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

The
role
of
signaling
pathways
in
controling
cell
cycle

M

G2 S

G1

Adapté de ProteinLounge.com

Cell
cycle
[Basic]

G2

M

G1

S

CyclinBCDK1

CyclinACDK2

CyclinDCDK4,6

CyclinECDK2

Cell
cycle
and
signaling
pathway
[Basic]

G2

M

G1

S

CyclinBCDK1

CyclinACDK2

CyclinECDK2

CyclinDCDK4,6

TGF‐βp15

p16

Rb

E2F

Rb

E2F

p27

p21

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

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

ADAM12
in
TGF‐β
receptor
trafficking

Vilar et al. (2006) Plos ComputationZi et al. (2007) Plos One

Afti et al. (2007) J Cell Bio.

ADAM12
and
TGF‐β
signal
strength

J. Gruel et al. in preparation

internalization towards the endosomerecycling from the endosomeconstitutive degradation

ADAM12
and
TGF‐β
signal
shape

J. Gruel et al in preparation

ConstitutiveCIRlike =

Ligand-induced

TGF-βsignalingactivity

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]

G2

M

G1

S

CyclinBCDK1

CyclinACDK2

CyclinECDK2

CyclinDCDK4,6

TGF‐βp15

p16

Rb

E2F

Rb

E2F

p27

p21

p53

Modeling
the
Cell
Cycle

DifferentialStochasticsDiscrete Graphs

dP/dt = Kev(E)+Kgv(G)+…

P

G

H

O

--

-

++

Qualitative

P

EG H …

DynamicQuantitative

Network
Modeling
methods

Modeling
the
Cell
Cycle

Regulatory
Graph
of
Cell
Cycle

Fauré
et
al.
(2006)
BioinformaLcs


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

Davidich et al. (2006) Plos One

Temporal
evoluUon
in
the
cell
cycle

Synchronous
versus
Asynchronous

Fauré
et
al.
(2006)
BioinformaLcs


Synchronous = parallel updatingAsynchronous = sequential updating

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

hx

hy

X

Y

«
Tic……..Uc…
»

«
Tic..Uc………..
»

10

1

0

hx
∨ hy

Discrete
mulU‐clock
modeling:
first
results

State: D, f(), D0Clock: h_DF()= 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

p21

Erk1/Erk2

TransientacUvaUon

?

Raf1+MEK1

AP‐1
protein(Jos
+
Jun)

Sustained
acUvaUon

transcripUo

n

Meloche
and
Pouysségur
(2007)
Oncogene

Acknowledgements

N. Théret G. Baffet Y. Arlot D. Lagadic-Gossmann

M. Le Borgne J. Gruel O. Radulescu J. Nicolas

Shapiro G. (2006) Journal of Clinical Oncology

Kinase
and
cell
cycle

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

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