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（申请人提供）：该提案重点介绍信号 用于连接神经系统的转导级联。没有 质疑大脑和脊髓形成最复杂的器官 作为控制体内所有物体的生物超级计算机，从传感 环境和启动运动，学习，记忆，语音和 行为。最令人惊讶的是，这个超级计算机在 当每个神经元发出薄导线的伸展时，发育，轴突， 可以走很长的距离才能达到其目标。 EPH受体和 他们的膜锚定的埃弗林配体在引导轴突中起着重要作用 他们的目标。除了轴突探测器外，以法和以弗林蛋白控制着许多 其他细胞 - 细胞相互作用，包括在后脑期间发生的相互作用 分割和心血管发育。 EPH受体具有细胞质 蛋白 - 酪氨酸激酶催化结构域，而B-子类ephrins具有A 短细胞质结构域。我们以前的遗传和生化研究是 首先证明当表达受体的细胞接触时 表达ephrin的细胞，这两个分子都被磷酸化，并且均变为 将信号发送到各自的单元格中。在过去的五年中，我们的 ephrins和eph受体传递双向信号的假设具有 成为研究这个14个受体和8个大家庭的关键特征 以弗林斯。除了持续的EPH/Ephrin功能生物学研究外，我们还 专注于定义该双向细胞细胞的生物化学 通信系统了解如何在 分子水平。我们已经确定了许多物理上的蛋白质 与以弗林蛋白和以EPH受体的细胞质结构域结合。这些 分子包含重要的蛋白质 - 蛋白质相互作用域 信号转导和亚细胞定位，包括SRC同源2 （SH2）域（结合磷酸酪氨酸序列），SH3结构域（结合 多生序列）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ephrins和eph受体结合，我们的长期目标是定义 信号转导级联和细胞反应 双向信号传导。除了提高我们对 控制细胞 - 细胞相互作用的生化信号转导级联 和轴突指导，这些研究可能会洞悉潜在的分子 可能用于开发未来疗法的靶标，例如 需要在脊髓损伤后再生切断的连接。