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(申请人提供)：磷脂酰肌醇4-激酶(PI4Ks)催化PI的D-4羟基的磷酸化生成PI(4)P。PI(4)P本身是高尔基体萌发和鞘磷脂代谢的重要调节者，此外它还作为合成PI(4，5)P2和PI(3，4，5)P3l的前体，这两种脂控制着广泛的细胞过程，包括细胞骨架组装、膜运输、离子通道开放和细胞信号的许多方面。有两类PI4K，类型II和类型III，它们在序列上基本上是无关的，具有不同的催化性质。II型激酶(PI4KM)是最近在本实验室克隆和表达的。在哺乳动物细胞中，它们以？然后呢？异构体。PI4Kll？几乎只作为一种完整的膜蛋白存在于细胞内细胞器中。相比之下，PI4Kll？在细胞质和膜之间均匀分布，并响应生长因子受体的激活而部分重新分布到质膜。我们的长期目标是确定II型PI4-激酶的功能和调节。在这个提案中，我们试图了解PI4Kll？的调节功能和机制，我们认为PI4Kll？主要参与质膜上的肌醇磷脂信号和皮质细胞骨架的调节。为此，我们将研究：1.PI4Kll是如何扰动的？活性影响细胞信号、黏附和胞内转运。为了探索果蝇中单一的PI4KII酶在这些环境中的功能，我们将使用RNAi和基因组突变产生的功能丧失模型。2.PI4Kll如何？以刺激依赖的方式移位到质膜，以及它是否被招募到膜亚结构域和信号复合体；3.PI4Kll是如何？作为一种动态的翻译后修饰，棕榈酰化是受调控的，以及与伴侣Hsp90的结合如何影响棕榈酰化。这项研究的结果将极大地促进我们对这一新的脂蛋白激酶家族的理解。