Type II PI 4-Kinases in Cell Signaling

细胞信号转导中的 II 型 PI 4 激酶

• 批准号: 7265713
• 负责人: JOSEPH P ALBANESI
• 金额: $ 29.83万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-11 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265713
• 关键词: 1-Phosphatidylinositol 3-Kinase; 1-Phosphatidylinositol 4-Kinase; Adhesions; Affect; Anabolism; Antibodies; Binding; Biochemical Genetics; Biological; Cell membrane; Cell physiology; Cells; Class; Cloning; Complex; Cytoskeleton; Cytosol; Drosophila genus; Endocytosis; Enzymes; Family; 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

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羟基磷酸化生成PI(4)P。PI(4)P本身是高尔基出芽和鞘脂代谢的重要调节剂，此外它还作为PI(4,5)P2和PI(3,4,5)P3l两种脂质的合成前体，这两种脂质的合成控制着大量的细胞过程，包括细胞骨架组装、膜运输、离子通道打开和细胞信号传导的许多方面。PI4K有两类，II型和III型，它们在序列上基本不相关，具有不同的催化性能。II型激酶（pi4km）最近在我们的实验室被克隆和表达。在哺乳动物细胞中，它们以？然后呢?亚型。PI4Kll吗?在胞内细胞器中几乎完全是一种完整的膜蛋白。相比之下，PI4Kll？在细胞质溶胶和细胞膜之间均匀分布，并在生长因子受体激活时部分重新分布到质膜。我们的长期目标是明确II型PI 4激酶的功能和调控。在本研究中，我们试图了解PI4Kll的功能和调控机制。我们认为它主要参与质膜上的磷酸肌苷信号传导和皮质细胞骨架的调节。为此，我们将研究：1。PI4Kll的摄动如何？活动影响细胞信号，粘附和内吞运输。为了在这些情况下探索果蝇中单个PI4KII酶的功能，我们将使用由RNAi和基因组突变产生的功能丧失模型。2. PI4Kll如何?以刺激依赖的方式易位到质膜，以及它是否被招募到膜亚域和信号复合体；和3。PI4Kll如何?作为一种动态的翻译后修饰，受棕榈酰化调节，以及与伴侣蛋白Hsp90的结合如何影响棕榈酰化。这项研究的结果将显著促进我们对这一新型脂质激酶家族的理解。