Wing Michele R, Bourdon David M, Harden T Kendall
Department of Pharmacology University of North Carolina School of Medicine Chapel Hill, NC 27599, USA.
Mol Interv. 2003 Aug;3(5):273-80. doi: 10.1124/mi.3.5.273.
The conceptual segregation of G protein-stimulated cell signaling responses into those mediated by heterotrimeric G proteins versus those promoted by small GTPases of the Ras superfamily is no longer vogue. PLC-epsilon, an isozyme of the phospholipase C (PLC) family, has been identified recently and dramatically extends our understanding of the crosstalk that occurs between heterotrimeric and small monomeric GTPases. Like the widely studied PLC-beta isozymes, PLC-epsilon is activated by Gbetagamma released upon activation of heterotrimeric G proteins. However, PLC-epsilon markedly differs from the PLC-beta isozymes in its capacity for activation by Galpha(12/13) - but not Galpha(q) -coupled receptors. PLC-epsilon contains two Ras-associating domains located near the C terminus, and H-Ras regulates PLC-epsilon as a downstream effector. Rho also activates PLC-epsilon, but in a mechanism independent of the C-terminal Ras-associating domains. Therefore, Ca(2+) mobilization and activation of protein kinase C are signaling responses associated with activation of both H-Ras and Rho. A guanine nucleotide exchange domain conserved in the N terminus of PLC-epsilon potentially confers a capacity for activators of this isozyme to cast signals into additional signaling pathways mediated by GTPases of the Ras superfamily. Thus, PLC-epsilon is a multifunctional nexus protein that senses and mediates crosstalk between heterotrimeric and small GTPase signaling pathways.
将G蛋白刺激的细胞信号转导反应概念性地分为由异源三聚体G蛋白介导的反应和由Ras超家族的小GTP酶促进的反应，这种分类方式已不再流行。磷脂酶C（PLC）家族的一种同工酶PLC-ε最近已被鉴定出来，它极大地扩展了我们对异源三聚体和小单体GTP酶之间发生的信号串扰的理解。与广泛研究的PLC-β同工酶一样，PLC-ε可被异源三聚体G蛋白激活时释放的Gβγ激活。然而，PLC-ε在被Gα(12/13)偶联受体激活的能力上与PLC-β同工酶明显不同，而不是被Gα(q)偶联受体激活。PLC-ε在靠近C末端处含有两个Ras结合结构域，H-Ras将PLC-ε作为下游效应器进行调节。Rho也能激活PLC-ε，但作用机制独立于C末端的Ras结合结构域。因此，Ca(2+)动员和蛋白激酶C的激活是与H-Ras和Rho激活相关的信号转导反应。PLC-ε N末端保守的鸟嘌呤核苷酸交换结构域可能赋予该同工酶的激活剂将信号传递到由Ras超家族的GTP酶介导的其他信号通路中的能力。因此，PLC-ε是一种多功能连接蛋白，可感知并介导异源三聚体和小GTP酶信号通路之间的信号串扰。
