Bidirectional Tyrosine Kinase Signal Transduction

描述(申请人提供)：本建议书侧重于信号 用来连接神经系统的转导级联。如果没有 质疑大脑和脊髓构成最复杂的器官，起作用 作为生物超级计算机来控制身体中的一切，从感知 环境和启动运动，到学习、记忆、言语和 行为。最令人惊叹的是，这台超级计算机在 当每个神经元发出一个细丝状的延伸，轴突， 它可以长途跋涉到达目标。Eph受体和 它们的膜锚定的肾上腺素配体在引导轴突 他们的目标。除了轴突寻路外，Ephs和Ephin还控制着许多 其他细胞间的相互作用，包括发生在后脑的那些 分割与心血管发育。Eph受体具有细胞质 蛋白-酪氨酸激酶催化结构域，而B亚类肾上腺素有一个 胞质结构域较短。我们之前的遗传和生化研究是 第一个证明当表达Eph受体的细胞接触 表达肾上腺素的细胞，这两个分子都被酪氨酸磷酸化， 将信号发送到各自的单元中。在过去的五年里，我们 肾上腺素和Eph受体转导双向信号的假说 成为研究这个由14个受体和8个受体组成的大家族的关键特征 伊弗林。除了正在进行的对Eph/Ephin功能的生物学研究外，我们 专注于定义这种双向细胞的生物化学-细胞 通信系统以了解这些信号是如何在 分子水平。我们已经确定了一些蛋白质，它们在物理上 与肾上腺素和Eph受体的细胞质结构域相关联。这些 分子包含重要的蛋白质-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2 (Sh2)结构域(结合磷酸酪氨酸序列)、SH3结构域(结合 多-脯氨酸序列)和PDZ结构域(它们结合了 某些蛋白质)。通过鉴定和表征物理上可以 与肾上腺素和EPH受体相关，我们的长期目标是确定 信号转导的级联反应和细胞反应 双向信令。除了增加我们对以下方面的一般知识 控制细胞间相互作用的生化信号转导 和轴突引导，这些研究可能提供对潜在分子的洞察 可能被用来开发未来治疗方法的目标，例如 在脊髓损伤后需要重建切断的连接。

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.