Harden T Kendall, Sondek John
Departments of Pharmacology, Biochemistry and Biophysics, and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Annu Rev Pharmacol Toxicol. 2006;46:355-79. doi: 10.1146/annurev.pharmtox.46.120604.141223.
The physiological effects of many extracellular stimuli are mediated by receptor-promoted activation of phospholipase C (PLC) and consequential activation of inositol lipid-signaling pathways. These signaling responses include the classically described conversion of PtdIns(4,5)P(2) to the Ca(2+)-mobilizing second messenger Ins(1,4,5)P(3) and the protein kinase C-activating second messenger diacylglycerol as well as alterations in membrane association or activity of many proteins that harbor phosphoinositide binding domains. Here we discuss how the family of PLCs elaborates a minimal catalytic core typified by PLC-delta to confer multiple modes of regulation on their phospholipase activities. Although PLC-dependent signaling is prominently regulated by direct interactions with heterotrimeric G proteins or tyrosine kinases, the existence of at least 13 divergent PLC isozymes promises a diverse repertoire of regulatory mechanisms for this class of important signaling proteins. We focus here on the recently realized and extensive regulation of inositol lipid signaling by Ras superfamily GTPases directly acting on PLC isozymes and conclude by considering the biological and pharmacological ramifications of this regulation.
许多细胞外刺激的生理效应是由受体促进的磷脂酶C（PLC）激活以及随之而来的肌醇脂质信号通路激活介导的。这些信号反应包括经典描述的磷脂酰肌醇-4,5-二磷酸（PtdIns(4,5)P(2)）转化为可动员钙离子的第二信使肌醇-1,4,5-三磷酸（Ins(1,4,5)P(3)）和激活蛋白激酶C的第二信使二酰基甘油，以及许多含有磷酸肌醇结合结构域的蛋白质的膜结合或活性改变。在这里，我们讨论PLC家族如何精心构建以PLC-δ为代表的最小催化核心，以赋予其磷脂酶活性多种调节模式。虽然PLC依赖性信号传导主要通过与异源三聚体G蛋白或酪氨酸激酶的直接相互作用进行调节，但至少13种不同的PLC同工酶的存在为这类重要信号蛋白提供了多样的调节机制。我们在此重点关注Ras超家族GTP酶直接作用于PLC同工酶对肌醇脂质信号传导的最新认识和广泛调节，并通过考虑这种调节的生物学和药理学影响来得出结论。
