RT Journal Article
SR Electronic
T1 Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 633891
DO 10.1101/633891
A1 Mohammadreza Dorvash
A1 Mohammad Farahmandnia
A1 Pouria Mosaddeghi
A1 Mitra Farahmandnejad
A1 Hosein Saber
A1 Mohammadhossein Khorraminejad-Shirazi
A1 Amir Azadi
A1 Iman Tavassoly
YR 2019
UL http://biorxiv.org/content/early/2019/05/10/633891.abstract
AB Signal integration in the mTOR pathway plays a vital role in cell fate decision making in cancer cells. As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent inhibitory effects on mTORC1 and mTORC2, the two main complexes of mTOR. Two explanations were previously provided for this phenomenon: 1-Rapamycin does not inhibit mTORC2 directly, whereas it prevents mTORC2 formation by sequestering free mTOR protein. 2-Components like Phosphatidic Acid further stabilize mTORC2 compared with mTORC1. To understand the mechanism by which rapamycin differentially inhibits the mTOR complexes, we present a mathematical model of rapamycin mode of action based on the first explanation, i.e., Le Chatelier’s principle. Translating the interactions among components of mTORC1 and mTORC2 into a mathematical model revealed the dynamics of rapamycin action in different doses and time-intervals of rapamycin treatment. The model shows that rapamycin has stronger effects on mTORC1 compared with mTORC2, simply due to its direct interaction with free mTOR and mTORC1, but not mTORC2, without the need to consider other components that might further stabilize mTORC2. Based on our results, even when mTORC2 is less stable compared with mTORC1, it can be less inhibited by rapamycin.