Network Dynamics and Cell Physiology John J Tyson

Network Dynamics and Cell Physiology John J. Tyson Biological Sciences Virginia Tech

Collaborators Funding Agencies Kathy Chen Jill Sible Bela Novak Attila Csikasz DARPA Mc. Donnell Found

Cell signaling External signals Growth Development Internal Signals Death Information Processing System Division Reproduction Hanahan & Weinberg (2000)

Information Processing Systems Laptop Brain Cell Silicon Carbon Solid state Membrany Analog/digital Watery $$ Digital Sequential Programmable Precise Manufactured Designed Parallel Learning Accurate Soma/germ Analog Parallel Hard-wired Sloppy Self-reproducing Evolved

Signal Transduction Network Smad p 21 MKK MAPK-P PP 2 A Hanahan & Weinberg (2000)

Gene Expression linear rate (d. R/dt) S S=3 S=2 R S=1 response (R) rate of degradation rate of synthesis R signal (S) Signal-Response Curve

Protein Phosphorylation Kinase RP Pi response (RP) R ADP 1. 5 rate (d. RP/dt) ATP 2 1 0. 5 H 2 O 0. 25 Phosphatase RP 1 R Signal (Kinase) 0 “Buzzer” Goldbeter & Koshland, 1981

Protein Synthesis: Positive Feedback S=16 S=8 rate (d. R/dt) R EP S=0 Closed E R Bistability Griffith, 1968 Open response (R) S signal (S) “Fuse”

response (R) Example: Fuse dying living signal (S) Eissing et al. (2004) J Biol Chem 279: 36892 Apoptosis (Programmed Cell Death)

Coupled Buzzers S = Rtotal R RP S=1. 5 E S=0. 5 response (R) 1 SN 0. 5 SN E EP 0 0 0. 5 R 1 Bistability 1. 5 signal (S) “Toggle”

m et a ph as e response (MPF) interphase signal (cyclin) Frog egg S = Total Cyclin MPF = MPF Cyc. B Wee 1 MPF-P (inactive) M-phase Promoting Factor Cdc 25 -P

MPF activity depends on total cyclin concentration and on the history of the extract I MPF activity Cyclin concentration increasing I I I M M I n. M Dcyclin B MPF activity Cyclin concentration decreasing inactivation threshold at 90 min I I Wei Sha & Jill Sible (2003) I I/M M n. M Dcyclin B M M bistability

MPF Oscillations Hopf response (MPF) cyclin synthesis sss uss APC cyclin degradation sss MPF (inactive) signal (rate of cyclin synthesis) negative feedback loop MPF-P Cdc 25 -P

Pomerening, Kim & Ferrell Cell (2005)

If knock-out positive feedback loop, then oscillations become faster and smaller amplitude… With + feedback Without + feedback Figure 4. Pomerening, Kim and Ferrell

P Wee 1 Cdc 20 Cdc 14 P TFBA Wee 1 Cyc. B Cdc 25 Cdc 14 Cdc 25 TFBI APC-P Cdc 14 0 P c 2 Cd Cyc. B MPF

P Wee 1 Cdc 20 Cdc 14 Wee 1 Cyc. B Cdc 25 TFBI APC-P 0 P c 2 Cd Cyc. B Cdc 14 h 1 Cd CKI Cdc 25 Cyc. D Cyc. B Cyc. E TFII Cdh 1 TFIA CKI Cyc. A Cyc. D CKI P TFBA Cyc. A 0 c 2 Cd Cyc. A TFEA Cyc. B TFEI SPF

Cell Cycle Regulation high SPF high MPF primed MEN fired RC Cdk 2 Cdk 1 Cyc. A Cyc. B primed RC low SPF fired MEN low MPF

Cdk 2 Cyc. A SPF Licensing Factor Replication Complex Csikasz-Nagy & Novak, 2005 time “Cock-and-Fire”

Cdk 1 Cyc. B Primer Mitotic Exit Network Csikasz-Nagy & Novak, 2005 MPF time

P Wee 1 mass/nucleus Cdc 14 P TFBA Wee 1 Cyc. B Cdc 25 Cdc 20 TFBI neg fdbk osc APC-P Cdc 14 0 P c 2 Cd Cyc. B Cdc 14 h 1 Cd CKI Cdc 25 bistable switch Cyc. D Cyc. B Cyc. E TFII Cdh 1 TFIA CKI CKI Cyc. A Cyc. D Cyc. E Cyc. A bistable switch Cyc E, A, B 0 c 2 Cd Cyc. E TFEA Fission Yeast Cyc. B Cyc. D Cyc. A TFEI Cyc. A

P Wee 1 mass/nucleus Cdc 14 TFBA M Wee 1 Cyc. B S/G 2 Cdc 25 TFBI M APC-P Cdc 14 0 P c 2 Cd Cyc. B Cdc 14 h 1 Cd CKI Cdc 25 M Cyc. D Cyc. B Cyc. E TFII Cdh 1 TFIA CKI Cyc. A Cyc. D CKI P Cdc 20 Cyc. E G 1 Cyc. A Cyc E, A, B 0 c 2 Cd Cyc. E TFEA Fission Yeast Cyc. B Cyc. D Cyc. A TFEI Cyc. A

3. 0 Wild type M Cdk 1: Cyc. B 0. 8 SNIC 0. 4 S/G 2 G 1 0 0 1 2 3 mass/nucleus 4 5

SNIC Bifurcation Invariant Circle Saddle-Node on an Invariant Circle SNIC saddle max Limit Cycle x 2 node min p 1

3. 0 Wild type M Cdk 1: Cyc. B 0. 8 enter M exit M 0. 4 G 1 0 S/G 2 cell division G 1 0 1 2 3 mass/nucleus 4 5

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 EH 9 3 JT, UK wild-type wee 1

P Wee 1 Cdc 20 Cdc 14 Wee 1 Cyc. B Cdc 25 TFBI APC-P Cdc 14 0 P c 2 Cd Cyc. B Cdc 14 h 1 Cd CKI Cdc 25 Cyc. D Cyc. B Cyc. E TFII Cdh 1 TFIA CKI Cyc. A Cyc. D CKI P TFBA Cyc. E Cyc. A Cyc E, A, B 0 c 2 Cd Cyc. E Cyc. A TFEA Cyc. B Cyc. D Cyc. A TFEI

wee 1 cells are about one-half the size of wild type 1. 2 wee 1 Cdk 1: Cyc. B M 0. 8 0. 4 S/G 2 0 G 1 0 1 2 3 mass/nucleus 4 5

Two-parameter Bifurcation Diagram 2 x wee 1+ HB 1 Wee 1 activity Genetics B SN 2 wild-type wee 1+/wee 1 SN 1 cell mass (au. ) Physiology period (min) <30 60 90 120 150 180 210 240 270 300<

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, ” Bio. Essays 24: 1095 (2002). • Tyson, Chen & Novak, “Sniffers, buzzers, toggles and blinkers, ” Curr. Opin. Cell Biol. 15: 221 (2003). • Csikasz-Nagy et al. , “Analysis of a generic model of eukaryotic cell-cycle regulation, ” Biophys. J. 90: 4361 (2006).