PCP-regulated directed cell motility

描述（由申请人提供）：上皮细胞通常需要在两个轴上进行极化以实现其功能，即普遍存在的顶部-底部极性和上皮平面内的第二个轴，称为平面细胞极性（PCP）。典型的哺乳动物五氯苯酚的例子突出表现在皮肤和许多内脏器官的组织，例如内耳及其感觉纤毛，重要的是，还包括哺乳动物原肠胚形成和神经管闭合期间的定向细胞迁移。在果蝇中，所有成年表皮结构都显示PCP特征。五氯苯酚在果蝇体内的确定为研究发育和疾病中五氯苯酚的测定提供了范例。PCP由卷曲（Fz）受体（Wnt家族成员作为其配体）及其相关信号级联（Fz/PCP信号传导）的活性协调，其在整个进化过程中高度保守，并调节协调细胞极化的许多方面，包括定向细胞迁移。虽然调控PCP的信号通路的框架正在开始建立，但PCP信号传导与所产生的细胞反应（包括细胞粘附和细胞运动的调控）之间的特定联系才刚刚开始被剖析。类似地，PCP途径的细胞粘附效应物在很大程度上是未知的。本申请的范围是剖析PCP相关的信号传导途径和各自的细胞粘附因子之间的机械调节相互作用，使用果蝇的眼睛范例作为模型。基于我们的初步研究，我们假设来自Fz/PCP、Notch和受体酪氨酸激酶（RTK）/Ras信号传导的调节输入会聚于E-钙粘蛋白/连环蛋白、Nectin/Afadin和整合素/ECM介导的细胞粘附/细胞运动调节。引人注目的是，所有涉及的信号传导途径（Wnt/Fz-PCP、Notch和RTK/Ras信号传导）采用非经典途径分支。这些细胞粘附特异性信号分支的组成部分现在才被发现，因此一个令人兴奋的新信号网络正在出现。我们将使用果蝇在体内的研究相结合，在蝇眼的现场成像，和生化实验来定义的信号传导组件和细胞粘附因子之间的机械调节相互作用，导致一个高度调节的细胞运动过程。信号通路和细胞粘附模块的几个组成部分与癌症和其他疾病密切相关，并且也与干细胞生物学相关。因此，本应用中获得的信息不仅将促进我们对调节细胞运动的理解，而且在多种疾病相关背景下也具有医学相关性。

DESCRIPTION (provided by applicant): Epithelial cells often require polarization in two axes for their function, ubiquitous apical-basal polarity and a second axis within the plane of the epithelium, called Planar Cell Polarity (PCP). Typical mammalian PCP examples are highlighted by the organization of the skin and many internal organs, e.g. the inner ear with its sensory cilia and, importantly, also include directed cell migration during mammalian gastrulation and neural tube closure. In Drosophila, all adult cuticular structures show PCP features. The establishment of PCP in Drosophila serves as a paradigm to study PCP determination in development and disease. PCP is coordinated by the activity of the Frizzled (Fz) receptor (with Wnt family members as their ligands) and it's associated signaling cascade (Fz/PCP signaling), which is highly conserved throughout evolution and regulates many aspects of coordinated cellular polarization, including directed cell migration. Although the frame work of the signaling pathway(s) regulating PCP is beginning to be established, the specific links between PCP-signaling and the resulting cellular responses, including the regulation of cell adhesion and cell motility are only beginning to be dissected. Similarly, the cell adhesion effectors of the PCP pathway(s) are largely unknown. The scope of this application is to dissect the mechanistic regulatory interactions between PCP associated signaling pathways and the respective cell adhesion factors, using the Drosophila eye paradigm as a model. Based on our preliminary studies we hypothesize that regulatory input from Fz/PCP, Notch and receptor tyrosine kinase (RTK)/Ras signaling converges on E-cadherin/catenin, Nectin/Afadin, and Integrin/ECM mediated cell adhesion/cell motility regulation. Strikingly, all signaling pathways involved (Wnt/Fz-PCP, Notch and RTK/Ras-signaling) employ a non-canonical pathway branch. The components of these cell adhesion specific signaling branches are only being discovered now, and thus an exciting new signaling network is emerging. We will use a combination of Drosophila in vivo studies, live imaging in the fly eye, and biochemical experiments to define the mechanistic regulatory interactions between the signaling components and the cell adhesion factors, leading to a highly regulated cell motility process. Several components of the signaling pathways and cell adhesion modules are critically linked to cancer and other diseases, and are also associated with stem cell biology. Thus the information acquired in this application will not only advance our understanding of regulated cellular motility but will also be of medical relevance in several disease associated contexts.