的偶联，如 TCR，与T细胞中AP-1复合体的转录激活有关。这个 本项目的具体目标是：(1)进一步确定功能 通过识别与PKC-theta相互作用的蛋白在T细胞激活中的作用 并作为这种蛋白激酶的底物。这一目标还将包括 表达野生型和A基因转基因小鼠的功能研究 PKC-theta蛋白激酶失活版本的调控 胸腺细胞特异性lck近端启动子。(2)了解监管 控制Syk家族激酶活性的机制，并进一步 定义Syk与两种潜在底物Vav和HS1的相互作用。 拟议的研究旨在填补我们在以下方面的一些重要空白 了解通过TCR进行的信号转导。

DESCRIPTION (Adapted from the Applicant's Abstract): Engagement of T-cell antigen receptors (TCRs) on resting T cells triggers a rapid increase in intracellular protein tyrosine phosphorylation due to the activation of Src and Syk family tyrosine kinases. These tyrosine phosphorylation events, in turn, provoke the release of second messengers that increase intracellular free Ca2+ concentrations and activate protein kinase C (PKC). Dr. Altman's laboratory has focused on the roles of the Src family kinase, Lck, and the Syk family members, Syk and ZAP-70, in the initiation of signal output from the TCR. In addition a novel PKC isoform, PKC-theta, has been discovered and was found to be expressed primarily in hematopoietic cells and skeletal muscle. Preliminary evidence suggests that this PKC isoform may specifically mediate the coupling of cell surface receptors, such as the TCR, to the transriptional activation of the AP-1 complex in T cells. The Specific Aims of this project are: (1) To further characterize the function of PKC-theta in T-cell activation by identifying proteins that interact with and serve as substrates for this protein kinase. This aim will also include functional studies with transgenic mice expressing either wild-type or a kinase-inactive version of PKC-theta under the control of the thymocyte-specific lck proximal promoter. (2) To understand the regulatory mechanisms that control the activities of Syk family kinases, and to further define the interactions of Syk with two potential substrates, Vav and HS1. The proposed studies are intended to fill some important gaps in our understanding of signal transduction through the TCR.