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

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

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 (unpublished)

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

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

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

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

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

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

MAPK cascade and PI3K pathway

Pathways for phosphoinositide synthesis Toker & Cantley (1997), Nature 387,

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

„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.

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