...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Diacylglycerol kinase ι regulates Ras guanyl-releasing protein 3 and inhibits Rap1 signaling
【24h】

Diacylglycerol kinase ι regulates Ras guanyl-releasing protein 3 and inhibits Rap1 signaling

机译：二酰基甘油激酶1调节Ras鸟苷酸释放蛋白3并抑制Rap1信号传导

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

To study the physiological function of diacylglycerol (DAG) kinase ι (DGKι). which converts DAG to phosphatidic acid, we deleted this gene in mice. In contrast to previous studies showing that DGK isoforms decrease Ras activity, signaling downstream of Ras in embryonic fibroblasts was significantly reduced in cells lacking DGKi. DGKs regulate Ras signaling by attenuating the function of the DAG-dependent Ras guanyl nucleotide-releasing proteins (RasGRPs). We tested whether DGKι inhibited the four known RasGRPs and found that it inhibited only RasGRP3. In addition to activating Ras, RasGRP3 also activates Rap1, which in some cases can antagonize the function of Ras. We demonstrate that DGKι bound to RasGRP3 and inhibited its activation of Rap1 by metabolizing DAG. This inhibition consequently affected Ras signaling. We tested the physiological consequence of deleting DGKι by crossing wild-type or DGKι-deficient mice with mice carrying a v-Ha-Ras transgene, and then we assessed tumor formation. We observed significantly fewer tumors in DGKι-deficient mice. Because Rap1 can antagonize the function of Ras, our data are consistent with a model in which DGKι regulates RasGRP3 with a predominant effect on Rap1 activity. Additionally, we found that DGKζ, which is structurally similar to DGKι, inhibited RasGRPs 1, 3, and 4 and predominantly affected Ras signaling. Thus, type Ⅳ DGKs regulate RasGRPs, but the downstream effects differ depending on the DGK.
机译：研究二酰基甘油（DAG）激酶1（DGK1）的生理功能。将DAG转化为磷脂酸，我们在小鼠中删除了该基因。与先前的研究表明DGK亚型降低Ras活性相反，在缺乏DGKi的细胞中，胚胎成纤维细胞中Ras的下游信号显着降低。 DGK通过减弱DAG依赖性Ras鸟嘌呤核苷酸释放蛋白（RasGRP）的功能来调节Ras信号传导。我们测试了DGK1是否抑制四种已知的RasGRP，并且发现它仅抑制RasGRP3。除了激活Ras，RasGRP3还激活Rap1，在某些情况下可以拮抗Ras的功能。我们证明DGK1结合RasGRP3并通过代谢DAG抑制了Rap1的活化。因此，这种抑制影响了Ras信号传导。我们通过将野生型或缺乏DGK1的小鼠与携带v-Ha-Ras转基因的小鼠杂交来测试删除DGK1的生理学后果，然后我们评估了肿瘤的形成。我们在缺乏DGK1的小鼠中观察到明显更少的肿瘤。因为Rap1可以拮抗Ras的功能，所以我们的数据与其中DGK1调节RasGRP3并对Rap1活性起主要作用的模型一致。另外，我们发现结构上与DGK1相似的DGKζ抑制RasGRP 1、3和4，并且主要影响Ras信号传导。因此，Ⅳ型DGKs调节RasGRPs，但下游效应取决于DGK。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号