Bidirectional Tyrosine Kinase Signal Transduction

双向酪氨酸激酶信号转导

• 批准号: 6438004
• 负责人: MARK J HENKEMEYER
• 金额: $ 26.74万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6438004
• 关键词: biological signal transduction; neuronal guidance; protein localization; protein protein interaction; protein tyrosine kinase; receptor binding; tissue /cell culture

DESCRIPTION (provided by applicant): This proposal focuses on the signal transduction cascades that are used to wire the nervous system. Without question the brain and spinal cord form the most complicated organ, functioning as the biological supercomputer to control everything in the body, from sensing the environment and initiating movement, to learning, memory, speech and behavior. What is most amazing is that this supercomputer self-assembles during development as each neuron sends out a thin wire-like extension, the axon, which can travel great distances to reach its target. The Eph receptors and their membrane-anchored ephrin ligands play important roles in guiding axons to their targets. In addition to axon pathfinding, Ephs and ephrins control many other cell-cell interactions, including those that occur during hindbrain segmentation and cardiovascular development. Eph receptors have a cytoplasmic protein-tyrosine kinase catalytic domain, while the B-subclass ephrins have a short cytoplasmic domain. Our previous genetic and biochemical studies were the first to demonstrate that when Eph receptor-expressing cells contact ephrin-expressing cells, both molecules become tyrosine phosphorylated and both send signals into their respective cell. Over the past five years, our hypothesis that ephrins and Eph receptors transduce bidirectional signals has become a key feature in the study of this large family of 14 receptors and 8 ephrins. In addition to ongoing biological studies of Eph/ephrin functions, we have focused on defining the biochemistry of this bidirectional cell-cell communication system to understand how these signals are transduced at the molecular level. We have identified a number of proteins that physically associate with the cytoplasmic domains of the ephrins and Eph receptors. These molecules contain important protein-protein interaction domains involved in signal transduction and subcellular localization, including Src homology 2 (SH2) domains (which bind phosphotyrosine sequences), SH3 domains (which bind poly-proline sequences) and PDZ domains (which bind the carboxy-terminus of certain proteins). By identifying and characterizing proteins that physically associate with ephrins and Eph receptors, our long-term objective is to define the signal transduction cascades and cellular responses initiated by bidirectional signaling. In addition to increasing our general knowledge about biochemical signal transduction cascades that control cell-cell interactions and axon guidance, these studies may provide insight into potential molecular targets that may be used to develop therapies of the future, such as those needed to regenerate severed connections following a spinal cord injury.

描述（由申请人提供）：本提案侧重于信号 用于连接神经系统的传导级联。没有 大脑和脊髓是最复杂的器官， 作为生物超级计算机来控制身体的一切， 环境和启动运动，学习，记忆，语言和 行为最令人惊讶的是，这台超级计算机在 当每个神经元发出一个细的线状延伸，轴突， 它可以穿越很远的距离到达目标Eph受体和 它们的膜锚定肝配蛋白配体在引导轴突 他们的目标除了轴突寻路，Ephs和ephrins还控制着许多神经元， 其他细胞间的相互作用，包括那些发生在 分割和心血管发育。Eph受体在细胞质中 蛋白酪氨酸激酶催化结构域，而B亚类肝配蛋白具有一个 短胞质结构域。我们以前的遗传和生化研究是 首次证明当Eph受体表达细胞接触 在表达肝配蛋白的细胞中，两种分子都变得酪氨酸磷酸化， 向各自的细胞发送信号在过去的五年里，我们 假设ephrin和Eph受体是双向信号， 成为研究这个由14种受体和8种受体组成的大家族的关键特征。 肝配蛋白除了正在进行的Eph/ephrin功能的生物学研究，我们 专注于定义这种双向细胞-细胞的生物化学 通信系统，以了解这些信号是如何在 分子水平。我们已经鉴定出一些蛋白质， 与肝配蛋白和Eph受体的胞质结构域相关。这些 分子包含重要的蛋白质-蛋白质相互作用结构域， 信号转导和亚细胞定位，包括Src同源2 (SH2)结构域（其结合磷酸酪氨酸序列）、SH 3结构域（其结合 多聚脯氨酸序列）和PDZ结构域（其结合多聚脯氨酸序列的羧基末端）。 某些蛋白质）。通过识别和表征蛋白质， 与ephrins和Eph受体相关，我们的长期目标是确定 信号转导级联和细胞反应引发的 双向信令除了增加我们的一般知识， 控制细胞间相互作用的生化信号转导级联 和轴突的引导，这些研究可能提供深入了解潜在的分子 可用于开发未来疗法的靶点，例如 需要再生脊髓损伤后切断的连接。