MAP-Kinase-Cascade: Switch, Amplifier or Feedback Controller?

Nils Blüthgen¹ and Hanspeter Herzel
Institute for Theoretical Biologie
Humboldt University Berlin
Invalidenstr. 43, 10115 Berlin, Germany

1.6.2001

Abstract:

The three-step MAP-Kinase-Cascade is a highly conserved module in signaling pathways. By modeling the reaction kinetics of the cascade we investigate the properties of steady state solutions and the dynamical behavior under the action of a negative feedback loop.

The system shows different behavior depending on the fraction of activated MAPKK: in the low activation range a rather switch-like response is observed while in the intermediate activation range amplification increases. This corresponds to a shift of the operating point. In order to characterize the steady-state behavior of the whole MAP-kinase cascade we fit the signal response with a Hill curve. This defines a Hill coefficient for the entire system. Within this framework the models of Bhalla/Iyengar[4] and Huang/Ferrell[9] are compared and the remarkably different characteristics of their models can be understood. The robustness of the switch-like response is investigated by calculation of Hill-coefficients for varying reaction parameters.

Introducing an indirect negative feedback loop, the MAPK-Cascade shows damped oscillations, which can be interpreted as adaptation to different upstream signals. Asthagiri and Laufenburger suggest that the integral of activated MAPK over time is a reasonable metric for encapsulating information for transcription[1].