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Spatial Regulation of RGS and G Protein Signaling

RGS 和 G 蛋白信号传导的空间调控

基本信息

批准号：
8817041
负责人：
MARILYN Gist FARQUHAR
金额：
$ 43.36万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-17 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8817041
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Affect Affinity Autophagocytosis Binding Binding Proteins Biogenesis Biological Assay CDK5 gene Cell Proliferation Cell membrane Cell physiology Cells Clathrin-Coated Vesicles Co-Immunoprecipitations Coat Protein Complex I Cytoplasm Data Development Disease Dissociation Dominant-Negative Mutation EGF gene Early Endosome Electron Microscopy Endocytic Vesicle Endocytosis Endoplasmic Reticulum Endosomes Epidermal Growth Factor Receptor Equilibrium Fluorescence Resonance Energy Transfer Funding G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors GTP-Binding Protein Regulators GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins GTPase-Activating Proteins Goals Golgi Apparatus Grant Green Fluorescent Proteins Growth Growth Factor Growth Factor Receptors Guanine Guanine Nucleotide Dissociation Inhibitors Guanine Nucleotide Exchange Factors Guanosine Triphosphate Hand Heterotrimeric GTP-Binding Proteins Immunofluorescence Immunologic Immunoprecipitation In Situ Intracellular Membranes Ligation Light Link Malignant Neoplasms Mass Spectrum Analysis Mediating Membrane Mitosis Modeling Molecular Monomeric GTP-Binding Proteins Neoplasm Metastasis Normal Cell Pathway interactions Phosphorylation Phosphotransferases Physiological Positioning Attribute Proliferating Property Protein Binding Protein C Proteins RGS Proteins RGS19 gene Receptor Protein-Tyrosine Kinases Recycling Regulation Relative (related person)Role Signal Pathway Signal Transduction Site Small Interfering RNA Testing Transducers Transport Vesicles Vesicle Vesicle Transport Pathway Work anticancer research antitumor agent base cell behavior cell motility genetic regulatory protein inhibitor/antagonist insight migration mutant new therapeutic target novel protein complex protein function public health relevance receptor downregulation research study response secretory protein tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Under this grant we have discovered a number of G protein binding proteins, established their properties and revealed new roles for heterotrimeric G proteins in cells. During the current funding period we characterized GIV, a non-receptor GEF that activates G�proteins. GIV serves as a multimodular signal transducer that assembles protein complexes and links G�ubunits to other signaling pathways (growth factor and PI3K/Akt signaling) and to several important cell functions, including cell migration, autophagy, transport of secretory proteins, and endocytosis of growth factor receptors. GIV also binds G� promotes EGF receptor downregulation, and shuts down proliferative signaling from endosomes. The overall goal of the work proposed is to take advantage of the tools and insights we have developed to shed light on some well-known but poorly understood functions of G proteins especially on intracellular membranes. We will focus on two specific aims: Specific Aim #1: To pinpoint the mechanisms by which GIV and its interactions with G�and G�regulate EGFR trafficking and growth factor signaling. Our working model based on preliminary data is that GIV sequentially binds G� and G�after EGF stimulation and that phosphomodification of GIV regulates the relative binding to the two G proteins and determines whether cells migrate or proliferate. Specific Aim #2: To determine the role of G� and GIV in Golgi functions and to define the mechanisms involved. Our data indicate that depletion of GIV or a GIV mutant that fails to activate G� slows transport of newly synthesized proteins through the Golgi. Our working hypothesis based on preliminary data is that GIV does so by activating G�, down-regulating Arf1 activity, and facilitating vesicle uncoating. These studies can be expected to provide novel insights into how GIV binds and regulates two different G proteins and influences growth factor signaling, Golgi functions, cell migration and cell proliferation. Based on its crucil functions in regulating cell behavior, it is essential to define GIV's functions and interactions. Our studies will not only provide insights into fundamental roles of G proteins in cell functions, but also it may establish new paradigms that will help to identify new therapeutic targets for development of pharmacologic and anti-tumor agents. We are uniquely positioned to tackle these problems by taking advantage of the new tools, expertise, and information we have in hand.

描述（由申请人提供）：在这项资助下，我们发现了许多 G 蛋白结合蛋白，确定了它们的特性并揭示了异源三聚体 G 蛋白在细胞中的新作用。在当前资助期间，我们对 GIV 进行了表征，它是一种激活 G�蛋白的非受体 GEF。 GIV 作为多模块信号转导器，可组装蛋白质复合物并将 Gubunits 与其他信号传导途径（生长因子和 PI3K/Akt 信号传导）以及多种重要的细胞功能连接起来，包括细胞迁移、自噬、分泌蛋白的运输和生长因子受体的内吞作用。 GIV 还与 G� 结合，促进 EGF 受体下调，并关闭内体的增殖信号传导。这项工作的总体目标是利用我们开发的工具和见解来阐明 G 蛋白的一些众所周知但知之甚少的功能，尤其是在细胞内膜上的功能。我们将重点关注两个具体目标：具体目标#1：查明 GIV 及其与 G�和 G�的相互作用调节 EGFR 运输和生长因子信号传导的机制。我们基于初步数据的工作模型是，GIV 在 EGF 刺激后依次结合 G� 和 G�，并且 GIV 的磷酸化调节与两种 G 蛋白的相对结合，并决定细胞是否迁移或增殖。具体目标#2：确定 G� 和 GIV 在高尔基体功能中的作用并定义所涉及的机制。我们的数据表明，GIV 的耗尽或无法激活 G� 的 GIV 突变体会减慢新合成蛋白质通过高尔基体的运输。我们基于初步数据的工作假设是，GIV 通过激活 G�、下调 Arf1 活性和促进囊泡脱壳来实现这一点。这些研究有望为 GIV 如何结合和调节两种不同的 G 蛋白以及如何影响生长因子信号传导、高尔基体功能、细胞迁移和细胞增殖提供新的见解。基于其在调节细胞行为中的关键功能，有必要定义 GIV 的功能和相互作用。我们的研究不仅将深入了解 G 蛋白在细胞功能中的基本作用，而且可能建立新的范式，有助于确定药理学和抗肿瘤药物开发的新治疗靶点。我们拥有独特的优势，可以利用我们现有的新工具、专业知识和信息来解决这些问题。