ROLE AND REGULATION OF PROTEIN KINASE C ISOENZYMES

描述：蛋白激酶C（PKC）是一个蛋白激酶超家族 由三个主要亚家族组成：由二酰基甘油（DAG）激活的cPKCs 和钙、DAG激活的nPKC和未知激活剂的aPKC。 这个同工酶家族在信号转导中起着关键作用 和细胞调节。事实上，PKC充当了 脂质信号，尽管大量的注意力已经集中在 磷脂酰肌醇衍生的DAG和钙作为关键的调节剂， cPKCs。我们的实验室对PKC的调节有着长期的兴趣 由脂质第二信使，研究人员推断， 通过特异性脂质鉴定特异性同工酶的调节意味着 存在特定的脂质介导的信号通路，导致PKC activation.初步研究表明：（1）nPKCs可能被 由磷脂酶D（PLD）和鞘磷脂作用产生的DAG 合成酶（SMS）途径; 2）cPKC是特异性 通过神经酰胺的失活/抑制;和3）aPKC特异性地 由D-β-鞘氨醇（但不是其非天然异构体）激活。这些 结果使研究者假设：PKC同工酶接受 来自多种脂质的输入，由不同的机制产生。因此，PKC 同工酶作为一系列脂质代谢的分子转换器， 细胞调节的途径。这一假设将通过以下方式进行研究： 具体目的如下：1）明确磷脂酶D（PLD）的作用 和鞘磷脂合酶（SMS）对PKC同工酶的细胞调节; 2） 以确定神经酰胺在失活PKC中的机制和作用;和3） 确定鞘氨醇激活PKC λ的作用和机制。 这些研究开始定义新的信号通路， 不同的PKC亚家族，对于理解 肿瘤促进、细胞凋亡及其他由PKC调控的重要事件。

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.