network dynamics and cell physiology
DESCRIPTION
Network Dynamics and Cell Physiology. John J. Tyson Dept. Biological Sciences Virginia Tech. Collaborators. Budapest Univ. Techn. & Econ. Bela Novak Attila Csikasz-Nagy Andrea Ciliberto Virginia Tech Kathy Chen Dorjsuren Battogtokh. Funding James S. McDonnell Foundation DARPA. DNA. - PowerPoint PPT PresentationTRANSCRIPT
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Network Dynamics andNetwork Dynamics andCell PhysiologyCell Physiology
John J. Tyson John J. Tyson
Dept. Biological Sciences Dept. Biological Sciences
Virginia TechVirginia Tech
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Budapest Univ. Techn. & Econ.Budapest Univ. Techn. & Econ.
Bela NovakBela Novak
Attila Csikasz-NagyAttila Csikasz-Nagy
Andrea CilibertoAndrea Ciliberto
Virginia TechVirginia Tech
Kathy ChenKathy Chen
Dorjsuren BattogtokhDorjsuren Battogtokh
CollaboratorsCollaborators
FundingFunding
James S. McDonnell FoundationJames S. McDonnell Foundation
DARPADARPA
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Computational Molecular BiologyComputational Molecular Biology
DNA
mRNA
Protein
Enzyme
Reaction Network
Cell Physiology
…TACCCGATGGCGAAATGC...
…AUGGGCUACCGCUUUACG...
…Met -Gly -Tyr -Arg -Phe -Thr...
ATP ADP
-P
X Y ZE1
E2
E3E4
Last Step
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S
G1
DNAreplication
G2Mmitosis
cell division
The cell cycle is thesequence of events wherebya growing cell replicates allits components and dividesthem more-or-less evenly
between two daughter cells...
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Cdk1
S
G1
DNAreplication
G2Mmitosis
cell division
CycB
P P
Cyclin-dependentkinase
Cyclin B
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P
Cdc25
Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
Coupled Intra-cellular Networks !
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R
S
0
0.5
0 1 2 3
res
po
ns
e (
R)
signal (S)
linear
0
5
0 0.5 1
S=1
R
rate
(d
R/d
t)
rate of degradation
rate of synthesis
S=2
S=3
Gene Expression
Signal-ResponseCurve
1 2
d,
d
Rk S k R
t 1
ss2
k SR
k
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R
Kinase
RP
ATP ADP
H2OPi
Protein Phosphorylation
0
1
2
0 0.5 1
RP
rate
(d
RP
/dt)
0.25
0.5
1
1.5
2
Phosphatase 0
0.5
1
0 1 2 3
res
po
ns
e (
RP
)
Signal (Kinase)
“Buzzer”
Goldbeter & Koshland, 1981
1 R 0
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R
S
EP E0
0.1
0.2
0.3
0.4
0.5
0.6
0 0.5R
rate
(d
R/d
t) S=0
S=8
S=16
0
0.5
0 10
res
po
ns
e (
R)
signal (S)
Protein Synthesis:Positive Feedback
“Fuse”Bistability
Closed
Open
Griffith, 1968
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Example: Fuse
0
0.5
0 10
resp
on
se (
R)
signal (S)
dying
Apoptosis(Programmed Cell Death)
living
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R
S
EP E0
0.05
0.1
0 0.5 1 1.5
0
0.5
1
0 1 2R
rate
(d
R/d
t)
res
po
ns
e (
R)
signal (S)
S=0.6
S=1.2
S=1.8
SN
SN
Protein Degradation:Mutual Inhibition
“Toggle”Bistability
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R
S
EP E
X
0 50
1
X
R
Positive Feedback & Substrate Depletion
positive
substrate
0.0 0.5
0
1
signal (S)
Hopf Hopf
res
po
ns
e (
R)
“Blinker”
Glycolytic Oscillations
Oscillation
sss
sssuss
Higgins, 1965; Selkov, 1968
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S
X
Y YP
R RP
0
5
0 25 50
0
0.5
1
0 2 4 6
0.0
0.1
0.2
0.3
0.4
0.5
time
XYP
RP
res
po
ns
e (
RP
)
signal (S)
HopfHopf
Negative Feedback Loop
Goodwin, 1965
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Example: Bacterial Chemotaxis
Barkai & Leibler, 1997 Goldbeter & Segel, 1986
Bray, Bourret & Simon, 1993
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R
S X
0
5
0 1 2R
rate
(d
R/d
t)
S=1
S=3
S=2
0.9
1.4
1.9
0 10 20
-1
0
1
2
3
4
5
S
X
R
time
Sniffer
Response isindependent
of Signal
1 2
3 4
d
dd
d
Rk S k XR
tX
k S k Xt
(Levchenko & Iglesias, 2002)
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primed RC
fired RC primed MEN
fired MEN
Cdk1
CycB
high MPF
low MPF
high SPF
low SPF
Cdk2
CycA
Example 2: Cell Cycle
(Csikasz-Nagy& Novak, 2005)
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LA
Response = F
L
Signal = CDK
Cock-and-Fire
LAL
+
Cdk2
CycA
F+
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Signal = MPF
Response = BA
TA T
TABAB
+
+
Cdk1
CycB
Cock-and-Fire-2
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P Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
bistable switch
bistable switch
bistable switch
oscillator
oscillator
Cdc25
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P
Cdc25
Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
mass/ DNA
0.0 0.5 1.0 1.5
Cdc2
/Cdc1
3
10-5
10-4
10-3
10-2
10-1
100
G1
Mmass/ DNA
0 1 2
Cdc2
/Cdc1
3
10-3
10-2
10-1
100
S/G2
M
mass/nucleus
mass/ DNA
0.0 0.5 1.0 1.5 2.0
Cdc2
/Cdc1
3
0.1
1
M
Fission Yeast
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0 1 2 3 4 5
0
0.4
0.8
3.0
mass/nucleus
Cd
k1:C
ycB
G1S/G2
MWild type
SNIPER
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Genetic control of cell size at cell division in yeastPaul NurseDepartment of Zoology, West Mains Road, Edinburgh EH9 3JT, UK
Nature, Vol, 256, No. 5518, pp. 547-551, August 14, 1975
wild-type wee1
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P
Cdc25
Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
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wee1
mass/nucleus
Cd
k1:C
ycB
0 1 2 3 4 5
0
0.4
0.8
1.2
G1
S/G2
M
wee1wee1 cells are about one-half the size of wild type cells are about one-half the size of wild type
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0 1 2 3 4 5 60.0
0.2
0.4
0.6
0.8
1.0
cell mass (au.)
Wee
1 ac
tivity
wild-type
wee1-
0 0 50 100 150 200 250 300 350 400 450 500 550
30 60
90
120
150
180
210
240
270 300
period(min)
PHYSIOLOGY
GENETICS
Two-parameter Bifurcation Diagram
SNIPER
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P
Cdc25
Wee1
Wee1P
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
Cdc25
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mass/nucleus
Cd
k1:C
ycB
G1S/G2
M
0 1 2 3 4 5
0
0.4
0.8
3.0 cki
The Start module is not required during mitotic cyclesThe Start module is not required during mitotic cycles
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P
Cdc25
Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
CycB
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0
0.4
0.8
2.0
0 1 2 3 4 5
G1
S/G2
M
cki wee1ts1st
2nd
3rd
4th
mass/nucleus
Cd
k1:C
ycB
Cells become progressively smaller without size controlCells become progressively smaller without size control
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P
Cdc25
Wee1
Wee1P
Cdc25
CycB
PCdc20
Cdc20
Cdh1
CK
I
CycB
CycBCK
I
CK
I
CycA
CycA
APC-PAPCTFBI
TFBA
CycE
CycD
TFEA
TFEI
Cyc E,A,B
CycE
TFIA
TFII
Cdc20
CK
I
CycE
Cdc14
Cdc14
Cdc14
CycA
CycA
CycB
CycD
Cdh1CycD
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endoreplication
0 1 2 3 4
0.0001
0.001
0.01
0.1
1
Act
Cyc
A
cdc13
Fission yeast
0 1 2 3 4 5 6
0.000
0.005
0.010
0.015
0.020
0.025
0.030
2 param bifn diag for Cdc13
mitoticcycles
endoreplication
S
G2G1
M
mitotic cycle
mass
Pro
duc
tion
of
Cdc
13
XNo production of cyclin B (Cdc13)
Wild type
cdc13
cdc13 +/??
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The Dynamical PerspectiveThe Dynamical Perspective
Molecular MechanismMolecular Mechanism
??
??
??
Physiological PropertiesPhysiological Properties
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The Dynamical PerspectiveThe Dynamical Perspective
Molecular MechanismMolecular Mechanism
Kinetic EquationsKinetic Equations
Vector FieldVector Field
Stable AttractorsStable Attractors
Physiological PropertiesPhysiological Properties
d CycBT
dt = k1 . M - (k2' + k2" . Ste9 +k2'" . Slp1A) . CycBT
dSte9
dt = k3' .
1 - Ste9J3 + 1 - Ste9 - (k4'
. SK + k4 . CycB) .
Ste9J4 + Ste9
d Rum1T
dt = k11 - (k12 + k12' . SK + k12" . CycB) . RUM1T
dSlp1A
dt = k7 . IE .
Slp1T - Slp1A
J7 + Slp1T - Slp1A - k8
. Slp1A
J8 + Slp1A - k6
. Slp1A
dMdt = . M
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References
• Tyson, Chen & Novak, “Network dynamics and cell physiology,” Nature Rev. Molec. Cell Biol. 2:908 (2001).
• Tyson, Csikasz-Nagy & Novak, “The dynamics of cell cycle regulation,” BioEssays 24:1095 (2002).
• Tyson, Chen & Novak, “Sniffers, buzzers, toggles and blinkers,” Curr. Opin. Cell Biol. 15:221 (2003).