Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells
Abstract
1. Introduction
2. Materials and Methods
2.1. ODE Model of The AMPK-Akt Network
- Total levels of each molecule are taken as a constant value of 100 arbitrary units (A.U.) and do not change throughout the simulation. However, the concentration of active and inactive molecular species can change.
- Only the active state of the molecule affects another molecule’s conversions between its active and inactive forms.
- Each molecule has its intrinsic activation and deactivation rate. The influence of interaction with other protein causing state changes is accounted by multiplying the corresponding rate term with a hill function.
2.2. Temporal Profiles and Steady State Estimation
2.3. Nullcline, Bifurcation and Phase Plane Analysis
2.4. Noise Induction
2.5. Clinical Data
2.6. Cell Line and Culture Condition, Fluorescence Activated Cell Sorting (FACS) Sorting and Analysis of The Plasticity
2.7. Markov Chain Modelling and Simulations
3. Results
3.1. AMPK-Akt Feedback Loop Can Give Rise To Two States: pAkthigh/ pAMPKlow and pAMPKhigh/pAktlo
3.2. The Two States (pAkthigh/ pAMPKlow and pAMPKhigh/pAktlow) Can Co-Exist and Stochastically Switch Between One Another
3.3. Experimental and Clinical Data Supports The Model Predictions of Bistability in AMPK-Akt Loop
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameter | Description | Value Range |
---|---|---|
totalAMPK | Total level of AMPK | 100 |
totalAKT | Total level of AKT | 100 |
totalPHLPP2 | Total level of PHLPP2 | 100 |
totalPP2Cα | Total level of PP2Cα | 100 |
kac_AMPK | Activation rate of AMPK | (0.02–0.2) |
kac_AKT | Activation rate of AKT | (0.02–0.2) |
kac_PHLPP2 | Activation rate of PHLPP2 | (0.02–0.2) |
kac_PP2Cα | Activation rate of PP2Cα | (0.02–0.2) |
kdac_AMPK | Deactivation rate of AMPK | (0.02–0.2) |
kdac_AKT | Deactivation rate of AKT | (0.02–0.2) |
kdac_PHLPP2 | Deactivation rate of PHLPP2 | (0.02–0.2) |
kdac_PP2Cα | Deactivation rate of PP2Cα | (0.02–0.2) |
λPP2cα | Effect of PP2Cα on AMPK | (5–10) |
λPHLPP2 | Effect of PHLPP2 on AKT | (5–10) |
λAKT | Effect of AKT on PP2Cα | (5–10) |
λAMPK | Effect of AMPK on PHLPP2 | (5–10) |
nPP2Cα | Hill coefficient of PP2Cα for deactivation of AMPK | 4, 5, 6 |
nPHLPP2 | Hill coefficient of PHLPP2 for deactivation of AKT | 4, 5, 6 |
nAKT | Hill coefficient of AKT for activation of PP2Cα | 4, 5, 6 |
nAMPK | Hill coefficient of AMPK for activation of PHLPP2 | 4, 5, 6 |
PP2Cα0 | Threshold value of PP2Cα for deactivation of AMPK | (0.25–0.75) × totalPP2Cα |
PHLPP20 | Threshold value of PHKLPP2 for deactivation of AKT | (0.25–0.75) × totalPHLPP2 |
AMPK0 | Threshold value of AMPK for activation of PHLPP2 | (0.25–0.75) × totalAMPK |
AKT0 | Threshold value of AKT for activation of PP2Cα | (0.25–0.75) × totalAKT |
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Chedere, A.; Hari, K.; Kumar, S.; Rangarajan, A.; Jolly, M.K. Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells. J. Clin. Med. 2021, 10, 472. https://doi.org/10.3390/jcm10030472
Chedere A, Hari K, Kumar S, Rangarajan A, Jolly MK. Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells. Journal of Clinical Medicine. 2021; 10(3):472. https://doi.org/10.3390/jcm10030472
Chicago/Turabian StyleChedere, Adithya, Kishore Hari, Saurav Kumar, Annapoorni Rangarajan, and Mohit Kumar Jolly. 2021. "Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells" Journal of Clinical Medicine 10, no. 3: 472. https://doi.org/10.3390/jcm10030472
APA StyleChedere, A., Hari, K., Kumar, S., Rangarajan, A., & Jolly, M. K. (2021). Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells. Journal of Clinical Medicine, 10(3), 472. https://doi.org/10.3390/jcm10030472