Abstract
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.
Highlights
The PI3K/mechanistic target of rapamycin (MTOR) signalling network plays an important role in the regulation of cell signal transduction and regulates a variety of key biological processes such as cell growth, metabolism and autophagy [1]
In contrary to commonly-held views that MTOR complex 2 (mTORC2) lies upstream and is a positive regulator of MTOR complex 1 (mTORC1), we found that their relationship is highly non-linear and dose dependent
This finding has major implications for anti-mTORC2 therapy as depending on the cellular contexts, inhibiting mTORC2 may either reduce or enhance mTORC1 activation, the latter could inadvertently dampen the effect of mTORC2 blockade
Summary
The PI3K/MTOR signalling network plays an important role in the regulation of cell signal transduction and regulates a variety of key biological processes such as cell growth, metabolism and autophagy [1]. The mechanistic target of rapamycin (MTOR) is a Ser/Thr kinase that lies at the center of this complex network, where it serves as an indispensable catalytic subunit for two functionally distinct complexes termed MTOR complex 1 (mTORC1) and MTOR complex 2 (mTORC2). Reflecting its importance in physiological regulation, the PI3K/MTOR network is frequently disrupted in human diseases, including cancer, metabolic and neurodegenerative disorders [2]. More than 40 inhibitors directed at various components of the network have been developed or are under active development [5]. Given the clinical relevance of PI3K/MTOR signalling, it is important to understand the interconnectivities within this network and emergent network behaviors
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