Ubiquitin-like protein modifications in planar cell polarity

平面细胞极性中的泛素样蛋白修饰

基本信息

批准号：
9240642
负责人：
Marek Mlodzik
金额：
$ 32.21万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240642
关键词：
APC2 gene Address Adult Anaphase Apical Architecture Biochemical Biological Assay Caenorhabditis elegans Cell Culture Techniques Cell Cycle Progression Cell Cycle Proteins Cell Cycle Regulation Cell Polarity Cells Cilia Complex Data Development Disease Drosophila genus Employee Strikes Epidermis Epithelial Epithelial Cells Epithelium Evolution Genes Hair Hair follicle structure Human Insecta Invertebrates Labyrinth Ligase Link Maintenance Malignant Neoplasms Mammalian Oviducts Mammals Mediating Mediator of activation protein Medical Mesenchymal Mitotic Molecular Morphogenesis Mosaicism Mutation Names Organ Organogenesis Pathway interactions Pattern Peptides Physiological Polycystic Kidney Diseases Post-Translational Protein Processing Process Proteins Proto-Oncogenes Regulation Role Sensory Signal Transduction Structure System Tissues Tumor Suppressor Proteins Ubiquitin Ubiquitin Like Proteins Ubiquitination Vertebrates Whole Organism anaphase-promoting complex base carcinogenesis cell motility cell type ciliopathy deafness experimental study follow-up gastrulation genetic approach genetic regulatory protein genome-wide analysis in vivo insight intercalation loss of function member negative affect novel planar cell polarity polarized cell protein degradation public health relevance receptor skin organogenesis ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Polarization of epithelial cells is evident in two axes, in the ubiquitous apical-basolateral axis and within the plane of the epithelium as a second axis, the latter generally referred to as Planar Cell Polarity (or PCP). Examples of PCP are present in almost all organs, and in mammals, for example, most obvious in aspects of skin development with hair follicle orientation or cellular arrangements in internal organs, like the inner ear epithelium with its sensory cilia. In Drosophila, all adult cuticular structures and organs display striking PCP features, which makes the study of PCP establishment in Drosophila serve as a paradigm for the process in developmental patterning and disease in general. Analyses in Drosophila have established a conserved molecular pathway anchored around the Frizzled (Fz)/PCP core factor cassette and associated regulatory factors. This core Fz/PCP pathway and its regulatory components are conserved throughout evolution regulating many aspects of cellular polarization not only in epithelial organs, but in mammals also in directed cell migration of mesenchymal cells during gastrulation and neurulation. Although a framework of the interactions among the core Fz/PCP factors is emerging, little is known about the actual molecular mechanisms underlying their interactions. The scope of this application is to follow-up on very interesting gene identifications from a genome wide screen for novel regulators of the core PCP factors. Based on interesting preliminary data, we propose as Specific Aims to (1) address the role of the Ubiquitin-ligase activity of the Anaphase Promoting Complex (APC/C) and define which components of this complex act in PCP and how, (2) define the function of the novel ubiquitin-like modifier encoded by CG15283 in PCP establishment and how it might regulate the activity of core Fz/PCP factors or APC/C components during PCP signaling, and (3) identify the PCP specific substrates of the APC/C and define their molecular regulation by the APC/C. We have established several assays that will allow us to address these aims via a combination of functional in vivo studies in Drosophila, biochemical experiments, and cell culture analyses. As the roles of the APC/C outside cell cycle control and a function of the conserved CG15283 peptide are largely obscure or completely unknown, respectively, our application will provide first insight(s) into the mechanism(s) of these. Fz/PCP establishment has been linked to several medical abnormalities, including deafness, cancer, polycystic kidney disease, and ciliopathies. Thus the information acquired in this application will both advance our understanding of PCP regulation and organ patterning, and will also be of medical relevance in several disease contexts.

描述（由申请人提供）：上皮细胞的极化在两个轴上是显而易见的，在无处不在的根尖 - 巴西外侧轴和上皮平面内为第二轴，后者通常称为平面细胞极性（或PCP）。 PCP的示例几乎存在于几乎所有器官中，例如，在哺乳动物中，在皮肤发育方面最为明显，内部器官中具有毛囊方向或细胞排列，例如内耳上皮和其感觉纤毛。在果蝇中，所有成年的表皮结构和器官显示引人注目的PCP特征，该特征使果蝇中的PCP建立研究是发育模式和疾病过程的范式。果蝇中的分析已经建立了一条固定在毛躁（FZ）/PCP核心因子盒和相关调节因子周围的保守分子途径。该核心FZ/PCP途径及其调节组件在整个演化过程中都保守了调节细胞极化的许多方面，不仅在上皮器官中，而且在哺乳动物中也是在定向的细胞迁移中胃和神经化过程中间充质细胞的。尽管出现了核心FZ/PCP因子之间相互作用的框架，但对它们相互作用的实际分子机制知之甚少。该应用程序的范围是从基因组宽屏幕上进行非常有趣的基因鉴定，以获取核心PCP因子的新调节剂。 Based on interesting preliminary data, we propose as Specific Aims to (1) address the role of the Ubiquitin-ligase activity of the Anaphase Promoting Complex (APC/C) and define which components of this complex act in PCP and how, (2) define the function of the novel ubiquitin-like modifier encoded by CG15283 in PCP establishment and how it might regulate the activity of core Fz/PCP factors or PCP信号传导期间的APC/C组件，（3）识别APC/C的PCP特异性底物，并通过APC/C定义其分子调节。我们已经建立了几种测定法，使我们能够通过果蝇，生化实验和细胞培养分析的体内研究的结合来解决这些目标。由于APC/C外部细胞周期控制的作用以及保守的CG15283肽的函数在很大程度上是模糊的或完全未知的，因此我们的应用将在这些机理中提供第一见解。 FZ/PCP建立与几种医学异常有关，包括耳聋，癌症，多囊性肾脏疾病和纤毛病。因此，本应用程序中获得的信息既可以提高我们对PCP调节和器官模式的理解，并且在几种疾病的情况下也将具有医学相关性。