Notch signaling and adhesion regulation

项目说明和总结 这项提案的目标是描述一种新的机制，通过它，Notch 受体调节细胞黏附动力学的变化。Notch信令高度保守 来调节发育过程中的细胞命运，而它的失调已经 与多种血管炎症性疾病，发育异常， 和癌症。配体与Notch受体的结合导致蛋白水解性切割，释放 细胞内域(ICD)作为转录激活剂，这一机制一直是 主要关注描述Notch在发育和疾病中的作用。调查员已经 最近发现，血流引起的剪应力会激活Notch，进而导致 内皮细胞-细胞连接的快速组装和屏障功能的增强。在这部作品中， 他们证明了Notch蛋白降解后留下的跨膜结构域(TMD) 启动负责刺激连接的皮质信号复合体的形成 集合。在这里，调查员将确定组件、基本机制和 这一先前未被认识的非转录、皮质途径对Notch的细胞影响 并阐明了这一途径所处的生物学背景。这些目标将是 通过围绕三个目标建立的跨学科计划实现：具体目标1将是 明确非典型皮质Notch信号通路的潜在机制。特定目标 2将研究黏附、力和皮质Notch信号通路之间的串扰。 具体目标3将是探索皮质Notch通路泛化到 更广泛的生物学背景。总之，这些研究将为了解这一新的 Notch信号的臂，并为转录和黏附如何提供分子基础 程序可能由一个单一的受体来协调。

Project Description and Summary The goal of this proposal is to characterize a new mechanism by which the Notch receptor regulates changes in cell adhesion dynamics. Notch signaling is highly conserved across the animal kingdom to regulate cell fates during development, and its dysregulation has been implicated in a variety of vascular inflammatory diseases, developmental abnormalities, and cancers. Binding of ligand to Notch receptor leads to proteolytic cleavages that release the intracellular domain (ICD) as a transcriptional activator, and this mechanism has been the primary focus in describing the role of Notch in development and disease. The investigator has recently found that shear stress caused by blood flow activates Notch, which in turn leads to rapid assembly of endothelial cell-cell junctions and heightened barrier function. In this work, they demonstrated that the transmembrane domain (TMD) left behind after Notch proteolysis initiates the formation of a cortical signaling complex that is responsible for stimulating junction assembly. Here, the investigator will identify the components, underlying mechanisms, and cellular impact of this previously unappreciated non-transcriptional, cortical pathway for Notch and elucidate the biological contexts in which this pathway is engaged. These objectives will be achieved through an interdisciplinary program built around three Aims: Specific Aim 1 will be to define mechanisms underlying the non-canonical cortical Notch signaling pathway. Specific Aim 2 will examine crosstalk between adhesion, force, and the cortical Notch signaling pathway. Specific Aim 3 will be to explore the extent to which the cortical Notch pathway generalizes to broader biological contexts. Together, these studies will offer important insights into this new arm of Notch signaling, and provide a molecular basis for how transcriptional and adhesive programs might be coordinated by a single receptor.