MAPK Modeling

Project
LING YANG, XIN ZOU, HAYREDDIN SAID UNSAL, QIYAO LI

Introduction
The Mitogen Activated Protein Kinase(MAPK) pathway is one of the most
important signal transduction pathways
Manages the growth, proliferation, differentiation and survival of many cell
types
Vital and vulnerable
Currently 6 models with specific proteins and reactions
The model Hatakeyama et al (2003) is used in the project

Hatakeyama, M., Kimura, S., Naka, T., Kawasaki, T., Yumoto, N., Ichikawa, M., Konagaya, A. (2003) Biochemical Journal, 373(Pt 2), 451
463

Kinetic model of the MAPK

pathway
Growth factor heregulin (HRG) binds to the
receptor ErbB4 (R) which causes receptor
dimerization
ErbB4 receptor kinases phosphorylate each
other and results in phosphorylated ErbB4
(RP)
The activated receptor interacts with the
phosphatidylinositol 3-kinase (PI3K) and
Shc domain docking protein
Shc binds to phosphorylated ErbB4 receptor
and activate the protein called GTP binding
exchange factor (Grb2-Sos complex)

Kinetic model of the MAPK

pathway
PI3K activates phosphatidylinositol(PI)
which produces PIP3.
PIP3 binds to Akt, and their phosphorylation
is regulated by PDK and PP2A.
The Raf-MEK-ERK phosphorylation cascade
follows by activation of RasGDP
As a result, ERK is activated and enters to
nucleus

al concentrations and Kinetic parameters

constants (Kn) in nM, the maximum velocity (Vn) in nM*s-1, first- and second-order constants are in s-1 and nM-1s-1
Parame Value Parame Value Parame Value Parame
Reactant
Concentration
ter
ter
ter
ter
(nM)
k1
1.2*10k18
0.058
k-1
7.6*10
K18
ErbB4
80
3
-4
receptor (R)
k2
0.01
k19
9.5
k-2
0.1
K19
Shc
1000
Grb2-Sos
10
k3
1.0
k20
0.3
k-3
0.01
K20
(GS)
V4
62.5
k21
16
K4
50
K21
RasGDP
120
Raf1
100
k5
0.1
k22
0.27
k-5
1
K22
MEK
120
k6
20
k23
0.1
k-6
5
k-23
ERK
1000
k7
60
k24
9.85
k-7
546
k-24
PI3K
10
k8
2040
k25
45.8
k-8
15700
k-25
PI
800
k9
40.8
V26
2620
k-9
0
K26
Akt
10
V10
0.0154
k27
16.9
K10
340
K27
Enzyme (E)
7
k11
0.222
V28
17000
K11
0.181
K28
MKP3
2.4
V12
0.289
k29
507
K12
0.057
K29
1
PP2A
11.4
k13
1.53
V30
2*104
K13
11.7
K30
HRG
10373(Pt 2), 451-463
Hatakeyama, M.,
et al. (2003). Biochemical Journal,
Tzahar, E., et al. (1997) EMBO J. 16, 49384950
Kholodenko, B. N., et al. (1999) J. Biol. Chem. 274, 3016930181
Kholodenko, B. N. (2000) Eur. J. Biochem. 267, 15831588

k14
k15

6.73*1
0-3
3.5

Value
60
1.46*1
05
160
1.46*1
05
60
2
0.0985
0.047
3680
39.1
9.02
234

k31

0.107

K14

8.07

K31

80000
4.35

V32

2*104

K15

317

K32

80000

Simulation on HRG-induced
ErbB4 signaling
[Raf*] vs time
In variable [HRG]

[MEKPP] vs time
In variable [HRG]

[ERKPP] vs time
In variable [HRG]

[HRG]=10nM
[HRG]= 1.0nM
[HRG]= 0.1nM

time delay of lower

[HRG]

Effect of PI3K Inhibitor

[Raf*] vs time
In variable [PI3K]

[MEKPP] vs time
In variable [PI3K]

[ERKPP] vs time
In variable [PI3K]

[PI3K]=100nM
[PI3K]= 10nM
[PI3K]= 1nM
[PI3K]= 0.1nM
[PI3K]= 0.01nM

Effect of Ras
[Raf*] vs time

[MEKPP] vs
time

[RasGDP]=120nM
[RasGDP]= 12nM
[RasGDP]= 1.2nM

[ERKPP] vs
time

Cancer Model
[Raf*] vs
time

[MEKPP] vs
time

[ERKPP] vs
time

Vm12=0.289nM/s
Vm12=0.144nM/s
Vm12=0.072nM/s

Conclusion
Output of the MAPK
pathway
Activation
of PI3K

[HRG ]
growth
factor

[PI3K]
Inhibitor

[RasGDP]

Inactivated
Ras

V(GTP-GDP)

Exchanging
rate

and that of the RafMEK-ERK cascade remains unclear--deficient evidence

Application: Tipifarnib (trade name

Zarnestra) as inhibitor for acute
myeloid leukemia

Thank
you!
Question
s?