Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.

The PI3K/MTOR signalling network regulates a broad array of critical cellular processes, including cell growth, metabolism and autophagy. The mechanistic target of rapamycin (MTOR) kinase functions as a core catalytic subunit in two physically and functionally distinct complexes mTORC1 and mTORC2, w...

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Autores principales:	Milad Ghomlaghi, Guang Yang, Sung-Young Shin, David E James, Lan K Nguyen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/712302b6419c4aefa8ed03c345a6d2de
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spelling	oai:doaj.org-article:712302b6419c4aefa8ed03c345a6d2de2021-12-02T19:57:47ZDynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.1553-734X1553-735810.1371/journal.pcbi.1008513https://doaj.org/article/712302b6419c4aefa8ed03c345a6d2de2021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1008513https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358The PI3K/MTOR signalling network regulates a broad array of critical cellular processes, including cell growth, metabolism and autophagy. The mechanistic target of rapamycin (MTOR) kinase functions as a core catalytic subunit in two physically and functionally distinct complexes mTORC1 and mTORC2, which also share other common components including MLST8 (also known as GβL) and DEPTOR. Despite intensive research, how mTORC1 and 2 assembly and activity are coordinated, and how they are functionally linked remain to be fully characterized. This is due in part to the complex network wiring, featuring multiple feedback loops and intricate post-translational modifications. Here, we integrate predictive network modelling, in vitro experiments and -omics data analysis to elucidate the emergent dynamic behaviour of the PI3K/MTOR network. We construct new mechanistic models that encapsulate critical mechanistic details, including mTORC1/2 coordination by MLST8 (de)ubiquitination and the Akt-to-mTORC2 positive feedback loop. Model simulations validated by experimental studies revealed a previously unknown biphasic, threshold-gated dependence of mTORC1 activity on the key mTORC2 subunit SIN1, which is robust against cell-to-cell variation in protein expression. In addition, our integrative analysis demonstrates that ubiquitination of MLST8, which is reversed by OTUD7B, is regulated by IRS1/2. Our results further support the essential role of MLST8 in enabling both mTORC1 and 2's activity and suggest MLST8 as a viable therapeutic target in breast cancer. Overall, our study reports a new mechanistic model of PI3K/MTOR signalling incorporating MLST8-mediated mTORC1/2 formation and unveils a novel regulatory linkage between mTORC1 and mTORC2.Milad GhomlaghiGuang YangSung-Young ShinDavid E JamesLan K NguyenPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 9, p e1008513 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Milad Ghomlaghi Guang Yang Sung-Young Shin David E James Lan K Nguyen Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.
description	The PI3K/MTOR signalling network regulates a broad array of critical cellular processes, including cell growth, metabolism and autophagy. The mechanistic target of rapamycin (MTOR) kinase functions as a core catalytic subunit in two physically and functionally distinct complexes mTORC1 and mTORC2, which also share other common components including MLST8 (also known as GβL) and DEPTOR. Despite intensive research, how mTORC1 and 2 assembly and activity are coordinated, and how they are functionally linked remain to be fully characterized. This is due in part to the complex network wiring, featuring multiple feedback loops and intricate post-translational modifications. Here, we integrate predictive network modelling, in vitro experiments and -omics data analysis to elucidate the emergent dynamic behaviour of the PI3K/MTOR network. We construct new mechanistic models that encapsulate critical mechanistic details, including mTORC1/2 coordination by MLST8 (de)ubiquitination and the Akt-to-mTORC2 positive feedback loop. Model simulations validated by experimental studies revealed a previously unknown biphasic, threshold-gated dependence of mTORC1 activity on the key mTORC2 subunit SIN1, which is robust against cell-to-cell variation in protein expression. In addition, our integrative analysis demonstrates that ubiquitination of MLST8, which is reversed by OTUD7B, is regulated by IRS1/2. Our results further support the essential role of MLST8 in enabling both mTORC1 and 2's activity and suggest MLST8 as a viable therapeutic target in breast cancer. Overall, our study reports a new mechanistic model of PI3K/MTOR signalling incorporating MLST8-mediated mTORC1/2 formation and unveils a novel regulatory linkage between mTORC1 and mTORC2.
format	article
author	Milad Ghomlaghi Guang Yang Sung-Young Shin David E James Lan K Nguyen
author_facet	Milad Ghomlaghi Guang Yang Sung-Young Shin David E James Lan K Nguyen
author_sort	Milad Ghomlaghi
title	Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.
title_short	Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.
title_full	Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.
title_fullStr	Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.
title_full_unstemmed	Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.
title_sort	dynamic modelling of the pi3k/mtor signalling network uncovers biphasic dependence of mtorc1 activity on the mtorc2 subunit sin1.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/712302b6419c4aefa8ed03c345a6d2de
work_keys_str_mv	AT miladghomlaghi dynamicmodellingofthepi3kmtorsignallingnetworkuncoversbiphasicdependenceofmtorc1activityonthemtorc2subunitsin1 AT guangyang dynamicmodellingofthepi3kmtorsignallingnetworkuncoversbiphasicdependenceofmtorc1activityonthemtorc2subunitsin1 AT sungyoungshin dynamicmodellingofthepi3kmtorsignallingnetworkuncoversbiphasicdependenceofmtorc1activityonthemtorc2subunitsin1 AT davidejames dynamicmodellingofthepi3kmtorsignallingnetworkuncoversbiphasicdependenceofmtorc1activityonthemtorc2subunitsin1 AT lanknguyen dynamicmodellingofthepi3kmtorsignallingnetworkuncoversbiphasicdependenceofmtorc1activityonthemtorc2subunitsin1
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Dynamic modelling of the PI3K/MTOR signalling network uncovers biphasic dependence of mTORC1 activity on the mTORC2 subunit SIN1.

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