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Signaling pathways and cell cycle: modeling control mechanisms
Nolwenn Le MeurJ. Gruel ‐ M. Le Borgne ‐ N. Théret
6ème journée de la plate‐forme GenOuest
Rennes, 21 October 2008
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The role of signaling pathways in controling cell cycle
M
G2 S
G1
Adapté de ProteinLounge.com
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Cell cycle [Basic]
G2
M
G1
S
CyclinBCDK1
CyclinACDK2
CyclinDCDK4,6
CyclinECDK2
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Cell cycle and signaling pathway [Basic]
G2
M
G1
S
CyclinBCDK1
CyclinACDK2
CyclinECDK2
CyclinDCDK4,6
TGF‐βp15
p16
Rb
E2F
Rb
E2F
p27
p21
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Cell cycle, Signaling and Cancer
Weinberg (2006) The biology of cancer. Garland
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From fibrosis to hepatocellular carcinoma
Bataller R. and Brenner D.A (2007). J. Clin. Inv.
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TGF‐β signaling pathway
• Extracellular matrix production
• Cell proliferation
• Functional differentiation
• Cell motility
• Apoptosis
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ADAM12 and TGF‐β receptors
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Smad2
TGF‐β signaling pathways
P
IP
Smad7II
TGFβ
ADAM12
Smad2
P
IPII
P
IP
Smad2
II
SARA
TGFβ
P
SARA
Proteasome
Nucleus
Clathrin-coated pit Caveolae
Le Pabic et al. (2003) HepatologyAfti et al. (2006) J. Cell Biol
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ADAM12 in TGF‐β receptor trafficking
Vilar et al. (2006) Plos ComputationZi et al. (2007) Plos One
Afti et al. (2007) J Cell Bio.
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ADAM12 and TGF‐β signal strength
J. Gruel et al. in preparation
internalization towards the endosomerecycling from the endosomeconstitutive degradation
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ADAM12 and TGF‐β signal shape
J. Gruel et al in preparation
ConstitutiveCIRlike =
Ligand-induced
TGF-βsignalingactivity
Time
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FiNng algorithm as a exploratory tool
• Mathematical model
• Differential equation
• Solution space
• Biological insigths
• Signal strength
• Signal shape
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Signaling pathways and cell cycle
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Cell cycle and signaling pathway [Basic]
G2
M
G1
S
CyclinBCDK1
CyclinACDK2
CyclinECDK2
CyclinDCDK4,6
TGF‐βp15
p16
Rb
E2F
Rb
E2F
p27
p21
p53
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Modeling the Cell Cycle
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DifferentialStochasticsDiscrete Graphs
dP/dt = Kev(E)+Kgv(G)+…
P
G
H
O
--
-
++
Qualitative
P
EG H …
DynamicQuantitative
Network Modeling methods
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Modeling the Cell Cycle
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Regulatory Graph of Cell Cycle
Fauré et al. (2006) BioinformaLcs
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Logical States
!
G = g1,....gn{ }
S = s1,...,sn( ) si " 0,...Maxi{ }
Regulatory graphLogical state vector
CycD Rb E2F CycE CycA P27 Cdc20 Chd1 UbcH10 CycB
1 0 1 1 0 0 0 1 0 0
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Davidich et al. (2006) Plos One
Temporal evoluUon in the cell cycle
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Synchronous versus Asynchronous
Fauré et al. (2006) BioinformaLcs
Synchronous = parallel updatingAsynchronous = sequential updating
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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?– …
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Discrete mulU‐clock modeling: a new formalism
• Time in the model• State X is modified by a signal with a clock hx
hx
hy
X
Y
« Tic……..Uc… »
« Tic..Uc……….. »
10
1
0
hx ∨ hy
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Discrete mulU‐clock modeling: first results
State: D, f(), D0Clock: h_DF()= A and B when h_D
synchronous asynchrone
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Future work
• Temporal constraints• Methods and metrics
– analysis– diagnosUcs
• ValidaUon– In silico– In vivo
• Interface biologist/computaUonal model• Include signaling pathways
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Plug‐ins: Signaling Pathways
p15
p16 TGFb
p21
Erk1/Erk2
TransientacUvaUon
?
Raf1+MEK1
AP‐1 protein(Jos + Jun)
Sustained acUvaUon
transcripUo
n
Meloche and Pouysségur (2007) Oncogene
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Acknowledgements
N. Théret G. Baffet Y. Arlot D. Lagadic-Gossmann
M. Le Borgne J. Gruel O. Radulescu J. Nicolas
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Shapiro G. (2006) Journal of Clinical Oncology
Kinase and cell cycle
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P
IP
Smad4
Raf
ERK1/ERK2
MEK’1/2
PP
PP
PP
Ras
Sos GTPGrb2Smad2/3
Smad2/3
IISARA
TAK1/TABMEKK1/4MLK3
MEK/4
P38/JNK
P
P
P
Ras/Rho
PI3K
EGFR
EGF and TGF‐β
TGFβEGF
ProliferaUon
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DegradaUonof mitoUc cyclin
Cycline Dcdk6
KRP
Cycline Acdk2
Cycline Acdk1 (cdc2?)
Cycline Bcdk1 (cdc2)
Cycline Dcdk4
Cycline Dcdk6
Cycline ECdk2
APCCSS52ubiquiUnylaUon
Cycline Bcdk1
WEE1Cycline B‐‐‐‐‐‐‐‐‐‐‐‐cdk1
inacUve
inacUve
KRP
cycline?cdk3
TGFbeta
p15p16
RbE2F
RbP
P
P
E2F+
p21
p27
p53p19 MDM2
P
The role of signaling pathways in controling cell cycle