Signaling pathways and cell cycle modeling control mechanisms

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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