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MAPK Cascade - a Robust Decision-Maker

MAPK Cascade - a Robust Decision-Maker. Nils Blüthgen and Hanspeter Herzel FachInstitut f ür Theoretische Biology Humboldt-Universität zu Berlin. Gradual Stimuli Binary Response. Stimulus: Concentration of Ligands. Computation: Intracellular Signaling Network.

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MAPK Cascade - a Robust Decision-Maker

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 (unpublished)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

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

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

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

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

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

  10. MAPK cascade and PI3K pathway

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

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

  13. „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.

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

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