PCP-regulated directed cell motility

PCP 调节的定向细胞运动

• 批准号: 8731920
• 负责人: Marek Mlodzik
• 金额: $ 34.64万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731920
• 关键词: Address; Adhesions; Adult; Affect; Animals; Apical; Behavior; Biochemical; Biological Assay; Cell Adhesion; Cell Adhesion Molecules; Cell Culture Techniques; Cell Polarity; Cell-Cell Adhesion; Cells; Cilia; Complex; Data; Defect; Development; Disease; Drosophila eye; Drosophila genus; E-Cadherin; Epidermis; Epithelial; Epithelial Cells; Epithelium; Evolution; Extracellular Matrix; Eye; Eye Development; Family member; Fibroblast Growth Factor Receptors; Genetic; Hair; Hearing; Image; Individual; Integrins; Labyrinth; Lead; Life; Ligands; Link; MAP Kinase Gene; Malignant Neoplasms; Mammalian Oviducts; Mammals; Mediating; Medical; Membrane Proteins; Modeling; Molecular; Morphogenesis; Movement; Neural Tube Closure; Notch Signaling Pathway; Organ; Organogenesis; Pathway interactions; Pattern; Phosphorylation; Phosphotransferases; Process; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Regulation; Role; Rotation; Sensory; Signal Pathway; Signal Transduction; Skin; Structure; Tissues; Transgenic Organisms; Vertebrates; Work; afadin; base; cell motility; fly; gastrulation; genetic regulatory protein; in vivo; nectin; notch protein; receptor; research study; response; stem cell biology

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.

描述（由申请人提供）：上皮细胞通常需要在两个轴上具有极化，以使其功能，无处不在的基质基质极性和上皮平面内的第二轴，称为平面细胞极性（PCP）。典型的哺乳动物PCP例子由皮肤的组织和许多内部器官（例如内耳的感觉纤毛，重要的是，还包括在哺乳动物胃和神经管闭合期间的定向细胞迁移。在果蝇中，所有成年表皮结构均显示PCP特征。果蝇中的PCP建立是研究发育和疾病中PCP确定的范例。 PCP由毛躁（FZ）受体的活性（以Wnt家族成员作为配体）的活性进行了协调，并且它是相关的信号级联（FZ/PCP信号传导），该信号级联（FZ/PCP信号传导）在整个演化过程中都高度保守，并调节了协调的细胞极化的许多方面，包括定向细胞的迁移。尽管开始建立调节PCP的信号通路的框架工作，但PCP信号和所得细胞反应之间的特定联系，包括调节细胞粘附和细胞运动性的调节，才开始解剖。同样，PCP途径的细胞粘附效应子（S）在很大程度上未知。该应用的范围是使用果蝇眼范式作为模型来剖析PCP相关信号通路与相应细胞粘附因子之间的机械调节相互作用。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信号的调节输入会收敛于E-钙粘蛋白/catenin/catenin/catenin/catenin/afadin，以及整合蛋白/ECM介导的细胞粘附/细胞粘附/细胞运动调节。令人惊讶的是，所有涉及的信号通路（Wnt/FZ-PCP，Notch和RTK/RAS-Signaling）都采用非典型途径分支。这些细胞粘附特定的信号分支的组件现在仅被发现，因此出现了令人兴奋的新信号网络。我们将结合果蝇在体内研究，蝇眼中的实时成像以及生化实验来定义信号成分与细胞粘附因子之间的机械调节相互作用，从而导致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，也与干细胞生物学有关。因此，本应用程序中获得的信息不仅会提高我们对受调节的细胞运动的理解，而且在几种疾病相关的情况下也将具有医学相关性。