Article (Scientific journals)
Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
Posada, IMD; Lectez, B; Siddiqui, FA et al.
2017In Scientific Reports
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Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Posada, IMD
Lectez, B
Siddiqui, FA
Oetken-Lindholm, C
Sharma, M
Abankwa, Daniel  ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
External co-authors :
yes
Language :
English
Title :
Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
Publication date :
21 August 2017
Journal title :
Scientific Reports
ISSN :
2045-2322
Publisher :
Nature Publishing Group, London, United Kingdom
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 01 February 2018

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