Understanding the mTOR signaling pathway via mathematical modeling

Abstract

The mechanistic target of rapamycin (mTOR) is a central regulatory pathway that integrates a variety of environmental cues to control cellular growth and homeostasis by intricate molecular feedbacks. In spite of extensive knowledge about its components, the molecular understanding of how these function together in space and time remains poor and there is a need for Systems Biology approaches to perform systematic analyses. In this work, we review the recent progress how the combined efforts of mathematical models and quantitative experiments shed new light on our understanding of the mTOR signaling pathway. In particular, we discuss the modeling concepts applied in mTOR signaling, the role of multiple feedbacks and the crosstalk mechanisms of mTOR with other signaling pathways. We also discuss the contribution of principles from information and network theory that have been successfully applied in dissecting design principles of the mTOR signaling network. We finally propose to classify the mTOR models in terms of the time scale and network complexity, and outline the importance of the classification toward the development of highly comprehensive and predictive models. WIREs Syst Biol Med 2017, 9:e1379. doi: 10.1002/wsbm.1379For further resources related to this article, please visit the WIREs website.

Immunomodulatory role of branched-chain amino acids

“…An important role in maintenance of immune function was attributed to these amino acids, given that leucine is an activator of the mammalian target of rapamycin (mTOR) signaling pathway, 10 that regulates several biological processes, such as autophagy, ribosome biogenesis, cell growth and proliferation, by monitoring the availability of nutrients, mitogenic signals, energy status, oxygen levels and growth factors. [11][12][13][14] cysteine-preferring transporter (ASCT2), 23 belonging to the SLC1 family (SLC1A5), and then is transported out of the cells by LAT1, that uses intracellular glutamine as an efflux substrate to regulate the uptake of extracellular leucine into the cells. 24 Studies show that leucine increases gene expression of ACST2 and the cationic amino 72 acid transporter 1 (CAT1), as well as other proteins involved in BCAA transport, such as 4F2hc and rBAT of the heteromeric amino acid transporters (HAT), emphasizing the importance of leucine in the regulation of transport of other neutral and cationic amino acids.…”

Investigation of Novel Regulation of N-myristoyltransferase by Mammalian Target of Rapamycin in Breast Cancer Cells

“…We treated ER positive breast cancer cells with rapamycin and determined the effect of mTOR inhibition on NMT1 in a time dependent manner. Signaling pathways involving mTOR have not been extensively studied mathematically or computationally 32 – 35 . Most models of mTOR pathway computationally investigate the signaling upstream of mTOR, in particular, the relationship between insulin signaling and mTOR.…”

Cracking the context-specific PI3K signaling code

“…In the same year, Sedaghat et al (44) published the first computational model of metabolic insulin signaling, demonstrating how mathematical approaches can be used to capture pathway complexity and how they can serve as hypothesis-generating tools for known and unknown signaling mechanisms. Subsequently, several other dynamic models of PI3K signaling, with a particular focus on AKT and mTOR regulation, have emerged, differing with respect to time scale and network complexity [for a review of mTOR models, see (45)]. There is also an increasing appreciation that temporal and spatial regulation must be considered jointly (46), especially when it comes to understanding the exact dynamics and thresholds of pathway activation that are required to control metabolic versus mitogenic outputs (47).…”