1. MAPK Cascade - a Robust Decision-Maker Nils Blüthgen and Hanspeter Herzel FachInstitut für Theoretische Biology Humboldt-Universität zu Berlin

2. Gradual Stimuli Binary Response Stimulus: Concentration of Ligands Computation:Intracellular Signaling Network Reponse: Changes in Genexpression Decision:either Apoptosis or Surviaval either Devision or Rest

3. MAPKKK MAPKK MAPK J. Wolf et al. (unpublished)

4. A Model of the MAPK Cascade Kinetics: A+E AE A*+E Irreversible Mass Action Stimulus MAPK shows switch-like stimulus response curves. Response

5. Mechanisms leading to Ultrasensitivity multisite phosphorylation enzyme saturation enhanced by cascade-like structure Are these mechanisms robust and evolutionary favorable?

6. Investigating the Robustness of Ultrasensitivity Cytosolic and allelic variability correspont to random changes of all kinetic parameters and concentrations.

7. Stimulus Response h - Hill coefficient Quantification of......parameter changes...ultrasensitivity Investigating the Robustness of Ultrasensitivity Total parameter variation Generate new Parametersets Measure the Ultrasensitivity

8. Robustness with respect to random parameter variations MAPK Model Switch-like behaviour of MAPK cascade more robust than that of the Goldeter-Koshland switch Goldbeter/ Koshland model AA* Goldbeter-Koshland switch

9. Conclusions Double phosphorylation + Enzyme saturation + cascade-like structure = switch-like behavior This is a robust property of MAPK cascade

11. MAPK cascade and PI3K pathway

12. Pathways for phosphoinositide synthesis Toker & Cantley (1997), Nature 387, 673-676.

13. Enhanced lipid signaling is likely to lead to anchorage-independent growth, increased proliferative potential, increases cell motility, evasion of apoptosis -> Cell Transformation

15. „It is likely, that some of the apparent complexity in mammalian signaling reflects timing differences in the activation of these pathways.“ Noselli & Perrimon (2000), Science 290, 68. „The use of transiently expressed, constitutively-active or dominant-negative PKB constructs may force interactions that rarely occur naturally.“ Scheid & Woodgett (2000), Curr. Biol. 10, 191.

17. MAPK cascade and PI3K pathway: crosstalk MAPKKK PKB-PPPP Ras