Turku Centre for Biotechnology, Åbo Akademi University, Tykistökatu 6B, 20520, Turku, Finland.
Sci Rep. 2017 Aug 21;7(1):8944. doi: 10.1038/s41598-017-09387-8.
As a major growth factor transducer, Ras is an upstream activator of mTORC1, which further integrates nutrient and energy inputs. To ensure a contextual coupling of cell division via Ras/MAPK-signalling and growth via mTORC1-signalling, feedback loops from one pathway back to the other are required. Here we describe a novel feedback from mTORC1, which oppositely affects oncogenic H-ras- and K-ras-signalling output, and as a consequence stemness properties of tumourigenic cells. Amino acid stimulation of mTORC1 increases the processed form of SREBP1, a major lipidome regulator. We show that modulation of the SREBP1 levels downstream of S6K1 has opposite effects on oncogenic H-ras and K-ras nanoscale membrane organisation, ensuing signalling output and promotion of mammospheres expressing these oncogenes. Our data suggest that modulation of phosphatidic acid, a major target of SREBP1 controlled lipid metabolism, is sufficient to affect H-ras and K-ras oppositely in the membrane. Thus mTORC1 activation increases H-ras-, but decreases K-ras-signalling output in cells transformed with the respective oncogene. Given the different impact of these two Ras isoforms on stemness, our results could have implications for stem cell biology and inhibition of cancer stem cells.
作为一种主要的生长因子转导蛋白，Ras 是 mTORC1 的上游激活剂，它进一步整合了营养和能量的输入。为了确保 Ras/MAPK 信号通路通过细胞分裂与 mTORC1 信号通路通过生长的上下文耦合，需要从一条通路反馈回另一条通路的反馈回路。在这里，我们描述了一种来自 mTORC1 的新型反馈，它对致癌的 H-ras 和 K-ras 信号输出产生相反的影响，从而影响肿瘤发生细胞的干性特性。mTORC1 对氨基酸的刺激增加了 SREBP1 的加工形式，SREBP1 是主要的脂质组调节剂。我们表明，S6K1 下游的 SREBP1 水平的调节对致癌的 H-ras 和 K-ras 纳米级膜组织具有相反的影响，从而影响信号输出并促进表达这些致癌基因的乳球体。我们的数据表明，磷酸脂酸的调节，SREBP1 控制的脂质代谢的主要靶标，足以在膜中对 H-ras 和 K-ras 产生相反的影响。因此，mTORC1 的激活增加了转化为相应致癌基因的细胞中的 H-ras-，但降低了 K-ras 信号输出。鉴于这两种 Ras 同工型对干性的不同影响，我们的结果可能对干细胞生物学和抑制癌症干细胞具有重要意义。
