ROLE AND REGULATION OF PROTEIN KINASE C ISOENZYMES

蛋白激酶 C 同工酶的作用和调节

• 批准号: 6194438
• 负责人: YUSUF AWNI HANNUN
• 金额: $ 30.46万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6194438
• 关键词: biological signal transduction; confocal scanning microscopy; diacylglycerols; enzyme activity; enzyme inhibitors; enzyme mechanism; enzyme substrate; green fluorescent proteins; immunofluorescence technique; immunoprecipitation; isozymes; lipid biosynthesis; mutant; phospholipase D; phosphorylation; protein kinase C; protein structure function; sphingolipids; sphingomyelin phosphodiesterase; sphingosine; tissue /cell culture; western blottings

DESCRIPTION: Protein kinase C (PKC) is a superfamily of protein kinases composed of three major subfamilies: the cPKCs activated by diacylglcerol (DAG) and calcium, the nPKCs activated by DAG, and the aPKC, of unknown activators. This family of isoenzymes has assumed a critical role in signal transduction and cell regulation. Indeed, PKC serves as the prototype of transducers of lipid signals although the bulk of attention has been focused on phosphatidylinositol-derived DAG and calcium as the key regulators of the cPKCs. Our laboratory has had a longstanding interest in the regulation of PKC by lipid second messengers, and the investigator has reasoned that identification of regulation of specific isoenzymes by specific lipids implies the existence of specific lipid-mediated signaling pathways that lead to PKC activation. The preliminary studies show that 1) the nPKCs may be activated by DAG generated from the action of the phospholipase D (PLD) and sphingomyelin synthase (SMS) pathways; 2) the cPKCs are targets for specific inactivation/inhibition by ceramide; and 3) the aPKCs are specifically activated by D-erythro-sphingosine (but not its un-natural isomers). These results have led the investigator to hypothesize that: PKC isoenzymes receive inputs from multiple lipids, generated by different mechanisms. Therefore, PKC isoenzymes serve as molecular transducers of a vast array of lipid metabolic pathways in cell regulation. This hypothesis will be investigated by pursuing the following specific aims: 1) To define the roles of phospholipase D (PLD) and sphingomyelin synthase (SMS) on cellular regulation of PKC isoenzymes; 2) to determine the mechanism and role of ceramide in inactivating PKC; and 3) To determine the role and mechanism of activation of PKC lambda by sphingosine. These studies are beginning to define novel signaling pathways that regulate distinct sub-families of PKC, with important implications for the understanding of tumor promotion, apoptosis and the other critical events regulated by PKC.

描述：蛋白激酶C(PKC)是蛋白激酶的一个超家族 由三个主要的亚家族组成：二酰甘油(DAG)激活的cPKCs 钙、DAG激活的nPKCs和未知激活剂的aPKC。 这一同工酶家族在信号转导中起着至关重要的作用。 和细胞调节。事实上，pkc是传感器的原型。 尽管大部分的注意力都集中在血脂信号上 磷脂酰肌醇衍生的DAG和钙作为细胞周期的关键调节因子 Cpkcs。我们的实验室长期以来一直对PKC的调节感兴趣 通过脂质第二信使，调查员推断 识别特定脂类对特定同工酶的调节意味着 导致PKC的特定脂质介导的信号通路的存在 激活。初步研究表明：1)npkcs可被激活 磷脂酶D(PLD)和鞘磷脂作用产生的DAG 合成酶(Sms)途径；2)CPKC是特异性靶标 神经酰胺的失活/抑制；以及3)APKC是特异性的 被D-红血鞘氨醇(但不是它的非天然异构体)激活。这些 研究结果导致研究人员假设：PKC同工酶 来自多种脂质的输入，由不同的机制产生。因此，PKC 同工酶是一系列脂肪代谢的分子传导器。 细胞调节中的途径。这一假说将通过追查 具体目的如下：1)确定磷脂酶D(PLD)的作用 和鞘磷脂合成酶对细胞内PKC同工酶的调节；2) 确定神经酰胺灭活PKC的机制和作用；3) 确定鞘氨醇激活PKC lambda的作用和机制。 这些研究开始定义新的信号通路， PKC的不同亚家族，对理解具有重要意义 肿瘤促进、细胞凋亡和其他由PKC调控的关键事件。