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Signaling
pathways
and
cell
cycle:
modeling
control
mechanisms
Nolwenn
Le
Meur
J.
Gruel
‐
M.
Le
Borgne
‐
N.
Théret
6ème
journée
de
la
plate‐forme
GenOuest
Rennes,
21
October
2008
The
role
of
signaling
pathways
in
controling
cell
cycle
G1
M
G2 Adapté de ProteinLounge.com
S
Cell
cycle
[Basic]
M
CyclinB
CDK1
CyclinD
G2 G1 CDK4,6
S
CyclinE
CyclinA
CDK2
CDK2
Cell
cycle
and
signaling
pathway
[Basic]
TGF‐β
M p1
5
CyclinB p1
CDK1 6
CyclinD
G2 G1 CDK4,6
Rb
E2F
Rb
S E2F
CyclinE
CyclinA
CDK2
CDK2
p2
7
p2
1
Cell
cycle,
Signaling
and
Cancer
Weinberg (2006) The biology of cancer. Garland
From
fibrosis
to
hepatocellular
carcinoma
Bataller R. and Brenner D.A (2007). J. Clin. Inv.
TGF‐β
signaling
pathway
• Extracellular matrix production
• Cell proliferation
• Functional differentiation
• Cell motility
• Apoptosis
ADAM12
and
TGF‐β
receptors
TGF‐β
signaling
pathways
TGFβ
ADAM12
P P
II
P P
I II I
Clathrin-coated pit SARA
Smad2 Smad7 Caveolae
TGFβ
P
II
P
I Proteasome
SARA
Smad2
Nucleus
P
Smad2 Le Pabic et al. (2003) Hepatology
Afti et al. (2006) J. Cell Biol
ADAM12
in
TGF‐β
receptor
trafficking
Vilar et al. (2006) Plos Computation
Zi et al. (2007) Plos One
Afti et al. (2007) J Cell Bio.
ADAM12
and
TGF‐β
signal
strength
internalization towards the endosome
recycling from the endosome
constitutive degradation
J. Gruel et al. in preparation
ADAM12
and
TGF‐β
signal
shape
Constitutive
CIRlike =
Ligand-induced
TGF-β
signaling
activity
J. Gruel et al in preparation
Time
FiNng
algorithm
as
a
exploratory
tool
• Mathematical model
• Differential equation
• Solution space
• Biological insigths
• Signal strength
• Signal shape
Signaling
pathways
and
cell
cycle
Cell
cycle
and
signaling
pathway
[Basic]
TGF‐β
M p1
5
CyclinB p1
CDK1 6
CyclinD
G2 G1 CDK4,6
Rb
E2F
Rb
S E2F
CyclinE
CyclinA
CDK2
CDK2
p2
7
p2 p5
1 3
Modeling
the
Cell
Cycle
Network
Modeling
methods
Qualitative Quantitative
Dynamic
Discrete Graphs Stochastics Differential
G + G H
+ …
O E
-
P -
-
H P
dP/dt = Kev(E)+Kgv(G)+…
Modeling
the
Cell
Cycle
Regulatory
Graph
of
Cell
Cycle
Fauré
et
al.
(2006)
BioinformaLcs
Logical
States
Regulatory graph G = {g1,....gn }
Logical state vector S = ( s1,...,sn ) si " {0,...Max i }
CycD Rb E2F CycE CycA P27 Cdc20 Chd1 UbcH10 CycB
1 0 1 1 0 0 0 1 0 0
!
Temporal
evoluUon
in
the
cell
cycle
Davidich et al. (2006) Plos One
Synchronous
versus
Asynchronous
Synchronous = parallel updating
Asynchronous = sequential updating
Fauré
et
al.
(2006)
BioinformaLcs
Discrete
dynamic
modeling
• Signal
updaUng
in
the
model
– Synchronous
– Asynchronous
– Interlacing
• Answer
quesUons
– Is
molecule
A
always
before
molecule
B?
– Are
C
and
E
never
acUve
at
the
same
Ume?
–…
Discrete
mulU‐clock
modeling:
a
new
formalism
• Time
in
the
model
• State
X
is
modified
by
a
signal
with
a
clock
hx
1
0
X
hx «
Tic……..Uc…
»
1
0
Y
hy «
Tic..Uc………..
»
hx
hy
Discrete
mulU‐clock
modeling:
first
results
State: D, f(), D0
Clock: h_D
F()= A and B when h_D
synchronous asynchrone
Future
work
• Temporal
constraints
• Methods
and
metrics
– analysis
– diagnosUcs
• ValidaUon
– In
silico
– In
vivo
• Interface
biologist/computaUonal
model
• Include
signaling
pathways
Plug‐ins:
Signaling
Pathways
p15
p16 TGFb
Uo
ip
s cr
n
tra
n p21
AP‐1
protein
(Jos
+
Jun) ? Transient
acUvaUon
Erk1/Erk2
Raf1+MEK1
Sustained
acUvaUon
Meloche
and
Pouysségur
(2007)
Oncogene
Acknowledgements
N. Théret
G. Baffet
Y. Arlot
D. Lagadic-Gossmann
M. Le Borgne
J. Gruel
O. Radulescu
J. Nicolas
Kinase
and
cell
cycle
Shapiro G. (2006) Journal of Clinical Oncology
EGF
and
TGF‐β
TGFβ
EGF
EGFR
P
P
P P Ras Ras/Rho
II I
P P Grb2 Sos
SARA Smad2/3
GTP Raf
P P TAK1/TAB
MEKK1/4 P
MLK3 Smad2/3
P Smad4
PI3K MEK’1/2 MEK/4
P
ERK1/ERK2 P38/JNK
ProliferaUon
The
role
of
signaling
pathways
in
controling
cell
cycle
ubiquiUnylaUon TGF
APC DegradaUon beta
CSS52 of
mitoUc
cyclin
p15
p16
Cycline
B Cycline
D
cdk1
(cdc2) cdk4
Cycline
D
cdk6 KRP
Rb
E2F
Cycline
D
cdk6 KRP
P
Rb P inacUve
P
E2F
+
Cycline
E
Cycline
A Cdk2
cdk1
(cdc2?)
cycline?cdk p27
3
Cycline
A
cdk2
P Cycline
B p21
inacUve cdk1 Cycline
B
WEE1 ‐‐‐‐‐‐‐‐‐‐‐‐
cdk1
p19 MDM2 p53
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