FYB--A NOVEL T CELL SIGNALING PROTEIN

FYB--一种新型T细胞信号蛋白

• 批准号: 2882204
• 负责人: Christopher E. Rudd
• 金额: $ 24.53万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2882204
• 关键词: T lymphocyte; binding proteins; biological signal transduction; cell differentiation; interleukin 2; laboratory mouse; phenotype; phosphorylation; protein biosynthesis; protein kinase; thymus; tissue /cell culture; transfection

DESCRIPTION (Adapted from the Investigator's Abstract): Engagement of the T-cell antigen receptor (TCR) complex triggers a cascade of protein tyrosine phosphorylation events that are crucial for triggering of the T-cell activation program. While the proximal protein tyrosine kinases (PTKs) responsible for the initiation of this phosphorylation cascade are well-defined, the downstream targets of these PTKs are incompletely understood. The investigator's laboratory has cloned a novel Fyn-binding protein, termed Fyb, which is phosphorylated in response to TCR ligation. The Fyb protein contains multiple tyrosine phosphorylation sites, a putative nuclear localization signal, and an SH3-like domain. Fyb expression is restricted to myeloid cell lines and T cells. Immunofluorescence studies indicate that Fyb is widely distributed throughout T cells, including a significant level of staining in the nucleus. Perhaps most importantly, phosphorylated Fyb binds to the SH2 domains of Fyn and SLP-76, two candidate signal transducers for the TCR complex. Over-expression of Fyb in T cells leads to augmented IL-2 secretion following TCR cross-linkage, suggesting that Fyb is a positive effector of activation-induced cytokine production. The goals of the project described in this application are: (1) to identify the PTK(s) responsible for the phosphorylation of Fyb in response to TCR ligation, (2) to identify the mechanism by which Fyb augments IL-2 production, (3) to understand the biochemical basis and functional importance of the cytoplasmic versus nuclear localization of Fyb, and (4) to examine the impact of Fyb over-expression on intra-thymic T-cell development using transgenic mouse models.

描述（改编自研究者的摘要）： T 细胞抗原受体 (TCR) 复合物触发蛋白酪氨酸级联反应 对于触发 T 细胞至关重要的磷酸化事件 激活程序。 而近端蛋白酪氨酸激酶 (PTK) 负责启动该磷酸化级联的是 这些PTK的下游目标定义明确，但并不完整 明白了。 研究人员的实验室克隆了一种新的 Fyn 结合蛋白 蛋白质，称为 Fyb，响应 TCR 连接而磷酸化。 Fyb 蛋白含有多个酪氨酸磷酸化位点，这是一个假定的 核定位信号和 SH3 样结构域。 Fyb 表达式为 仅限于骨髓细胞系和 T 细胞。 免疫荧光研究 表明 Fyb 广泛分布于整个 T 细胞中，包括 细胞核中的染色水平显着。 也许最重要的是， 磷酸化 Fyb 与 Fyn 和 SLP-76（两个候选者）的 SH2 结构域结合 TCR 复合物的信号传感器。 T 细胞中 Fyb 的过度表达 TCR 交联后导致 IL-2 分泌增加，表明 Fyb 是激活诱导的细胞因子产生的正效应子。 本申请中描述的项目的目标是：（1）确定 负责 Fyb 响应 TCR 磷酸化的 PTK 连接，(2) 确定 Fyb 增强 IL-2 的机制 生产，（3）了解生化基础和功能 Fyb 的细胞质与核定位的重要性，以及 (4) 检查 Fyb 过度表达对胸腺内 T 细胞发育的影响 使用转基因小鼠模型。