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Coordinate Regulation Of Nuclear DGK-theta and PLD

核 DGK-theta 和 PLD 的协调调控

基本信息

批准号：
7924942
负责人：
Daniel M. Raben
金额：
$ 13.53万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-24 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924942
关键词：
1,2-diacylglycerol 1-Phosphatidylinositol 3-Kinase Agonist Area Binding Cell Nucleus Cell membrane Cell surface Coupling Cytoplasm Data Diacylglycerol Kinase Diglycerides Elements Enzymes Event Fibroblasts GTP-Binding Proteins Generations Growth Heterotrimeric GTP-Binding Proteins Laboratories Lipids Mediating Metabolism Molecular Molecular Weight Nuclear Nuclear Protein Nuclear Proteins Nuclear Translocation Pathway interactions Phosphatidic Acid Phospholipase D Phosphotransferases Physiological Play Production Protein Kinase C Protein Kinase C Alpha Protein Subunits Publishing Receptor Activation Regulation Research Role Scheme Signal Transduction Signaling Molecule System Testing Thrombin Thrombin Receptor Time Tissues Wound Healing alpha-Thrombin in vivo insight interest lipid metabolism response rhoA GTP-Binding Protein

项目摘要

DESCRIPTION (provided by applicant): This proposal focuses on an emerging signal transduction paradigm which counters the prevailing view that the nucleus is a passive recipient of signals produced at the plasma membrane. Our laboratory and others have shown that receptor activation at the cell surface results in regulation of nuclear enzymes that produce and modify potent lipid signaling molecules. While this area has garnered increasing interest, we still understand neither the molecular aspects of the regulation nor the precise physiological roles of the induced lipid metabolism. The proposed studies aim at elucidating key elements of this signal transduction mechanism and its functional consequences. We find that the small molecular weight GTP-binding protein RhoA reciprocally regulates two signaling enzymes, diacylglycerol kinase-theta and phospholipase D, at the nucleus in response to alpha-thrombin stimulation of fibroblasts. We have termed this regulation the "RhoA Switch". We predict that the resulting modulation of diacylglycerol and phosphatidic acid levels and molecular composition have important physiological consequences such as the regulation of nuclear localization and activity of protein kinase C-alpha. Two heterotrimeric GTP-binding proteins, Gq and G13, and the lipid kinase PI 3-kinase mediate thrombin activation of this pathway. We hypothesize that; alpha-thrombin, after initiating an early Gq-dependent increase in nuclear diacylglycerol kinase-theta activity, stimulates a G13/PI 3-kinase-dependent nuclear translocation of RhoA that acts as a temporal "switch" to inhibit nuclear diacylglycerol kinase-theta while activating nuclear phospholipase D. We will test the hypothesis that Gq is essential for the induced increase in nuclear diacylglycerol kinase-theta activity, and identify the diacylglycerol-theta domains essential for its nuclear translocation in Aim I. Aim II will determine the molecular mechanism of the RhoA Switch by testing whether PI 3-kinase activation is responsible for nuclear RhoA translocation. Further, we will determine the molecular interactions between RhoA, diacylglycerol kinase-theta and phospholipase D. The physiological consequences of the RhoA Switch will be examined in Aim III. We will focus on the effect of the Switch on nuclear protein kinase C-alpha activity, composition of nuclear phosphatidic acids, and growth. We believe that an understanding of nuclear lipid signaling is key to our ability to intervene in events such as wound repair and tissue remodeling.

描述(由申请人提供)：这项建议侧重于一种新兴的信号转导范例，它与主流观点相反，即细胞核是质膜产生的信号的被动接受者。我们的实验室和其他实验室已经证明，细胞表面的受体激活会导致核酶的调节，这些核酶可以产生和修改有效的脂质信号分子。虽然这一领域已经引起了越来越多的兴趣，但我们仍然不知道这种调节的分子方面，也不知道诱导脂代谢的确切生理作用。拟议的研究旨在阐明这种信号转导机制的关键要素及其功能后果。我们发现，小分子GTP结合蛋白RhoA在α-凝血酶刺激成纤维细胞的反应中，在细胞核内相互调节两种信号酶--二酰甘油激酶-theta和磷脂酶D。我们将这一规定称为“RhoA开关”。我们预测，由此导致的二酰甘油和磷脂酸水平和分子组成的调节具有重要的生理后果，如调节核定位和蛋白激酶C-α的活性。两个异源三聚体GTP结合蛋白Gq和G13和脂质激酶PI3-Kinase介导了这一途径的凝血酶激活。我们假设；α-凝血酶，在启动早期GQ依赖的核二酰甘油激酶-theta活性增加后，刺激G13/PI 3-激酶依赖的RhoA核转位，作为一个临时“开关”，在激活核磷脂酶D的同时抑制核二酰甘油激酶-theta。我们将检验Gq是诱导核二酰甘油激酶-theta活性增加所必需的假说，并确定在Aim I中其核转位所必需的二酰甘油-theta结构域。此外，我们还将确定RhoA、二甘油激酶-theta和磷脂酶D之间的分子相互作用。RhoA开关的生理后果将在Aim III中进行检验。我们将重点研究该开关对核蛋白激酶C-α活性、核磷脂酸组成和生长的影响。我们认为，对核脂信号的理解是我们能够干预伤口修复和组织重塑等事件的关键。