Cell growth-dependent control of secretion by lipid signals

脂质信号对细胞生长依赖性分泌的控制

基本信息

批准号：
8306125
负责人：
PETER J MAYINGER
金额：
$ 30.19万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306125
关键词：
1-Phosphatidylinositol 4-Kinase 14-3-3 Proteins Abnormal Cell Cell Differentiation process Cell Proliferation Cell surface Cells Cellular biology Coupling Defect Diabetes Mellitus Disease Drug Delivery Systems Endoplasmic Reticulum Fibrosis Goals Golgi Apparatus Growth Growth Factor Health Human Intracellular Membranes Kidney Diseases Lead Link Lipids Malignant Neoplasms Membrane Protein Traffic Membrane Proteins Mitogens Molecular Organelles Organism Pathway interactions Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Process Production Proteins Regulation Role Signal Pathway Signal Transduction Site Sorting - Cell Movement Stimulus anterograde transport base cell growth glycosylation human disease neoplastic cell novel prevent response secretory protein stem trafficking

项目摘要

DESCRIPTION (provided by applicant): Growth is essential for cell proliferation and differentiation in all organisms and causes a wide range of severe human diseases if misregulated. Cell surface growth relies critically on coordinated delivery of membranes and proteins to the cell periphery via the secretory pathway. Although this phenomenon has been recognized for several decades, it remains unknown how the biosynthetic pathway is regulated in response to growth signaling. Phosphorylated lipids have been recently implicated in regulating cell growth-specific processes. Based on our preliminary evidence, we propose a central role for phosphoinositide lipids in growth regulation of secretion. While it is established that phosphoinositides are essential for intracellular membrane traffic, a link between lipid signaling within the biosynthetic pathway and cell growth has not been characterized. In this proposal, we aim to demonstrate a novel and essential role for the SAC1 lipid phosphatase in the regulation of the secretory pathway during cell growth. Our preliminary studies show that human SAC1 shuttles between endoplasmic reticulum (ER) and Golgi in response to growth conditions and regulates lipid signaling at these organelles. Our goal is to elucidate the mechanism of growth-dependent shuttling of SAC1 and to analyze the role of SAC1 in secretion and cell proliferation. We will investigate these questions in three distinct aims. Specifically, we will characterize the growth-regulated mechanism of SAC1 translocation between ER and Golgi. We will analyze how SAC1 regulates phosphoinositides at ER and Golgi and how this regulation relates to organellar function and trafficking. Finally we will identify the mitogen-dependent signaling pathway that controls SAC1 localization and we will examine how this process is related to growth stimulation of quiescent cells and to tumor cell growth. Characterization of the molecular mechanisms that integrate secretion and cell growth will lead to the identification of novel classes of drugs targets and eventually help preventing diseases stemming from abnormal cell proliferation. PUBLIC HEALTH RELEVANCE: Defects in phosphoinositide signaling cause human disease including cancer, diabetes and kidney disease. Characterization of the phosphoinositide-based regulation that integrates secretion and cell growth will facilitate identification of novel drug targets to prevent or cure such diseases.

描述（由申请人提供）：生长对于所有生物体的细胞增殖和分化至关重要，如果不调查，会导致广泛的严重人类疾病。细胞表面生长严格依赖于通过分泌途径将膜和蛋白质的协调递送到细胞周围。尽管这种现象已被认可了几十年，但尚不清楚如何根据生长信号传导调节生物合成途径。磷酸化的脂质最近与调节细胞生长特异性过程有关。根据我们的初步证据，我们提出了磷酸肌醇脂质在分泌生长调节中的核心作用。虽然确定磷酸肌醇对于细胞内膜流量至关重要，但尚未表征生物合成途径内脂质信号传导与细胞生长之间的联系。在此提案中，我们旨在展示SAC1脂质磷酸酶在细胞生长过程中分泌途径中的新颖而重要的作用。我们的初步研究表明，对生长条件的响应，内质网（ER）和高尔基体之间的人类SAC1穿梭，并调节这些细胞器的脂质信号传导。我们的目标是阐明SAC1的生长依赖性穿梭机理，并分析SAC1在分泌和细胞增殖中的作用。我们将以三个不同的目的调查这些问题。具体而言，我们将表征ER和高尔基体之间SAC1易位的生长调节机制。我们将分析SAC1如何调节ER和高尔基体的磷酸肌醇，以及该调节与细胞器功能和运输的关系。最后，我们将确定控制SAC1定位的有丝分裂原依赖性信号通路，并将研究该过程与静态细胞的生长刺激和肿瘤细胞生长有关。整合分泌和细胞生长的分子机制的表征将导致鉴定新的药物靶标，并最终有助于预防因异常细胞增殖而导致的疾病。公共卫生相关性：磷酸肌醇信号传导的缺陷会导致人类疾病，包括癌症，糖尿病和肾脏疾病。基于磷酸肌醇的调节的表征，将分泌和细胞生长整合的调节表征将促进鉴定新的药物靶标，以预防或治愈此类疾病。