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Abstract
The mechanistic Target of Rapamycin (mTOR) signalling network is an evolutionarily conserved network that controls key cellular processes, including cell growth and metabolism. Consisting of the major kinase complexes mTOR Complex 1 and 2 (mTORC1/2), the mTOR network harbours complex interactions and feedback loops. The DEP domain-containing mTOR-interacting protein (DEPTOR) was recently identified as an endogenous inhibitor of both mTORC1 and 2 through direct interactions, and is in turn degraded by mTORC1/2, adding an extra layer of complexity to the mTOR network. Yet, the dynamic properties of the DEPTOR-mTOR network and the roles of DEPTOR in coordinating mTORC1/2 activation dynamics have not been characterised. Using computational modelling, systems analysis and dynamic simulations we show that DEPTOR confers remarkably rich and complex dynamic behaviours to mTOR signalling, including abrupt, bistable switches, oscillations and co-existing bistable/oscillatory responses. Transitions between these distinct modes of behaviour are enabled by modulating DEPTOR expression alone. We characterise the governing conditions for the observed dynamics by elucidating the network in its vast multi-dimensional parameter space, and develop strategies to identify core network design motifs underlying these dynamics. Our findings provide new systems-level insights into the complexity of mTOR signalling contributed by DEPTOR.
Highlights
MTOR belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family
To probe the range of possible dynamics exhibited by this system, we carried out large-scale simulations where model kinetic parameters were allowed to freely and simultaneously vary over their physiological ranges, revealing the system could display a variety of distinct complex behaviours that can be exploited by cells to modulate mTOR complex 1 (mTORC1)/2 activities and cellular responses, including bistable switches and sustained oscillations
BS regimes (BS1-3) that are characterised by co-existence of either two fixed-point stable steady states (BS1,3) or a fixed-point state and an oscillatory one (BS2). These analyses show that DEPTOR confers extremely complex dynamic behaviours to the mechanistic Target of Rapamycin (mTOR) network, and DEPTOR level critically controls the dynamics of mTOR complexes activation
Summary
MTOR belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family. It interacts with several proteins to form two physically and functionally distinct complexes named mTOR complex 1 (mTORC1) and 2 (mTORC2), both having kinase activity. mTORC1 and 2 share common subunit proteins (e.g. mLST8, Tti1/ Tel[2] complex, DEPTOR)[6] and possess their own components (e.g. Raptor, PRAS40 for mTORC1 and Rictor, mSin[1], protor1/2 for mTORC2). The sharing of DEPTOR by mTORC1 and mTORC2 suggests possible competition of these complexes for DEPTOR that may elicit functional consequences when DEPTOR level is limited How these feedback mechanisms, protein competition and various post-translational modifications (PTMs) interplay to regulate mTOR signalling, and how DEPTOR coordinates mTORC1/2 activation dynamics have not been characterized. Increased DEPTOR was thought to relieve the negative feedback from mTORC1 to IRS1 and activate the PI3K/Akt signalling axis, driving oncogenesis. These observations implies DEPTOR as a promising therapeutic target, they point to a possible dual role of DEPTOR in cancer cells that is likely context specific. Given the important role of mTOR signalling in cancer, our findings provide new insights that will facilitate the development of intervention strategies targeting this signalling network
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