Bidirectional Tyrosine Kinase Signal Transduction

双向酪氨酸激酶信号转导

• 批准号: 6699973
• 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/6699973
• 关键词: biological signal transduction; ephrins; 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）：该提案重点关注信号 用于连接神经系统的转导级联。没有 质疑大脑和脊髓构成最复杂的器官，其功能 作为生物超级计算机来控制体内的一切，从传感到 环境和发起运动，到学习、记忆、言语和 行为。最令人惊奇的是，这台超级计算机在 当每个神经元发出一根细线状的延伸物（轴突）时，就会发育， 它可以长途跋涉到达目标。 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。除了轴突寻路之外，Ephs 和 ephrins 还控制许多 其他细胞间相互作用，包括后脑期间发生的相互作用 细分和心血管发育。 Eph受体具有细胞质 蛋白酪氨酸激酶催化结构域，而 B 亚类肝配蛋白具有 短胞质结构域。我们之前的遗传和生化研究是 首先证明当表达 Eph 受体的细胞接触 在表达肝配蛋白的细胞中，两个分子都被酪氨酸磷酸化，并且都 将信号发送到各自的细胞中。过去五年，我们 肝配蛋白和 Eph 受体转导双向信号的假设 成为这个由 14 种受体和 8 种受体组成的大家族研究的一个关键特征 肝配蛋白。除了正在进行的 Eph/ephrin 功能生物学研究之外，我们 专注于定义这种双向细胞的生物化学 通信系统来了解这些信号是如何在 分子水平。我们已经鉴定出许多蛋白质，它们在物理上 与肝配蛋白和 Eph 受体的细胞质结构域相关。这些 分子含有重要的蛋白质-蛋白质相互作用结构域，参与 信号转导和亚细胞定位，包括 Src 同源性 2 (SH2) 结构域（结合磷酸酪氨酸序列）、SH3 结构域（结合 聚脯氨酸序列）和 PDZ 结构域（结合羧基末端） 某些蛋白质）。通过识别和表征物理上的蛋白质 与肝配蛋白和 Eph 受体相关，我们的长期目标是定义 信号转导级联和细胞反应引发 双向信令。除了增加我们的常识之外 控制细胞间相互作用的生化信号转导级联 和轴突引导，这些研究可能会提供对潜在分子的见解 可用于开发未来疗法的目标，例如 需要在脊髓损伤后重建断开的连接。