Hindawi

Journal of Applied Mathematics

Volume 2018, Article ID 2983138, 9 pages
https://doi.org/10.1155/2018/2983138

Research Article
A Dynamic Model of PI3K/AKT Pathways in
Acute Myeloid Leukemia

Yudi Ari Adi ,1,2 Fajar Adi-Kusumo ,2 Lina Aryati,2 and Mardiah S. Hardianti3
1
Department of Mathematics, Faculty of Mathematics and Natural Sciences, Ahmad Dahlan University, Yogyakarta 55166, Indonesia
2
Department of Mathematics, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
3
Department of Internal Medicine, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia

Correspondence should be addressed to Yudi Ari Adi; [email protected]

Received 28 June 2018; Revised 10 October 2018; Accepted 5 November 2018; Published 13 November 2018

Academic Editor: Oluwole D. Makinde

Copyright © 2018 Yudi Ari Adi et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Acute myeloid leukemia (AML) is a malignant hematopoietic disorder characterized by uncontrolled proliferation of immature
myeloid cells. In the AML cases, the phosphoinositide 3-kinases (PI3K)/AKT signaling pathways are frequently activated and
strongly contribute to proliferation and survival of these cells. In this paper, a mathematical model of the PI3K/AKT signaling
pathways in AML is constructed to study the dynamics of the proteins in these pathways. The model is a 5-dimensional system
of the first-order ODE which describes the interaction of the proteins in AML. The interactions between those components are
assumed to follow biochemical reactions, which are modelled by Hill’s equation. From the numerical simulations, there are three
potential components targets in PI3K/AKT pathways to therapy in the treatment of AML patient.

1. Introduction in a patient with AML are chemotherapy, irradiation, and

hematopoietic stem cell transplantation (HSCT) [1, 5, 7–10].
Acute myeloid leukemia (AML) is a hematological malig- The main objective of those treatments is inducing remission
nancy originating in the bone marrow. It is characterized and preventing the relapse [11]. In recent years, despite the
by the infiltration of the bone marrow, blood, and other tis- potential gain of HSCT, the posttransplantation outcome
sues by proliferative, abnormally differentiated, and sporadic remains dismal, especially those with high-risk category
poorly differentiated cells of the hematopoietic system [1, 2]. [10]. Currently, the development of the new therapies has
The AML is the most common malignancy of hematological been challenging to further improve the clinical outcome of
system, illustrated by the accumulation of acquired somatic AML, such as cytotoxic agent, small molecule inhibitor, and
genetic alterations in hematopoietic progenitor cells. This targeted therapies [12].
alteration modifies the normal mechanisms of cells prolifera- During the last decade, the PI3K/AKT signaling pathway
tion, self-renewal, and differentiation [3, 4]. Based on the vali- has been studied extensively in human diseases. This pathway
dated cytogenetics and molecular abnormalities, the National plays a significant role in a number of cellular functions,
Comprehensive Cancer Network (NCCN) classifies patients including differentiation, apoptosis, and cell cycle progres-
into three risk categories, which are better risk, intermediate sion [8]. Aberrant PI3K/AKT activation is reported in 50-
risk, and poor risk. Patients with the NPM1 mutation in the 80% of AML cases [6]. The PI3K/AKT/mTOR network is
absence of FLT3-ITD and CEPBA mutations are classified activated in AML cells through a variety of mechanisms
as favorable risk and patients with FLT3-ITD mutated CN- including upstream oncogenes such as FLT3-ITD, KIT,
AML and with P53 mutations are classified as poor risk [5]. NRAS, and KRAS or autocrine/paracrine growth factors
Untreated AML patient results in fatal infection, bleeding, or such as VEGF and IGF-1. It can also be activated by
organ infiltration within 1 year of diagnosis but often within altered expression of p110d or phosphorylation of PTEN
weeks to months [6]. The standard therapeutic strategies of pathway components and microenvironmental signals
2 Journal of Applied Mathematics

k0

PIP3

d1
b
a2
AKT AKTp
d3

d2

p
FOXO3a FOXO3ap

m d5

Figure 1: Simplified diagram of PI3K/AKT/FOXO3a pathway.

including chemokines and adhesion molecules [13, 14]. The of AML disease through targeted therapy. For the model,
AKT activation is associated with significantly elevated levels the Michaelis Menten kinetics and Hill’s equation in some
of phosphorylation FOXO3a in AML blast cells, supressing components of biochemical reactions are used.
its normal function in induction apoptosis and cell cycle
regulation [4, 15, 16]. Normally, FOXO3a transcriptionally 2. Model Development
activates several genes as the target. The FOXO3a binds to the
promoter of apoptosis-inducing genes, such as Bim, FasL, and The mathematical model is constructed by extending the
TRAIL, and to the promoter of cell cycle inhibitors, such as AKT phosphorylation model in [21]. The extended model
p27 and p21. The FOXO3a also activates the autophagy genes is defined by adding FOXO3a, which is a potential down-
Gabarapl1, ATG12, and so forth [7, 9]. Researchers show that stream pathway of AKT in the leukemic progression. Figure 1
phosphorylation of FOXO3a is an adverse prognostic factor shows the simplification of the complex network diagram of
in AML associated with increased proliferation and overall PI3K/AKT signaling pathways which drives the AML cells.
survival [9, 16]. Our model is focused on discussing the activities of five
In a study of mathematical modelling of cancer, the proteins in PI3K/AKT pathways that have been observed
dynamics of autologous immune system in chronic myeiloid to be significant players in AML cells. We assume that the
leukemia have been constructed by Clapp et al. [17]. For interactions of the protein follow the Michaelis Menten and
mathematical models in leukemia and lymphoma, we refer Hill’s equation. The mutation of the growth regulatory genes
the reader to Clapp and Levy [15]. Hovewer, these models are such as FLT3-ITD is common in AML cases and results in the
cellular level modelling, which study the interactions between activation of PI3K [13]. The activation of PI3K then catalyzes
cells and there is no known published model that studies the phosphorylation of phosphatidylinositol bisphosphate
the dynamics of acute myeloid leukemia (AML) in molecular (PIP2) which can be phosphorylated at the D3 position of
level or biopathway. For modelling in biopathway, the model the inositol ring on extracellular stimulation, resulting in
of PI3K/AKT pathway has been conducted in [18, 19]. The the formation of phosphatidylinositol trisphosphate (PIP3).
modelling of the interaction protein-protein in cell repair In this model, the formation is grouped as a single process,
regulation also has been constructed in [20]. However, such called the PI3K level, and denoted by 𝑘0 . This formation can
models have not specifically studied a specific disease. In a be reversed by tumor suppressor PTEN that catalyzes PIP3
previous work, Adi et al. in [21] studied the mathematical dephosphorylation into PIP2. The PIP3 dephosphorylation
model of PI3K/AKT signaling pathway in AKT phosphoryla- that is assumed follows Hill’s equation with coefficient 4. It
tion. The model did not include the FOXO3a protein that has is according to the fact that PIP3 has four binding sites of
been known as prognostic factor in AML. This model also PH domain, that is, with PTEN, SHIP1, InsP4, and AKT
does not follow Hill’s equation that describes the substrate- [1].
enzyme interaction that has multiple ligand-binding sites. In Inactive AKT binds PIP3 which enables 3-phospho-
this paper, we construct a mathematical model of PI3K/AKT inositide-dependent kinase-1 (PDK1) to phosphorylate AKT
pathway in AML which considers FOXO3a, the most impor- at Thr308. For full activation, AKT is also phosphorylated at
tant downstream pathway of AKT. With deep understanding Ser473 by mTORC2. PDK1 and mTORC2 are grouped as a
of PI3K/AKT signaling pathways, the important parameters single enzyme catalyzing the phosphorylation (activation) of
that play a role in the development of AML will be identified. AKT. Activated AKT is regulated by protein phosphatase 2A
Furthermore, a strategy can be determined in the treatment (PP2A) and pleckstrin homology domain leucine-rich repeat
Journal of Applied Mathematics 3

Table 1: Initial concentration of the molecular component.

Protein Concentration (𝜇𝑀) References

PI3K 0.01 – 0.1 [21]
PIP3 0.7 – 0.8 [21]
AKT 0.01 – 1.0 [20, 21]
PP2A 0.004 – 0.15 [21]
FOXO3a 0.01 – 1.4 Assumed

protein phosphatase (PHLPP). The phosphate PP2A pref- In the next section, we do some numerical simulation to
erentially dephosphorylates AKT on the Thr308 site, while understand the dynamics of protein in PI3K/AKT pathways.
PHLPP specifically dephosphorylates AKT on Ser473 site. In The numerical simulation will be run in two different situ-
this model, the two phosphatases are grouped into a single ations based on the existence of the FOXO3a translocation
enzyme catalyzing the dephosphorylation of AKT. According from the nucleus to the cytoplasm as a normal cell or AML
to the fact that AKT has two binding sites, this protein activity cell to understand the dynamics of AKT/FOXO pathways.
is assumed to follow Hill’s equation with coefficient 2. In the In the normal cell, the activities of AKTp do not induce the
next downstream pathways, the activated AKT phosphory- translocation of FOXO3a from the nucleus to the cytoplasm.
lates and inhibits the forkhead transcription factor, FOXO3a. In the AML cell, aberrant PI3K/AKT signaling pathway
FOXO3a phosphorylation promotes its translocation from results in phosphorylation of FOXO3a leading to cytoplasmic
the nucleus to the cytoplasm. Phosphorylation by AKTp mislocalization and consequent degradation of these proteins
on Thr 24, Ser 256, and Ser 318 inhibits FOXO3a activities [9].
by increasing nuclear export and this in turn increases The situation of normal and AML cells is distinguished
proliferation. The FOXO3a in the cytoplasm, denoted by based on differences in some parameter values. First, the
FOXO3ap, is the interaction with the 14-3-3 nuclear export constant rate of PIP3 dephosphorylation in AML cells is lower
protein. This interaction preventing nuclear reimport by than normal cells as a result of various abnormal mechanisms
concealing nuclear localization signals and promotes the in the PI3K signal upstream pathway, for example, PTEN
FOXO3ap degradation by the proteasome [7, 16]. In this deletion [8]. Second, the value of dephosphorylation rate of
model, the growth of FOXO3a is assumed to follow the AKT in AML cells is smaller than the one in the normal
logistic model as well as the translocation and relocation of cells. This is due to the fact that, in AML, there is a
the cytoplasm and nucleus by phosphorylation and dephos- decrease of PIP3 level, a protein phosphatase that plays a
phorylation. According to the fact that FOXO3a has three role in the dephosphorylation of AKTp [8]. Furthermore, in
binding sites, Hill’s equation with coefficient 3 is used. The normal cells, it is assumed that AKTp does not induce the
FOXO3ap enhances the expression and phosphorylation of translocation of FOXO3a from the nucleus to the cytoplasm
RTKs which could in turn activate and sustain this pathways so that the parameter value of phosphorylation of FOXO3a
[3]. Thus, FOXO3a indirectly interacts and enhances PIP3 is tending to zero. The last difference is that the rate of
activity, resulting in a positive feedback loop. The reactivation dephosphorylation of FOXO3ap in AML is smaller than that
or dephosphorylation FOXO3a, which is mediated by PP2A, in normal cells. This is due to the degradation of FOXO3ap in
promotes the relocation to the nucleus. Based on the diagram AML cells in the cytoplasm [7, 9].
in Figure 1, a mathematical model is defined as follows:
𝑘 𝑥4
3. Results and Discussion
𝑑𝑥1
= 𝑘0 + 𝑏𝑥5 − 4 1 1 4 − 𝑑1 𝑥1 (1)
𝑑𝑡 𝐾1 + 𝑥1 The model equations (1)–(5) are not sufficiently accessible to
allow us to conduct the mathematical analysis. Therefore, in
𝑑𝑥2 𝑘 𝑥 𝑥2 𝑘 𝑥2 this paper, we only provide numerical simulations. In this
= 𝑎2 − 22 1 22 + 2 3 3 2 − 𝑑2 𝑥2 (2)
𝑑𝑡 𝐾2 + 𝑥2 𝐾3 + 𝑥3 section, the numerical results of system (1)–(5) are simulated
by employed the Runge-Kutta method of order 4 to provide
𝑑𝑥3 𝑘 𝑥 𝑥2 𝑘 𝑥2 the integration in some cases depending on the parameter
= 22 1 22 − 2 3 3 2 − 𝑑3 𝑥3 (3)
𝑑𝑡 𝐾2 + 𝑥2 𝐾3 + 𝑥3 values. The parameter values used in the system are based
on the clinical data that can be obtained in some medical
𝑑𝑥4 𝑘 𝑥 𝑥3 𝑘 𝑥3 literature as in Tables 1 and 2.
= 𝑥4 (𝑝 − 𝑚𝑥4 ) − 43 3 43 + 3 5 5 3 (4) Tables 1 and 2 show the kinetic rates and the initial
𝑑𝑡 𝐾4 + 𝑥4 𝐾5 + 𝑥5
concentration levels of the various proteins in PI3K and AKT
𝑑𝑥5 𝑘 𝑥 𝑥3 𝑘 𝑥3 pathways. For AML cells the parameter values are 𝑘0 = 0.01;
= 43 3 43 − 3 5 5 3 − 𝑑5 𝑥5 (5) 𝑏 = 0.0083; 𝑘1 = 0.005; 𝐾1 = 0.2; 𝑎2 = 0.09; 𝑘2 = 1; 𝑑1 =
𝑑𝑡 𝐾4 + 𝑥4 𝐾5 + 𝑥5
0.0083; 𝐾2 = 0.1; 𝑘3 = 0.36; 𝐾3 = 0.2; 𝑑2 = 0.08; 𝑑3 = 0.1;
The variables 𝑥1 , 𝑥2 , 𝑥3 , 𝑥4 , and 𝑥5 represent the concentra- 𝑝 = 0.3; 𝑚 = 0.25; 𝑘4 = 0.3; 𝐾4 = 0.1; 𝑘5 = 0.1; 𝐾5 = 0.1; and
tion of PIP3, AKT, AKT phosphorylation (AKTp), FOXO3a, 𝑑5 = 0.1. For normal cells, similar parameter values are used,
and FOXO3a phosphorylation (FOXO3ap), respectively. except 𝑘1 = 0.017; 𝑘3 = 0.67; 𝑘4 = 0.001; and 𝑘5 = 0.033.
4 Journal of Applied Mathematics

1.2

1.2
1
1
concentration (mM)

concentration (mM)
0.8
0.8
0.6
0.6

0.4 0.4

0.2 0.2

0 0
0 100 200 300 400 500 600 100 200 300 400 500 600
time (min) time (min)

FOXO3a in AML FOXO3a in Normal cell

FOXO3ap in AML FOXO3ap in Normal cell
(a) (b)
1

0.8
concentration (mM)

0.6

0.4

0.2

50 100 150 200 250 300 350 400 450 500 550
time (min)

FOXO3ap
(c)

Figure 2: Dynamic of FOXO3a and FOXO3ap concentration in AML cell (a), dynamic of FOXO3a and FOXO3ap concentration in the normal
cell (b), and FOXO3ap concentration in the absence of FOXO3a phosphorylation (c).

The dynamics concentrations of FOXO3a and FOXO3ap The increasing concentration of the FOXO3ap would
in the AML and the normal cell are given in Figure 2. affect the decreasing concentration of FOXO3a. It is illus-
Figure 2(a) shows that existence of the FOXO3a phosphoryla- trated in Figure 2(a) that the FOXO3a concentration ini-
tion plays a role in the increasing of FOXO3ap concentration. tially increases and peaks within 38 minutes. Moreover, the
The presence of inactive FOXO3a in the cytoplasm, FOXO3ap FOXO3a concentration immediately decreases and oscillates
in our model, means that the apoptosis mechanism is not in low concentration with small amplitude. Under the normal
working properly so that there is no cell death. The FOXO3ap condition, the concentration of FOXO3a transcription factor
also enhances proliferation cell, leading to accumulation of in the nucleus is much higher than those in the cytoplasm,
abnormal cells because they do not stop growing when they FOXO3ap; see Figure 2(b). The concentration of FOXO3a in
should. The lifespan of the white blood cell in a myeloid lin- the normal cell reaches the maximal level in short time. The
eage is about 3-12 days [23]. Therefore, there should be apop- increasing of FOXO3a is followed by the slightly increasing
tosis between 3-12 days characterized by low-level FOXO3ap FOXO3ap in much lower concentration. It indicates that
after that time, which does not occur in the AML cell. It can FOXO3a is not translocated to the cytoplasm. It shows that
be seen that FOXO3ap reaches a peak in 100 minutes and then FOXO3a promotes apoptosis and cell cycle regulation as
decreases and oscillates to a certain level (see Figure 2(a)). well. Thus the balancing of cell cycle regulation can be well
Journal of Applied Mathematics 5

0.27411 0.099648
0.099646
0.274105
0.099644
concentration (mM)

0.099642

concentration (mM)
0.2741
0.09964
0.274095 0.099638
0.099636
0.27409
0.099634
0.274085 0.099632
0.09963
0.27408 0.099628
2150 2200 2250 2300 2350 2400 2450 2500 2550 2600 2650 2150 2200 2250 2300 2350 2400 2450 2500 2550 2600 2650
time (min) time (min)
FOXO3ap in AML cell FOXO3a in AML cell
(a) (b)

Figure 3: The oscillation of the FOXO3ap concentration (a) and FOXO3a concentration (b) in AML cell.

×10-3
1.5 1.19964
1.19962
1.45
1.1996
1.4
1.19958
concentration (mM)
concentration (mM)

1.35 1.19956
1.3 1.19954

1.25 1.19952
1.1995
1.2
1.19948
1.15 1.19946
1.1 1.19944
2000 2100 2200 2300 2400 2500 2600 2700 2800 2150 2200 2250 2300 2350 2400 2450 2500 2550 2600 2650
time (min) time (min)
FOXO3ap in normal cell FOXO3a in normal cell
(a) (b)

Figure 4: The FOXO3ap (a) and FOXO3a (b) concentration in the normal cell.

preserved. We note that if the constant rate of FOXO3a Next, we will see the effect of phosphorylation of FOXO3a
phosphorylation is set to be zero, the concentration of on the other proteins, such as PIP3, AKT, and AKTp. Figures
FOXO3ap will be zero (see Figure 2(c)). 5 and 6 show the comparison of PIP3, AKT, and AKTp
Figure 3 shows the oscilation of FOXO3ap and FOXO3a concentration in the normal cell and AML cell. It can be
concentration in AML cell. The oscilation of FOXO3ap seen that, in the longtime behavior, the concentrations of
concentration is given in Figure 3(a) and the oscilation of PIP3 and AKTp in the AML cells are higher than those in
FOXO3a concentration is given in Figure 3(b). The oscillation the normal cells, while AKT in the AML cells is lower than
indicates that cell cycle and proliferation continue to occur that in the normal cells. In the AML cells, the concentration
and there is no maturation of these cells. The behavior of of PIP3 is gradually increasing and oscillates at a certain
FOXO3a can be used to identify the existence of AML disease. level as a response to FOXO3a phosphorylation. The PIP3
In addition, from the simulation, it is known that high level of concentration reaches the maximum level and remains at that
FOXO3a and low level of FOXO3ap in the normal cell do not level for a long time and oscillates with small amplitude; see
oscillate as in AML cell; see Figure 4. It indicates that FOXO3a Figure 5(b). Figure 5(c) illustrates the concentration of PIP3
works properly in cell cycle regulation and apoptosis. in the normal cells is at a low level without oscillation.
6 Journal of Applied Mathematics

0.9
0.8 0.878117935

0.7
0.87811793
concentration (mM)

0.6

concentration (mM)
0.5 0.878117925
0.4
0.87811792
0.3
0.2
0.878117915
0.1
0 0.87811791
0 100 200 300 400 500 600
time (min) 2350 2400 2450 2500 2550 2600 2650
time (min)
PIP3 in normal cell
PIP3 in AML cell PIP3 in AML cell
(a) (b)

0.19840025
0.19840024
0.19840023
concentration (mM)

0.19840022
0.19840021
0.1984002
0.19840019
0.19840018
0.19840017
0.19840016
0.19840015

2350 2400 2450 2500 2550 2600 2650

time (min)

PIP3 in normal cell

(c)

Figure 5: Dynamics of PIP3 in the normal cell and AML cell (a). Concentration of PIP3 in AML cell oscillates at a certain level (b), while
PIP3 in normal cell does not oscillate (c).

Figure 6 shows the differences between AKT and AKTp concentrations of FOXO3a and FOXO3ap. This condition
behavior in the normal cell and AKT and AKTp in the AML is due to the fact that the greater value of FOXO3a phos-
cell, respectively. Under normal conditions, when the levels phorylation rate will accelerate the translocation of FOXO3a
of PIP3 decrease, the AKT activity is attenuated by dephos- from the nucleus to the cytoplasm and lead to proteasome
phorylation by phosphatase. Figure 6(a) shows the AKT in degradation. The increase of FOXO3a phosphorylation rate
AML cell subsequently sustained at lower concentrations does not extremely affect the dynamics of AKT and AKTp,
than in the normal cell. In the AML cell, as the result of while the PIP3 concentration becomes slightly lower.
FOXO3a translocation from the nucleus to the cytoplasm,
the concentration level of AKT decreases quickly, while 4. Conclusions
AKTp immediately increases and remains at a certain level.
Figure 6(b) shows that the AKTp in AML cell is subsequently As shown in the numerical simulation, the key components in
sustained at a higher concentration than in the normal driven AML cell are high levels of PIP3, AKTp, and FOXO3ap,
cell. Figure 7 tested the model by increasing the constant that is, inactive FOXO3a in the cytoplasm. These results
rate of FOXO3a phosphorylation from 1 (Figure 7(a)) to suggest that these three components are potential targets
2 (Figure 7(b)), while keeping all other parameter values for AML therapy, of course with due regard to the other
the same as in Figure 2. The effect of this increase is that proteins that mediated protein interactions. For example, the
the greater the rate of FOXO3a phosphorylation, the lower parameter values associated with FOXO3a are taken from
Journal of Applied Mathematics 7

0.9
1
0.8
0.9
0.7
0.8

concentration (mM)
concentration (mM)

0.7 0.6

0.6 0.5
0.5 0.4
0.4 0.3
0.3
0.2
0.2
0.1
0.1
0
0 100 200 300 400 500 600 0 100 200 300 400 500 600
time (min) time (min)

AKT in normal cell AKTp in normal cell

AKT in AML cell AKTp in AML cell
(a) (b)

Figure 6: Dynamics of AKT (a) and AKTp (b) in normal and AML cell.

0.9 0.9

0.8 0.8

0.7 0.7
concentration (mM)
concentration (mM)

0.6 0.6

0.5 0.5

0.4 0.4

0.3 0.3

0.2 0.2

0.1 0.1

0 0
0 100 200 300 400 500 600 0 100 200 300 400 500 600
time (min) time (min)

PIP3 FOXO3a PIP3 FOXO3a

AKT FOXO3ap AKT FOXO3ap
AKTp AKTp
(a) (b)

Figure 7: Dynamics of PIP3, AKT, AKTp, FOXO3a, and FOXO3ap in the AML cell with increasing rate of FOXO3a phosphorylation from
1.0 (a) to 2.0 (b).

proteins that have a similar function to FOXO3a, such as Data Availability

MDM2. It could be very useful for determining reasonable
ranges for the rate of various biochemical reactions involved. The data used to support the findings of this study are
As more medical facts are known about the PI3K/AKT included within the article.
signaling pathways in AML, the model may be needed to
be modified. It is possible that other equations representing
Conflicts of Interest
rates of change of other proteins or other signaling pathways The authors declare that there are no conflicts of interest
that integrated with PI3K/AKT pathways may have to be regarding the publication of this paper.
added to the system. Mathematical analysis of the model may
also be useful in understanding protein interactions in this Acknowledgments
pathway. In the future studies, we will analyze mathematically
the dynamics of the system and study the bifurcation related This work was supported by the Ministry of Research and
to the variation of its parameter values. Higher Education (Kemenristek DIKTI) of Indonesia (Grant
8 Journal of Applied Mathematics

Table 2: Parameter values and kinetic rates being used.

Parameter Description Unit Value References

𝑘0 PI3K level 𝜇𝑀𝑚𝑖𝑛−1 0.01 – 0.1 [21]
𝑏 Increase activation PIP3 by FOXO3ap 𝑚𝑖𝑛−1 0.0083 ∗
𝑘1 Constant rate of PIP3 dephosphorylation by PTEN 𝜇𝑀𝑚𝑖𝑛−1 0.0006 – 0.21 [21]
𝑑1 PIP3 degradation 𝑚𝑖𝑛−1 0.001 – 0.01 [22]
𝑎2 AKT production rate 𝜇𝑀𝑚𝑖𝑛−1 0.036 – 0.108 [21, 22]
𝑘2 Constant rate of AKT phosphorylation 𝑚𝑖𝑛−1 1 – 20 [21]
𝑘3 Constant rates of AKTp dephosphorylation by PP2A 𝜇𝑀𝑚𝑖𝑛−1 0.36 – 13.5 [21, 22]
𝑑2 AKT degradation rate 𝑚𝑖𝑛−1 0.063 – 0.08 [21]
𝑑3 AKTp degradation rate 𝑚𝑖𝑛−1 0.0008 – 0.1 [21, 22]
𝑝 FOXO3a production rate 𝑚𝑖𝑛−1 0.002 – 0.5 ∗
𝑚 FOXO3a degradation rate by 14-3-3 protein 𝜇𝑀−1 𝑚𝑖𝑛−1 0.004 – 0.28 ∗
𝑘4 Constant rate of FOXO3a phosphorylation 𝑚𝑖𝑛−1 0 – 0.33 ∗
𝑘5 Constant rate of FOXO3a dephosphorylation by PP2A 𝜇𝑀𝑚𝑖𝑛−1 0.000297 – 2.92 ∗
𝑑5 FOXO3ap degradation rate 𝑚𝑖𝑛−1 0.033 – 0.125 ∗
𝐾1 Michaelis constant of PIP3 dephosphorylation 𝜇𝑀 0.01 – 1 [18, 20]
𝐾2 Michaelis constant of AKT phosphorylation 𝜇𝑀 0.1 [20]
𝐾3 Michaelis constant of AKTp dephosphorylation 𝜇𝑀 0.08 – 0.4 [20, 22]
𝐾4 Michaelis constant of FOXO3a phosphorylation 𝜇𝑀 0.1 ∗
𝐾5 Michaelis constant of FOXO3ap dephosphorylation 𝜇𝑀 0.1 ∗
∗Parameters values are assumed to be the same as other transcription factors such as MDM2 in [18, 22].

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