title: The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier.
abstract: 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.
authors.affiliation: Department of Computing Science, University of Glasgow, Glasgow G12 8QQ, UK. walter.kolch@ucd.ie
authors.forename: Oliver E
authors.initials: OE
authors.lastname: Sturm
authors.forename: Richard
authors.initials: R
authors.lastname: Orton
authors.forename: Joan
authors.initials: J
authors.lastname: Grindlay
authors.forename: Marc
authors.initials: M
authors.lastname: Birtwistle
authors.forename: Vladislav
authors.initials: V
authors.lastname: Vyshemirsky
authors.forename: David
authors.initials: D
authors.lastname: Gilbert
authors.forename: Muffy
authors.initials: M
authors.lastname: Calder
authors.forename: Andrew
authors.initials: A
authors.lastname: Pitt
authors.forename: Boris
authors.initials: B
authors.lastname: Kholodenko
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
mesh_terms: D000818:Animals; D002070:Butadienes; D002462:Cell Membrane / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D005434:Flow Cytometry; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D007211:Indoles; D007700:Kinetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D051379:Mice; D008962:Models, Theoretical; D041681:NIH 3T3 Cells; D009570:Nitriles; D010766:Phosphorylation; D011799:Quinazolines; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: C433938:4557 W; D002070:Butadienes; C463259:D-64406; D020662:Guanine Nucleotide Exchange Factors; D007211:Indoles; D009570:Nitriles; D011799:Quinazolines; C113580:U 0126; D006160:Guanosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins