(593a) The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier | AIChE

(593a) The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier


Birtwistle, M. R. - Presenter, University College Dublin
Kholodenko, B. N. - Presenter, University College Dublin
Kolch, W. - Presenter, University College Dublin
Sturm, O. - Presenter, University of Glasgow
Orton, R. - Presenter, University of Glasgow
Vyshemirsky, V. - Presenter, University of Glasgow
Gilbert, D. - Presenter, University of Glasgow
Calder, M. - Presenter, University of Glasgow
Grindlay, J. - Presenter, Beatson Institute for Cancer Research
Pitt, A. - Presenter, University of Glasgow

Three-tiered kinase modules, such as the Raf–MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase)–ERK (extracellular signal–regulated kinase) mitogen-activated protein kinase pathway, are widespread in biology, suggesting that this structure conveys evolutionarily advantageous properties. We show that the three-tiered kinase amplifier module combined with negative feedback recapitulates the design principles of a negative feedback amplifier (NFA), which is used in electronic circuits to confer robustness, output stabilization, and linearization of nonlinear signal amplification. We used mathematical modeling and experimental validation to demonstrate that the ERK pathway has properties of an NFA that (i) converts intrinsic switch-like activation kinetics into graded linear responses, (ii) conveys robustness to changes in rates of reactions within the NFA module, and (iii) stabilizes outputs in response to drug-induced perturbations of the amplifier. These properties determine biological behavior, including activation kinetics and the response to drugs.