Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1

Sci Rep. 2017 Aug 21;7(1):8944. doi: 10.1038/s41598-017-09387-8.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Feedback, Physiological*
  • HEK293 Cells
  • Humans
  • Lipid Metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Neoplastic Stem Cells / metabolism
  • Phosphatidic Acids / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / metabolism*

Substances

  • KRAS protein, human
  • Phosphatidic Acids
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Mechanistic Target of Rapamycin Complex 1
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)