Lucas L, del Peso L, Rodríguez P, Penalva V, Lacal J C
Instituto de Investigaciones Biomédicas, CSIC, Madrid, Spain.
Oncogene. 2000 Jan 20;19(3):431-7. doi: 10.1038/sj.onc.1203323.
Lipid-derived metabolites play an important role in the regulation of cell responses to external stimuli, including cell growth control, transformation and apoptosis. Phospholipase D (PLD) is one of the critical elements in the regulation of lipid metabolism and the generation of second messengers, some of them involved in cell growth control. Oncogenic Ras proteins affect the activity of PLD by two alternate mechanisms, involving a positive activation and a feedback negative loop. Here we investigate the involvement of the proto-oncogenic Ras protein in the physiological activation of PLD induced by platelet-derived growth factor (PDGF). Over-expression of the wild type Ras protein or some of its regulatory components, such as Shc or Grb2, induces an amplification of PLD activation by PDGF challenge. Furthermore, blocking the endogenous Ras by expression of the dominant negative mutant, H-Ras-Asn17 completely eliminated the activation of PLD by PDGF. Thus, PDGF requires a complex system for PLD regulation implying the existence of at least two positive regulatory pathways, a Ras-dependent and a PKC-dependent mechanism. These results imply that PLD is an important element in signaling by Ras proteins that is altered after ras-induced transformation.
脂质衍生的代谢产物在调节细胞对外界刺激的反应中起重要作用，包括细胞生长控制、转化和凋亡。磷脂酶D（PLD）是脂质代谢调节和第二信使生成中的关键要素之一，其中一些第二信使参与细胞生长控制。致癌性Ras蛋白通过两种不同机制影响PLD的活性，涉及正向激活和反馈负向回路。在此，我们研究原癌基因Ras蛋白在血小板衍生生长因子（PDGF）诱导的PLD生理激活中的作用。野生型Ras蛋白或其一些调节成分（如Shc或Grb2）的过表达会导致PDGF刺激下PLD激活的放大。此外，通过表达显性负性突变体H-Ras-Asn17阻断内源性Ras可完全消除PDGF对PLD的激活。因此，PDGF需要一个复杂的系统来调节PLD，这意味着至少存在两条正向调节途径，即Ras依赖性和PKC依赖性机制。这些结果表明，PLD是Ras蛋白信号传导中的一个重要元件，在ras诱导的转化后会发生改变。
