REGULATION OF CD28 SIGNAL TRNSDUCTION

描述（改编自研究者摘要）：在 对外来抗原的应答T细胞必须接受TCR信号和 共刺激信号。重要的T细胞共刺激受体是 CD 28分子还具有保护T细胞免受 抗原诱导无能和凋亡。除了对下列问题的答复之外， 外源抗原T细胞需要CD 28信号来启动有害的 自身免疫性疾病中对自身抗原的反应。因此，一种能力 特异性操纵CD 28信号将代表一种有效的 控制这些异常免疫反应的方法。以识别 治疗的潜在分子靶点， 建议是了解CD 28细胞内信号传导的本质 途径。先前的研究已经确定，CD 28信号转导涉及 PI 3-激酶和Grb-2向酪氨酸磷酸化的CD 28的募集 胞质尾然而，有证据表明，其他信号 分子被募集到CD 28尾部，这些分子发挥着 在CD 28信号转导中的重要作用。最近，额外的CD 28 鉴定了结合蛋白。一个是以前没有描述过的双重- MAP激酶磷酸酶家族的特异性磷酸酶MKP 5， 不依赖于酪氨酸磷酸化而结合CD 28尾。另一个是 GRAP衔接蛋白，其与Grb-2相关但不同， 并且也仅结合磷酸化的CD 28尾。初步证据 表明MKP 5作为CD 28信号的负调节剂起作用 转导相反，GRAP可能在CD 28中起积极作用， 发信号。具体地，这里建议使用各种 分子遗传学、生物化学和细胞技术，以1）确认 MKP 5和GRAP分别具有负和正信号传导作用， 和2）确定这些分子在CD 28中的精确功能。 信号转导途径此外，使用一种新的基于酵母的 遗传分析，已在实验室开发，它建议 为了表征结合所述抗体的其他信号传导中间体， 磷酸化的CD 28胞质尾区。

DESCRIPTION (Adapted from Investigator's Abstract): To proliferate in response to foreign antigens T cells must receive both TCR signals and co-stimulatory signals. An important T cell co-stimulatory receptor is the CD28 molecule that additionally functions to protect T cells from antigen induced anergy and apoptosis. In addition to responses to foreign antigens T cells require CD28 signals to initiate harmful responses to self antigens in autoimmune disease. Therefore, an ability to specifically manipulate CD28 signals would represent an effective means of controlling these aberrant immune responses. To identify potential molecular targets for therapy the long-term aims of this proposal are to understand the nature of CD28 intracellular signaling pathways. Previous studies have determined that CD28 signaling involves recruitment of PI3-kinase and Grb-2 to the tyrosine phosphorylated CD28 cytoplasmic tail. However, there is evidence that other signaling molecules are recruited to the CD28 tail and that these molecules play important roles in CD28 signal transduction. Recently, additional CD28 binding proteins were identified. One is a previously un-described dual- specific phosphatase of the MAP kinase phosphatase family, MKP5, which binds the CD28 tail independent of tyrosine phosphorylation. Another is the GRAP adaptor protein, which is related to but distinct from Grb-2, and also binds only the phosphorylated CD28 tail. Preliminary evidence indicates that MKP5 functions as a negative regulator of CD28 signal transduction. In contrast, GRAP likely performs a positive role in CD28 signaling. Specifically, here it is proposed to use a variety of molecular genetic, biochemical and cellular techniques to 1) Confirm negative and positive signaling roles for MKP5 and GRAP respectively, and 2) Determine the precise function of these molecules in the CD28 signal transduction pathway. In addition, using a novel yeast-based genetic assay that has been developed in the laboratory, it is proposed to characterize other signaling intermediates that bind the phosphorylated CD28 cytoplasmic tail.