Network Dynamics and Network Dynamics and Cell Physiology Cell - - PowerPoint PPT Presentation

Network Dynamics and Network Dynamics and Cell Physiology Cell Physiology

John J. Tyson John J. Tyson

• Dept. Biological Sciences
• Dept. Biological Sciences

Virginia Tech Virginia Tech

Budapest Univ. Budapest Univ. Techn

• Techn. & Econ.

. & Econ. Bela Bela Novak Novak Attila Attila Csikasz Csikasz-

• Nagy

Nagy Andrea Andrea Ciliberto Ciliberto

Collaborators Collaborators

Virginia Tech Virginia Tech Kathy Chen Kathy Chen Jill Jill Sible Sible

A little history… A little history…

1970’s Belousov-Zhabotinsky Yeast Glycolysis Higgins, Prigogine … general principles of kinetics & thermo. Hess, Noyes … specific mechanisms of oscillations BrO3

• +CH2(COOH)2

BrCH(COOH)2 Br-+CO2+… Fe2+ Fe3+ ½ C6H12O6 C3H4O3 C3H6O3 NAD NADH

I n t h i s m a n n e r , t h e c l a s s

• f

c h e m i c a l s w i t c h i n g n e t w

• r

k s w i l l b e p r

• m

i s i n g c a n d i d a t e s f

• r

a p

• s

s i b l e n e w t e c h n

• l
• g

y

• f

c h e m i c a l r e a c t i

• n

s y s t e m s .

Hanahan & Weinberg (2000)

The Cell’s Computer…

P

Cdc25

Wee1 Wee1 P

Cdc25

CycB P

Cdc20 Cdc20

Cdh1 CKI

CycB CycB

CKI CKI

CycA CycA

APC-P APC

TFBI TFBA

CycE

CycD

TFEA TFEI

Cyc E,A,B

CycE

TFIA TFII Cdc20

CKI

CycE

Cdc14

Cdc14 Cdc14

CycA

CycA

CycB

CycD

Cdh1

CycD

“Machine-readable” form…

( )

' ' 1 1 2 2 3

d[C ycB ] [T FB ] [C dh1] [C ycB] [C K I][C ycB] d k k k k k t = + − + −

( )(

)

' 6 6 T 7 6 T 7

[C ycB] [C dc25] [C dc25] [PPase][C dc25] d[C dc25] d [C dc25] [C dc25] [C dc25] k k k t J J + − = − + − +

4 5

[W ee1][C ycB ] [C dc25][C ycB ~P] k k − +

phosphorylation dephosphorylation synthesis degradation binding activation inactivation

• M-phase

S-phase G2 G1

P

Cdc25

Wee1 Wee1 P

Cdc25

CycB P

Cdc20 Cdc20

Cdh1 CKI

CycB CycB

CKI CKI

CycA CycA

APC-P APC

TFBI TFBA

CycE

CycD

TFEA TFEI

Cyc E,A,B

CycE

TFIA TFII Cdc20

CKI

CycE

Cdc14

Cdc14 Cdc14

CycA

CycA

CycB

CycD

Cdh1

CycD

Network Motifs !

R S

0.5 1 2 3

response (R) signal (S)

linear

5 0.5 1

S=1 R rate (dR/dt) rate of degradation rate of synthesis S=2 S=3

Gene Expression

Signal-Response Curve

1 2

d , d R k S k R t = −

1 ss 2

k S R k =

R Kinase RP

ATP ADP H2O Pi

Protein Phosphorylation

1 2 0.5 1

RP rate (dRP/dt) 0.25 0.5 1 1.5 2

Phosphatase

0.5 1 1 2 3

response (RP) Signal (Kinase)

“Buzzer” Goldbeter & Koshland, 1981

1 R

R S EP E

0.1 0.2 0.3 0.4 0.5 0.6 0.5

R rate (dR/dt) S=0 S=8 S=16

0.5 10

response (R) signal (S)

Protein Synthesis: Positive Feedback

“Fuse” Bistability

Closed Open

Griffith, 1968

R S = Rtotal E EP

0.5 1 0.5 1 1.5

R E

Coupled Buzzers

0.5 1 1 2

response (R) signal (S)

SN SN

“Toggle” Bistability

RP

S=0.5 S=1.5 S=1

Frog egg MPF Cdc25-P Cdc25 MPF-P Wee1

0.5 1 1 2

response (MPF) signal (cyclin)

interphase m e t a p h a s e (inactive)

S = Total Cyclin

CycB

MPF =

2 4 6 8 10 12 14 6 12 18 24 30 60

MPF activity depends on total cyclin concentration and on the history of the extract

Cyclin concentration increasing inactivation threshold at 90 min

MPF activity nM ∆ ∆ ∆ ∆cyclin B

• 2

4 6 8 10 12 14 6 12 18 24 30 60

MPF activity nM ∆ ∆ ∆ ∆cyclin B

• Cyclin concentration decreasing

I M bistability Wei Sha & Jill Sible (2003)

Oscillations

0.5 1 1 2

MPF cyclin

MPF Cdc25-P Cdc25 MPF-P

(inactive)

cyclin synthesis cyclin degradation APC

0.0 0.5 1

signal (rate of cyclin synthesis)

Hopf Hopf

response (MPF)

sss sss uss

If knock-out positive feedback loop, then oscillations become faster and smaller amplitude…

Figure 4. Pomerening, Kim and Ferrell

With + feedback Without + feedback

P

Wee1 Wee1 P

Cdc25

CycB P

Cdc20 Cdc20

Cdh1 CKI

CycB CycB

CKI CKI

CycA CycA

APC-P APC

TFBI TFBA

CycE

CycD

TFEA TFEI

Cyc E,A,B

CycE

TFIA TFII Cdc20

CKI

CycE

Cdc14

Cdc14 Cdc14

CycA

CycA

CycB

CycD

Cdh1

CycD

bistable switch bistable switch bistable switch

• scillator
• scillator

Cdc25

P

Cdc25

Wee1 Wee1 P

Cdc25

CycB P

Cdc20 Cdc20

Cdh1 CKI

CycB CycB

CKI CKI

CycA CycA

APC-P APC

TFBI TFBA

CycE

CycD

TFEA TFEI

Cyc E,A,B

CycE

TFIA TFII Cdc20

CKI

CycE

Cdc14

Cdc14 Cdc14

CycA

CycA

CycB

CycD

Cdh1

CycD

• Fission Yeast

• !"

• !"#$%&

!"#$%&

'$%$ (%) * + &

• &&

'$%$ *

• *

• !"

• abscissa
• rdinate

• !"

!,$&-% '&.

Genetic control of cell size at cell division in yeast

Paul Nurse

Department of Zoology, West Mains Road, Edinburgh EH9 3JT, UK

Nature, Vol, 256, No. 5518, pp. 547-551, August 14, 1975

wild-type wee1∆ ∆ ∆ ∆

P

Cdc25

Wee1 Wee1 P

Cdc25

CycB P

Cdc20 Cdc20

Cdh1 CKI

CycB CycB

CKI CKI

CycA CycA

APC-P APC

TFBI TFBA

CycE

CycD

TFEA TFEI

Cyc E,A,B

CycE

TFIA TFII Cdc20

CKI

CycE

Cdc14

Cdc14 Cdc14

CycA

CycA

CycB

CycD

Cdh1

CycD

#∆ ∆ ∆ ∆

• #

#∆ ∆ ∆ ∆ ∆ ∆ ∆ ∆ $! $!% %&'!&('#!" &'!&('#!" !,$&-% '&/ ""$% %0&%

P

Cdc25

Wee1 Wee1 P CycB P

Cdc20 Cdc20

Cdh1 CKI

CycB CycB

CKI CKI

CycA CycA

APC-P APC

TFBI TFBA

CycE

CycD

TFEA TFEI

Cyc E,A,B

CycE

TFIA TFII Cdc20

CKI

CycE

Cdc14

Cdc14 Cdc14

CycA

CycA

CycB

CycD

Cdh1

CycD

Cdc25

• ∆

∆ ∆ ∆ )&!!!*!! )&!!!*!!

P

Cdc25

Wee1 Wee1 P

Cdc25

CycB P

Cdc20 Cdc20

Cdh1 CKI

CycB

CKI CKI

CycA CycA

APC-P APC

TFBI TFBA

CycE

CycD

TFEA TFEI

Cyc E,A,B

CycE

TFIA TFII Cdc20

CKI

CycE

Cdc14

Cdc14 Cdc14

CycA

CycA

CycB

CycD

Cdh1

CycD

CycB

• ∆

∆ ∆ ∆ #!

!

• +

,!&

• $"-#!&!(!

$"-#!&!(! 12,$&-% '&/ (%.

? ?

? ?

d CycBT dt = k1 . M - (k2' + k2" . Ste9 +k2'" . Slp1A) . CycBT dSte9 dt = k3' . 1 - Ste9 J3 + 1 - Ste9 - (k4' . SK + k4 . CycB) . Ste9 J4 + 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

dM dt = µ µ µ µ . M

James S. McDonnell Found. James S. McDonnell Found. DARPA DARPA

Thanks to Thanks to

References

• Tyson, Chen & Novak, “Network dynamics and

cell physiology,” Nature Rev. Molec. Cell Biol. 2:908 (2001).

• Tyson, Csikasz-Nagy & Novak, “The dynamics
• f cell cycle regulation,” BioEssays 24:1095

(2002).

• Tyson, Chen & Novak, “Sniffers, buzzers,

toggles and blinkers,” Curr. Opin. Cell Biol. 15:221 (2003).

"!! "!!

DNA mRNA Protein Enzyme Reaction Network Cell Physiology …TACCCGATGGCGAAATGC... …AUGGGCUACCGCUUUACG... …Met -Gly -Tyr -Arg -Phe -Thr...

ATP ADP

• P

X Y Z

E1 E2 E3 E4

.!!"

)&/"!- )&/"!-

& & &"! &"!

)&/"!- )&/"!-

& & !1*! !1*! 2! 2! !$3!!! !$3!!! &"! &"!

d CycBT dt = k1 . M - (k2' + k2" . Ste9 +k2'" . Slp1A) . CycBT dSte9 dt = k3' . 1 - Ste9 J3 + 1 - Ste9 - (k4' . SK + k4 . CycB) . Ste9 J4 + 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

dM dt = µ µ µ µ . M

“Machine-readable” form…

' 1 1 2 5

d[C ycA ] [E 2F] [C ycA ] [C K I][C ycA ] d k k k k t = + − −

( )

' ' 3 3 4 4 5

d[C ycB ] [T FB ] [C dh1] [C ycB] [C K I][C ycB] d k k k k k t = + − + −

( )(

)

( )

' ' 6 6 T 7 7 6 T 7

[C dc20] [C dh1] [C dh1] [C lb5] [C dh1] d[C dh1] d [C dh1] [C dh1] [C dh1] k k k k t J J + − + = − + − +

synthesis degradation synthesis degradation binding activation inactivation binding

R S EP E

0.1 0.2 0.3 0.4 0.5 0.6 0.5

R rate (dR/dt) S=0 S=8 S=16

Change parameters…

Griffith, 1968

0.5 1 1 2

response (R) signal (S)

SN SN

“Toggle”