Network Dynamics and Cell Physiology

1
Network Dynamics andCell Physiology

• John J. Tyson
• Dept. Biological Sciences
• Virginia Tech

2
Collaborators

• Budapest Univ. Techn. Econ.
• Bela Novak
• Attila Csikasz-Nagy
• Andrea Ciliberto
• Virginia Tech
• Kathy Chen
• Dorjsuren Battogtokh

Funding James S. McDonnell Foundation DARPA
3
Computational Molecular Biology
4
G1
cell division
The cell cycle is the sequence of events
whereby a growing cell replicates all its
components and divides them more-or-less
evenly between two daughter cells ...
S
DNA replication
M mitosis
G2
5
G1
cell division
S
Cyclin-dependent kinase Cyclin B
DNA replication
Cdk1
CycB
M mitosis
G2
6
Wee1
P
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
CycD
CycB
CycA
TFEI
7
Gene Expression
S
R
Signal-Response Curve
8
Protein Phosphorylation
Kinase
ADP
ATP
R
RP
H2O
Pi
Phosphatase
Goldbeter Koshland, 1981
9
Protein Synthesis Positive Feedback
S
Open
R
EP
E
Closed
Bistability
Fuse
Griffith, 1968
10
dying
Example Fuse
response (R)
living
signal (S)
Apoptosis (Programmed Cell Death)
11
Protein Degradation Mutual Inhibition
S
R
EP
E
Toggle
Bistability
12
Positive Feedback Substrate Depletion
S
R
X
EP
E
Blinker Glycolytic Oscillations
Oscillation
Higgins, 1965 Selkov, 1968
13
Negative Feedback Loop
S
X
Y
YP
R
RP
Goodwin, 1965
14
Example Bacterial Chemotaxis
Barkai Leibler, 1997 Goldbeter Segel, 1986
Bray, Bourret Simon, 1993
15
Sniffer
X
S
R
(Levchenko Iglesias, 2002)
16
Example 2 Cell Cycle
high MPF
high SPF
DNA replication
primed MEN
fired RC
Cdk2
Cdk1
cell division
CycA
CycB
primed RC
fired MEN
low MPF
low SPF
(Csikasz-Nagy Novak, 2005)
17
Cock-and-Fire
LA
L
Signal CDK
Response F
18
Cock-and-Fire-2
Signal MPF
TA
Response BA
19
Wee1
P
Cdc20
Cdc14
TFBA
oscillator
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
bistable switch
CycB
Cdc14
Cdh1
Cdc25
bistable switch
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
bistable switch
oscillator
CycD
CycB
CycA
TFEI
20
Wee1
P
mass/nucleus
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
Fission Yeast
CycD
CycB
CycA
TFEI
21
3.0
Wild type
M
0.8
Cdk1CycB
0.4
S/G2
G1
0
SNIPER
0
1
2
3
4
5
mass/nucleus
22
Nature, Vol, 256, No. 5518, pp. 547-551, August
14, 1975
Genetic control of cell size at cell division in
yeast Paul Nurse Department of Zoology, West
Mains Road, Edinburgh EH9 3JT, UK
wild-type wee1D
23
Wee1
P
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
CycD
CycB
CycA
TFEI
24
wee1D cells are about one-half the size of wild
type
wee1?
M
Cdk1CycB
S/G2
G1
mass/nucleus
25
Two-parameter Bifurcation Diagram
SNIPER
wild-type
GENETICS
Wee1 activity
wee1-
cell mass (au.)
PHYSIOLOGY
26
Wee1
P
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
CycD
CycB
CycA
TFEI
27
The Start module is not required during mitotic
cycles
cki?
M
Cdk1CycB
S/G2
G1
mass/nucleus
28
Wee1
P
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
CycD
CycB
CycA
TFEI
29
Cells become progressively smaller without size
control
cki? wee1ts
2.0
0.8
M
Cdk1CycB
0.4
S/G2
G1
0
0 1 2 3 4 5
mass/nucleus
30
Wee1
P
Cdc20
Cdc14
TFBA
Wee1
TFBI
CycB
P
APC-P
APC
Cdc14
Cdc25
P
Cdc20
CycB
Cdc14
Cdh1
Cdc25
CycD
CKI
CycB
CycE
TFII
Cdh1
CycD
CycA
TFIA
CKI
CKI
CKI
CycA
CycE
Cyc E,A,B
Cdc20
CycA
CycE
TFEA
CycD
CycB
CycA
TFEI
31
Fission yeast
S
cdc13D
G2
G1
mitotic cycle
X
M
No production of cyclin B (Cdc13)
Production of Cdc13
?
?
mass
32
The Dynamical Perspective
Molecular Mechanism ?
? ? Physiological Properties
33
The Dynamical Perspective
Molecular Mechanism Kinetic Equations Vector
Field Stable Attractors Physiological
Properties
34
References

• Tyson, Chen Novak, Network dynamics and cell
  physiology, Nature Rev. Molec. Cell Biol. 2908
  (2001).
• Tyson, Csikasz-Nagy Novak, The dynamics of
  cell cycle regulation, BioEssays 241095 (2002).
• Tyson, Chen Novak, Sniffers, buzzers, toggles
  and blinkers, Curr. Opin. Cell Biol. 15221
  (2003).