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: 6536964
• 负责人: YUSUF AWNI HANNUN
• 金额: $ 32.18万
• 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/6536964
• 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) 是蛋白激酶超家族 由三个主要亚家族组成：二酰基甘油 (DAG) 激活的 cPKC 钙、DAG 激活的 nPKC 以及未知激活剂的 aPKC。 该同工酶家族在信号转导中发挥着关键作用 和细胞调节。事实上，PKC 是传感器的原型。 尽管大部分注意力都集中在脂质信号上 磷脂酰肌醇衍生的 DAG 和钙作为关键调节剂 cPKC。我们实验室长期以来对 PKC 的监管感兴趣 通过脂质第二信使，研究人员推断 鉴定特定脂质对特定同工酶的调节意味着 导致 PKC 的特定脂质介导信号通路的存在 激活。初步研究表明1）nPKCs可能被激活 由磷脂酶 D (PLD) 和鞘磷脂作用产生的 DAG 合成酶（SMS）途径； 2) cPKC 是特定的目标 神经酰胺失活/抑制； 3) aPKC 特别是 由 D-赤型鞘氨醇（但不是其非天然异构体）激活。这些 结果使研究者推测： PKC 同工酶接收 来自多种脂质的输入，通过不同的机制产生。因此，PKC 同工酶作为大量脂质代谢的分子传感器 细胞调控途径。该假设将通过追求 具体目标如下： 1) 明确磷脂酶 D (PLD) 的作用 和鞘磷脂合酶 (SMS) 对 PKC 同工酶细胞调节的作用； 2） 确定神经酰胺灭活 PKC 的机制和作用； 3) 至 确定鞘氨醇激活 PKC lambda 的作用和机制。 这些研究开始定义调节新的信号通路 PKC 的不同亚家族，对理解具有重要意义 PKC 调控的肿瘤促进、细胞凋亡和其他关键事件。