Mechanisms of Signaling Protein Retention in the Primary Cilium

初级纤毛中信号蛋白保留的机制

基本信息

批准号：
10375484
负责人：
YU JIANG
金额：
$ 31.3万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-24 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375484
关键词：
Apical Basic Amino Acids Benign Binding Proteins Biochemical Birt-Hogg-Dube Syndrome Cell Cycle Cell Differentiation process Cell Polarity Cell membrane Cell physiology Cell surface Cells Chemical Stimulation Chemicals Cilia Clinical Couples Cues Cytoplasm Data Defect Development Disease Epithelial Cells Event Folliculin Genetic Diseases Growth Guanine Nucleotide Exchange Factors Homeostasis Human Interphase Cell Investigation Kidney Ligands Link Lipids Maintenance Mammalian Cell Mammals Mediating Membrane Membrane Transport Proteins Microtubules Molecular Monomeric GTP-Binding Proteins Nephronophthisis Nucleotides Organ Organelles Pathway interactions Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphorylation Play Polycystic Kidney Diseases Protein Kinase Proteins Regulation Role SHH gene Sensory Signal Transduction Signaling Molecule Signaling Protein Sonic Hedgehog Pathway Stress Structure Surface Syndrome System Testing Tissues Tubular formation Tumor Suppressor Proteins base ciliopathy environmental chemical extracellular fluid flow glycogen synthase kinase 3 beta human disease insight novel polycystic kidney disease 1 protein prevent protein transport receptor recruit response smoothened signaling pathway sonic hedgehog receptor trafficking tumor

Apical Basic Amino Acids Benign Binding Proteins Biochemical Birt-Hogg-Dube Syndrome Cell Cycle Cell Differentiation process Cell Polarity Cell membrane Cell physiology Cell surface Cells Chemical Stimulation Chemicals Cilia Clinical Couples Cues Cytoplasm Data Defect Development Disease Epithelial Cells Event Folliculin Genetic Diseases Growth Guanine Nucleotide Exchange Factors Homeostasis Human Interphase Cell Investigation Kidney Ligands Link Lipids Maintenance Mammalian Cell Mammals Mediating Membrane Membrane Transport Proteins Microtubules Molecular Monomeric GTP-Binding Proteins Nephronophthisis Nucleotides Organ Organelles Pathway interactions Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphorylation Play Polycystic Kidney Diseases Protein Kinase Proteins Regulation Role SHH gene Sensory Signal Transduction Signaling Molecule Signaling Protein Sonic Hedgehog Pathway Stress Structure Surface Syndrome System Testing Tissues Tubular formation Tumor Suppressor Proteins base ciliopathy environmental chemical extracellular fluid flow glycogen synthase kinase 3 beta human disease insight novel polycystic kidney disease 1 protein prevent protein transport receptor recruit response smoothened signaling pathway sonic hedgehog receptor trafficking tumor

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项目摘要

PROJECT SUMMARY The primary cilium is a solitary membrane extrusion from the apical surface of noncycling resting cells in mammals. It functions as a sensory organelle that is responsible for the resting cells to sense environmental conditions and communicate with adjacent cells. This organelle is composed of a microtubule-based axoneme encased in the plasma membrane, resulting in formation of a ciliary compartment that is separated from the cytoplasm by a transition zone at its base. Protein trafficking within the ciliary compartment is mediated by intraflagellar transport that transverses the compartment bi- directionally on the microtubules. Accumulating evidence suggests that the ability of the primary cilium to function as a sensory organelle depends on selective accumulation of various signaling molecules. Many components of cilium-dependent pathways are found to be transported into and out of the primary cilium in response to environmental cues. However, the mechanisms underlying the regulated trafficking remain unknown. The proposed application is to define a previously unknown mechanism in intraflagellar protein trafficking that as suggested by our preliminary data, regulates ciliary accumulation of soluble protein kinases in response to flow stress and chemical stimulation. This novel mechanism is mediated by folliculin (FLCN), a tumor suppressor, of which defects cause the Birt-Hogg-Dube (BHD) syndrome, a genetic disorder that is manifested clinically by benign tumors and cystic growth in multiple organs. In ciliated resting cells inactivation of FLCN produces profound effects on several major cilium-dependent pathways, including the Sonic Hedgehog (Shh) pathway, which becomes fully active and unresponsive to ligand stimulation. Preliminary data suggest that FLCN couples Shh ligand stimulation to ciliary accumulation and activation of Smoothened (Smo), a key but poorly understood step in Shh signaling. The application is proposed to define the underlying molecular basis and its functional significance in general ciliary signaling. Three lines of investigation will be carried out in the context of ligand and flow stress regulated Shh signaling. including: 1) determining how FLCN-mediated ciliary protein accumulation controls Smo activation in response to Shh ligand stimulation; 2) determining the role of Rab23 small GTPase in the ciliary function of FLCN; 3) determining how flow stress controls Shh signaling through FLCN. Successful completion of the proposed studies will offer a new paradigm to explain how ciliary signaling is regulated by environmental cues and elucidate the mechanism underlying the Shh ligand- induced activation of Smo.

项目摘要原发性纤毛是从非循环静止的顶端挤出的孤立膜挤出哺乳动物中的细胞。它充当感官细胞器，负责静止细胞的感觉环境条件并与相邻细胞进行通信。该细胞器由基于微管的轴突包裹在质膜中，导致形成纤毛隔室通过其基部的过渡区与细胞质分离。蛋白质运输睫状室内的腔内转运介导，该转运横向室内在微管上方向。积累的证据表明，主要纤毛的能力作为感觉细胞器的功能取决于各种信号分子的选择性积累。许多发现纤毛依赖性途径的成分被转移到原发性纤毛中响应环境线索。但是，受监管贩运的基础机制仍然存在未知。所提出的应用是定义flagellar蛋白中先前未知的机制正如我们的初步数据所建议的那样，调节可溶性蛋白质的睫状积累激酶响应流动应力和化学刺激。这种新颖的机制是由 Folliculin（FLCN），一种抑制肿瘤，其缺陷导致Birt-Hogg-Dube（BHD）综合征，A 由良性肿瘤和多个器官中的囊性生长在临床上表现出来的遗传疾病。在纤毛静息细胞失活的FLCN对几种主要的纤毛依赖性产生深远的影响途径，包括声音刺猬（SHH）途径，该途径变得完全活跃且无反应配体刺激。初步数据表明，FLCN夫妇SHH配体刺激纤毛平滑（SMO）的累积和激活，这是一个关键但知之甚少的SHH信号传导步骤。提出了该应用以定义基本分子基础及其在功能上的意义一般睫状信号传导。将在配体和流动的背景下进行三条调查。应力调节的SHH信号传导。包括：1）确定FLCN介导的睫状蛋白的积累响应SHH配体刺激来控制SMO激活； 2）确定rab23小的作用 GTPase在FLCN的睫状功能中； 3）确定流动应力如何控制SHH信号通过 flcn。成功完成拟议的研究将提供一个新的范式来解释睫状信号传导受环境线索的调节，并阐明了SHH配体的机制诱导SMO的激活。