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: 7631323
• 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/7631323
• 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

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羟基的磷酸化以产生PI（4）p。 PI（4）P本身是高尔基萌芽和鞘脂代谢的重要调节剂，除了它作为PI（4,5）P2和PI（3,4,5）PI（3,4,5）PI（3,4,5）PI（3,4,5）的前体外，两个脂质控制了细胞界的广泛阵列，包括细胞骨骼clill频道的广泛渠道和许多方面，许多方面都会繁殖，并在许多方面开放了许多方面。有两类的PI4K，II型和III类，它们本质上是无关的，并且具有不同的催化特性。最近在我们的实验室中克隆并表达了II型激酶（PI4kms）。在哺乳动物细胞中它们存在？和 ？同工型。 pi4kll？在细胞内细胞器中几乎完全是作为整体膜蛋白。相反，PI4KLL？均匀分布在细胞质和膜之间，并部分重新分布到质膜，以响应生长因子受体激活。我们的长期目标是定义II型PI 4系的功能和调节。在此提案中，我们试图了解PI4KLL调节的功能和机制，我们认为这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，我们将研究：1。pi4kll的扰动如何？活动会影响细胞信号传导，粘附和内吞运输。为了探索果蝇中单个PI4KII酶在这些情况下的功能，我们将使用RNAi和基因组突变产生的功能丧失模型。 2。如何PI4KLL？以刺激依赖性的方式易位到质膜，以及它是否被募集到膜亚域和信号复合物中。和3。如何PI4KLL？由棕榈酰化作为动态翻译后修饰的调节，以及与伴侣HSP90的结合如何影响棕榈酰化。这项研究的结果应大大提高我们对这种新型脂质激酶家族的理解。