Fat-Dachsous signaling in growth control and planar cell polarity

生长控制和平面细胞极性中的脂肪-达克索信号传导

基本信息

批准号：
8828794
负责人：
SETH S BLAIR
金额：
$ 31.89万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-08-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828794
关键词：
Beryllium Binding Binding Sites Biological Assay Biology Cell Death Cell surface Cells Data Dimerization Distal Drosophila genus Enhancers Extracellular Domain Failure Family Fatty acid glycerol esters Genes Genetic Transcription Golgi Apparatus Grant Growth Health Human Human Development In Vitro Indium Integral Membrane Protein Joints Knowledge Light Link Malignant Neoplasms Maps Mediating MicroRNAs Molecular Genetics Mutation Myosin ATPase Organism Pathology Pathway interactions Pattern Phenotype Phosphotransferases Play Protein Binding Protein Binding Domain Protein Kinase Proteins RNA Interference Regulation Resources Response Elements Role Scallop Series Signal Transduction Speed Structure Testing appendage cofactor design extracellular gain of function in vitro Assay in vitro activity loss of function member mutant organ growth overexpression planar cell polarity polarized cell receptor research study screening tool transcription factor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): This proposal outlines a series of experiments designed to test the regulation of an important intracellular pathway for controlling growth, cell death and patterning in developing organisms: that mediated by the Hippo and Warts protein kinases. This pathway plays a major role in controlling organ growth, and misregulation of the pathway is tumorigenic, but little is known about how it is controlled. We are concentrating on how this pathway is regulated by the large Drosophila protocadherins Fat and Dachsous. The extracellular domains of these two transmembrane proteins bind each other, and this suppresses growth by activating the Hippo pathway. However, the mechanisms connecting Fat and Dachsous to the Hippo pathway are poorly understood. First, we are dissecting the activities of the intracellular domains of Fat, and are using that to develop an in vitro RNAi screen for molecules required for Fat activity. Second, we are examining how boundaries and gradients of Fat and Dachsous expression, and the resultant polarization of Fat and Dachsous on cell surfaces, inhibits the Hippo pathway and triggers growth. Third, we are examining the role of a downstream negative regulator of Fat activity, the atypical myosin Dachs/Myosin29D, and its regulator Approximated. Finally, we are examining how the Hippo pathway combines with additional (especially spatial) information to regulate the expression of an important downstream target, the miRNA bantam.

描述（由申请人提供）：该提案概述了一系列实验，旨在测试控制发育中生物体生长、细胞死亡和模式的重要细胞内途径的调节：由 Hippo 和 Warts 蛋白激酶介导。该通路在控制器官生长中发挥着重要作用，该通路的失调会导致肿瘤，但人们对其控制方式知之甚少。我们专注于研究果蝇原钙粘蛋白 Fat 和 Dachsous 如何调节该通路。这两种跨膜蛋白的胞外结构域相互结合，从而通过激活 Hippo 途径来抑制生长。然而，人们对 Fat 和 Dachsous 与 Hippo 通路之间的连接机制知之甚少。首先，我们正在剖析脂肪细胞内结构域的活性，并利用它来开发脂肪活性所需分子的体外 RNAi 筛选。其次，我们正在研究 Fat 和 Dachsous 表达的边界和梯度，以及由此产生的 Fat 和 Dachsous 在细胞表面的极化，如何抑制 Hippo 通路并触发生长。第三，我们正在研究脂肪活性的下游负调节因子、非典型肌球蛋白 Dachs/Myosin29D 及其调节器 Approximated 的作用。最后，我们正在研究 Hippo 通路如何与附加（尤其是空间）信息相结合来调节重要下游靶标 miRNA bantam 的表达。