SIGNAL TRANSDUCTION IN T LYMPHOCYTE ACTIVIATION

描述（改编自申请人的摘要）：T细胞的接合 静息T细胞上的抗原受体（TCR）触发T细胞的快速增加， 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， 反过来，刺激第二信使的释放， 游离Ca 2+浓度和激活蛋白激酶C（PKC）。 阿尔特曼医生 实验室一直专注于Src家族激酶Lck和 Syk家族成员，Syk和ZAP-70，在启动信号输出， TCR。 此外，还发现了一种新的PKC亚型PKC-θ， 并发现主要在造血细胞和骨骼肌中表达， 肌肉. 初步证据表明，这种PKC亚型可能 特异性介导细胞表面受体的偶联，例如 TCR，对T细胞中AP-1复合物的转录激活。 的 本课题的具体目的是：（1）进一步明确其功能 PKC-θ在T细胞活化中的作用， 并作为这种蛋白激酶的底物。 这一目标还将包括 用表达野生型或 PKC-θ的激酶失活形式， 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HS 1的相互作用。 拟议的研究旨在填补我们的一些重要空白， 了解通过TCR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.