Peña L A, Fuks Z, Kolesnick R
Laboratory of Signal Transduction, Memorial Sioan-Kettering Cancer Center, New York, NY 19921, USA.
Biochem Pharmacol. 1997 Mar 7;53(5):615-21. doi: 10.1016/s0006-2952(96)00834-9.
The sphingomyelin pathway is a ubiquitous, evolutionarily conserved signaling system initiated by hydrolysis of the plasma membrane phospholipid sphingomyelin to generate the second messenger ceramide. Sphingomyelin degradation is catalyzed by acid and neutral sphingomyelinase (SMase) isoforms. Most, if not all mammalian cells, appear capable of signaling though the sphingomyelin pathway. Diverse receptor types and environmental stresses utilize the sphingomyelin pathway as a downstream effector system. In some cellular systems, ceramide initiates differentiation or cell proliferation, while in other systems, ceramide signals apoptosis. Recent investigations link the activation of neutral SMase to the extracellular signal regulated kinase (ERK) cascade and pro-inflammatory responses, and acid SMase to the stress-activated protein kinase/c-jun kinase (SAPK/JNK) cascade and apoptotic responses. Environmental stresses act directly on membrane to activate acid pH-dependent sphingomyelinase (ASMase), whereas cytokine receptors signal ASMase activation through motifs termed death domains. The present review focuses on mechanisms of activation of ASMase and on ceramide signaling of the apoptotic response.
鞘磷脂途径是一种普遍存在的、进化上保守的信号系统，由质膜磷脂鞘磷脂水解引发，生成第二信使神经酰胺。鞘磷脂的降解由酸性和中性鞘磷脂酶（SMase）同工型催化。大多数（如果不是所有）哺乳动物细胞似乎都能够通过鞘磷脂途径进行信号传导。多种受体类型和环境应激利用鞘磷脂途径作为下游效应系统。在一些细胞系统中，神经酰胺启动分化或细胞增殖，而在其他系统中，神经酰胺则发出凋亡信号。最近的研究将中性SMase的激活与细胞外信号调节激酶（ERK）级联反应和促炎反应联系起来，将酸性SMase与应激激活蛋白激酶/c-jun激酶（SAPK/JNK）级联反应和凋亡反应联系起来。环境应激直接作用于细胞膜以激活酸性pH依赖性鞘磷脂酶（ASMase），而细胞因子受体则通过称为死亡结构域的基序发出ASMase激活信号。本综述重点关注ASMase的激活机制以及凋亡反应的神经酰胺信号传导。
