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

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...

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Autores principales:	Itziar M. D. Posada, Benoit Lectez, Farid A. Siddiqui, Christina Oetken-Lindholm, Mukund Sharma, Daniel Abankwa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/37bdb60d533147c484ba87879ea57fcb
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spelling	oai:doaj.org-article:37bdb60d533147c484ba87879ea57fcb2021-12-02T11:52:25ZOpposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP110.1038/s41598-017-09387-82045-2322https://doaj.org/article/37bdb60d533147c484ba87879ea57fcb2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09387-8https://doaj.org/toc/2045-2322Abstract 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.Itziar M. D. PosadaBenoit LectezFarid A. SiddiquiChristina Oetken-LindholmMukund SharmaDaniel AbankwaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Itziar M. D. Posada Benoit Lectez Farid A. Siddiqui Christina Oetken-Lindholm Mukund Sharma Daniel Abankwa Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
description	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.
format	article
author	Itziar M. D. Posada Benoit Lectez Farid A. Siddiqui Christina Oetken-Lindholm Mukund Sharma Daniel Abankwa
author_facet	Itziar M. D. Posada Benoit Lectez Farid A. Siddiqui Christina Oetken-Lindholm Mukund Sharma Daniel Abankwa
author_sort	Itziar M. D. Posada
title	Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
title_short	Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
title_full	Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
title_fullStr	Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
title_full_unstemmed	Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
title_sort	opposite feedback from mtorc1 to h-ras and k-ras4b downstream of srebp1
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/37bdb60d533147c484ba87879ea57fcb
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Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1

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