Regulation of Signal Transduction on Vesicles

描述（由申请人提供）：信号转导在细胞内区室内被精确控制，实现这一目标的主要机制是通过使用囊泡运输信号复合物。这一概念与神经营养作用、神经系统发育中轴突生长的机制以及对神经损伤的反应密切相关。囊泡介导的途径也代表了阿尔茨海默病、精神障碍和神经损伤的潜在治疗靶点。突触蛋白是囊泡表面丰富的神经元特异性磷酸化蛋白家族，是调控囊泡信号转导的理想候选分子。除了结合囊泡外，突触素还结合影响神经营养信号传导的信号分子，如适配器Grb2、PI3激酶和神经营养信号传导的重要辅助因子14-3-3z。在非洲爪蟾胚胎中，突触蛋白与14-3-3 -3z结合，作为磷酸化依赖的分子开关，调节脊髓轴突的生长，以响应cAMP。中心假设是突触是位于囊泡上的一个更大的信号复合体的组成部分。我们假设突触通过与14-3-3z和其他信号分子的相互作用，调节位于囊泡上的信号级联反应。我们将通过以下方法来验证我们的中心假设：1)确定由突触和14-3-3z调节的信号通路；2)确定14-3-3z磷酸化在神经元发育中的作用；3)确定突触、14-3-3z和囊泡上其他cAMP/神经营养信号分子之间的空间关系。这一结果不仅有助于更好地理解神经发育的分子基础，而且还可以为神经精神疾病的药理治疗提供见解。

DESCRIPTION (provided by applicant): Signal transduction is precisely controlled within intracellular compartments, and a major mechanism for achieving this is by using vesicles to transport signaling complexes. This concept is highly relevant to neurotrophic action, and to mechanisms of axon outgrowth in the developing nervous system and in response to nerve injury. Vesicle-mediated pathways also represent potential therapeutic targets for Alzheimer's Disease, psychotic disorders, and nerve injury. Synapsins, a family of abundant, neuron-specific phosphoproteins that coat vesicles, are ideal candidate molecules for regulating signal transduction on vesicles. In addition to binding vesicles, synapsins bind to signaling molecules that affect neurotrophic signaling, such as the adapter Grb2, PI3 kinase, and an essential co-factor for neurotrophic signaling, 14-3-3z. Synapsins bind to 14-3-3z at a site which acts as a phosphorylation-dependent molecular switch to regulate the growth of spinal axons in response to cAMP in Xenopus embryos. The central hypothesis is that synapsins are an integral part of a larger signaling complex located on vesicles. We hypothesize that synapsins, through interactions with 14-3-3z and other signaling molecules, regulates signaling cascades while situated on vesicles. We will test our central hypothesis by: 1) Identifying the signaling pathways modulated by synapsins and 14-3-3z; 2) Establishing the role of 14-3-3z phosphorylation in neuronal development; 3) Determining the spatial relationships between synapsins, 14-3-3z, and other cAMP/neurotrophic signaling molecules on vesicles. The results will contribute not only to a better understanding of the molecular basis of neural development, but could also provide insights into the pharmacological treatment of neuropsychiatric diseases.