How cells make decisions?

1. How cells make decisions?

2. outputs External signals Information Processing System The cell is a (bio)chemical computer Hanahan & Weinberg (2000)

3. ? ?

4. Smad p21 MKK MAPK MAPK-P PP Signal transduction networks Hanahan & Weinberg (2000)

5. d [protein] dt = synthesis - degradation ‘Birth control’ for proteins DNA transcription factor transciption RNA translation protein

6. synthesis degradation degradation S linear 3 rate (dR/dt) k1 2 k2 R S=1 response (R) synthesis R signal (S) Gene expression S = mRNA R = protein Signal-response curve

7. Protein phosphorylation-dephosphorylation

8. Michaelis-Menten enzyme kinetics since [Eo] = [E] + [ES]

9. S 2 ADP ATP 1.5 dephospho- rylation rate (dRP/dt) k1 1 R RP k2 phospho- rylation 0.5 H2O Pi 0.25 RP sigmoidal R 0 1 response (RP) dephosphorylation phosphorylation signal (S) Protein phosphorylation Signal-response curve ‘Buzzer’ graded and reversible zero order ultrasensitivity Goldbeter & Koshland, 1981

10. k p k p R RP RP2RPn …… for n=2 Multiple phosphorylation where K=k/p

11. n=3 RP3 R K=k/p n=4 Hill equation: RP4 R K=k/p K=k/p Multiple phosphorylation n=2 RP2 R K=k/p

12. Coupling of modules

13. k3 synthesis k4 X S 3 degradation k1 k2 R rate (dR/dt) 2 1 R adapted S R X Response is independent of Signal time Two linear modules Perfect adaptation

14. S + X - + R Feed-forward loop S + X + - R R increases for S increase R decreases for S decrease R decreases for S increase R increases for S decrease

15. X S + RA S XA RA R + XA Feed-forward loop with two buzzers Cock and fire

16. Another way to get perfect adaptation S k1 k3 k0 R’ R k2

17. Bacterial chemotaxis swimming (counter-clockwise) tumbling (clockwise) The same principle, different deployment S k0 k1 R’ R k3 k2

18. Bacterial chemotaxis

19. Feedback controls

20. 16 8 S 0 rate (dR/dt) open k1 k2 R k0 synthesis degradation k3 EP E closed k4 R mutual activation response (R) response (R) ‘Toggle’ switch Scrit1 Scrit2 signal (S) signal (S) Linear module & buzzer Protein synthesis: positive feedback bistability ‘Fuse’

21. Example: Fuse dying response (R) living signal (S) Apoptosis (Programmed Cell Death)

22. S k1 k2 R k0 k3 EP E k4 The lac operon (‘toggle’ switch) S (extracellular lactose) EP R (intracellular lactose)

23. Multistability in the lactose utilization network of Escherichia coli ERTUGRUL M. OZBUDAK1,*, MUKUND THATTAI1,*, HAN N. LIM1, BORIS I. SHRAIMAN2 & ALEXANDER VAN OUDENAARDEN1 Initially uninduced cells grown for 20 hrs in 18 M TMG Initially uninduced cells (lower panel) andinduced cells (upper panel)grown in media containing different concentration of TMG TMG = thio-methylgalactoside

24. ‘Death control’ for proteins d [protein] dt = synthesis - degradation   proteasome ubiquitilation system degraded protein

25. S k1 k2 R k0 k2' degradation k4 EP E 1.8 k3 rate (dR/dt) 1.2 synthesis mutual inhibition 0.6 response (R) R signal (S) Linear module & buzzer Protein degradation: mutual inhibition

26. Oscillators: three modules

27. Scrit1 Scrit2 k5 k6 response (R) X S k2' k1 R k2 k0 PhasePlane k3 EP E k4 signal (S) R X Positive and negative feedback oscillations (activator-inhibitor)

28. p53 Mdm2 p53-CFP and Mdm2-YFP levelsin the nucleus after -irradiation Period of oscillation: 440  100 min

29. S k0' k2 X R k1 k0 k3 Scrit2 Scrit1 EP E k4 response (R) R signal (S) X Positive and negative feedback oscillations (substrate depletion)

30. S k1 k2 X k0 k2' k3 (2) Scrit1 Scrit2 Y YP k4 response (RP) k5 YP RP R X k6 (1) RP signal (S) time Negative feedback and oscillation

32. production removal 1.5 1 rate (dR/dt) 0.5 homeostatic response (R) R signal (S) Negative feedback and homeostasis S k0 R k2 k4 EP E k3

33. Typical biosynthetic pathway aminoacid demand protein