Type II PI 4-Kinases in Cell Signaling

细胞信号转导中的 II 型 PI 4 激酶

基本信息

批准号：
7809458
负责人：
JOSEPH P ALBANESI
金额：
$ 29.53万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-11 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7809458
关键词：
1-Phosphatidylinositol 3-Kinase 1-Phosphatidylinositol 4-Kinase Adhesions Affect Anabolism Antibodies Binding Biochemical Biological Cell membrane Cell physiology Cells Cloning Complex Cytoskeleton Cytosol Drosophila genus Endocytosis Enzymes Family Genetic Genomics Goals Golgi Apparatus Growth Factor Receptors Hydroxyl Radical Integral Membrane Protein Ion Channel Laboratories Lipids Mammalian Cell Membrane Membrane Protein Traffic Metabolism Modeling Molecular Chaperones Molecular Cloning Mutation Organelles Participant Pathway interactions Phosphatidylinositols Phosphorylation Phosphotransferases Post-Translational Protein Processing Property Protein Isoforms RNA Interference Reagent Receptor Activation Recruitment Activity Regulation Role Signal Transduction Sphingolipids Stimulus Structure cell growth inhibitor/antagonist loss of function novel palmitoylation response trafficking

项目摘要

DESCRIPTION (provided by applicant): Phosphatidylinositol 4-kinases (PI4Ks) catalyze the phosphorylation of the D-4 hydroxyl of PI to yield PI(4)P. PI(4)P itself is an important regulator of Golgi budding and sphingolipid metabolism, in addition to its function as a precursor in the synthesis of PI(4,5)P2 and PI(3,4,5)P3l two lipids which control a vast array of cellular processes, including cytoskeletal assembly, membrane trafficking, ion channel opening, and many aspects of cell signaling. There are two classes of PI4K, Types II and III, which are essentially unrelated in sequence and have distinct catalytic properties. The Type II kinases (PI4KMs) were recently cloned and expressed in our laboratory. In mammalian cells they exist as ? and ? isoforms. PI4Kll? is found almost exclusively as an integral membrane protein in intracellular organelles. In contrast, PI4Kll? is distributed evenly between cytosol and membranes, and partially redistributes to the plasma membrane in response to growth factor receptor activation. Our long-term goal is to define the functions and regulation of the Type II PI 4-kinases. In this proposal we seek to understand the functions and mechanism of regulation of PI4Kll?, which we believe to be primarily involved in phosphoinositide signaling at the plasma membrane and in regulation of the cortical cytoskeleton. To this end we will examine: 1. How perturbation of PI4Kll? activity affects cell signaling, adhesion and endocytic trafficking. To explore the function of the single PI4KII enzyme in Drosophila in these contexts we will use loss-of-function models generated by RNAi and genomic mutations. 2. How PI4Kll? translocates to the plasma membrane in a stimulus-dependent manner, and whether it is recruited to membrane subdomains and signaling complexes; and 3. How PI4Kll? is regulated by palmitoylation as a dynamic post-translational modification, and how binding to the chaperone, Hsp90, influences palmitoylation. Results of this study should significantly advance our understanding of this novel family of lipid kinases.

描述（由申请人提供）：磷脂酰肌醇4-激酶（PI4Ks）催化PI的D-4羟基磷酸化产生PI(4)P。 PI(4)P本身是高尔基体出芽和鞘脂代谢的重要调节因子，此外它还作为控制PI(4,5)P2和PI(3,4,5)P3l两种脂质合成的前体。大量的细胞过程，包括细胞骨架组装、膜运输、离子通道开放以及细胞信号传导的许多方面。 PI4K 有两类：II 型和 III 型，它们在序列上基本上不相关，但具有不同的催化特性。 II 型激酶 (PI4KM) 最近在我们的实验室进行了克隆和表达。在哺乳动物细胞中，它们以？和？同工型。 PI4Kll？几乎完全作为细胞内细胞器中的整合膜蛋白被发现。相比之下，PI4Kll？均匀分布在细胞质和细胞膜之间，并响应生长因子受体激活而部分重新分布到质膜。我们的长期目标是确定 II 型 PI 4 激酶的功能和调节。在本提案中，我们试图了解 PI4Kll 的功能和调节机制，我们认为 PI4Kll 主要参与质膜上的磷酸肌醇信号传导和皮质细胞骨架的调节。为此我们将考察： 1.如何扰动PI4Kll？活性影响细胞信号传导、粘附和内吞运输。为了探索果蝇中单一 PI4KII 酶在这些情况下的功能，我们将使用由 RNAi 和基因组突变生成的功能丧失模型。 2.如何PI4Kll？以刺激依赖性方式易位到质膜，以及它是否被招募到膜子结构域和信号复合物； 3.如何PI4Kll？受棕榈酰化作为动态翻译后修饰的调节，以及与分子伴侣 Hsp90 的结合如何影响棕榈酰化。这项研究的结果将显着增进我们对这一新型脂质激酶家族的理解。