Song Chunhua, Satoh Takaya, Edamatsu Hironori, Wu Dongmei, Tadano Makoto, Gao Xianlong, Kataoka Tohru
Division of Molecular Biology, Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Oncogene. 2002 Nov 21;21(53):8105-13. doi: 10.1038/sj.onc.1206003.
Phospholipase C epsilon is a phosphoinositide-specific phospholipase C that selectively associates with Ras and Rap small GTPases as a target. Here we explored the molecular basis of the Rap1- as well as Ras-mediated regulation of phospholipase C epsilon upon platelet-derived growth factor stimulation by using a receptor mutant deficient in its ability to phosphorylate and activate phospholipase C gamma. Following platelet-derived growth factor treatment, this receptor induces persistent activation of ectopically expressed PLC epsilon through activation of Ras and Rap1. The rapid and initial phase of the activation is mediated by Ras, whereas Rap1 is responsible for the prolonged activation. We further demonstrate that the CDC25 homology domain, which exhibits guanine nucleotide exchange factor activity toward Rap1, but not Ras, is critical for the prolonged activation of phospholipase C epsilon. Platelet-derived growth factor prevented the hematopoietic BaF3 cells containing the mutant receptor from undergoing apoptosis, and enabled these cells to proliferate, only when phospholipase C epsilon was expressed. Therefore, the phospholipase C signal is suggested to be critical for survival and growth of BaF3 cells.
磷脂酶Cε是一种磷酸肌醇特异性磷脂酶C，它作为靶点与Ras和Rap小GTP酶选择性结合。在这里，我们通过使用一种缺乏磷酸化和激活磷脂酶Cγ能力的受体突变体，探索了血小板衍生生长因子刺激后Rap1以及Ras介导的磷脂酶Cε调节的分子基础。在血小板衍生生长因子处理后，该受体通过激活Ras和Rap1诱导异位表达的PLCε持续激活。激活的快速初始阶段由Ras介导，而Rap1负责延长激活。我们进一步证明，对Rap1而非Ras表现出鸟嘌呤核苷酸交换因子活性的CDC25同源结构域，对于磷脂酶Cε的延长激活至关重要。血小板衍生生长因子仅在表达磷脂酶Cε时，才阻止含有突变受体的造血BaF3细胞凋亡，并使这些细胞增殖。因此，磷脂酶C信号被认为对BaF3细胞的存活和生长至关重要。
