The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier

Oliver E. Sturm, Richard Orton, Joan Grindlay, Marc Birtwistle, Vladislav Vyshemirsky, David Gilbert, Muffy Calder, Andrew Pitt, Boris Kholodenko, Walter Kolch

Research output: Contribution to journalArticle

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.
LanguageEnglish
Pagesra90
JournalScience Signaling
Volume3
Issue number153
DOIs
Publication statusPublished - 21 Dec 2010

Fingerprint

Feedback amplifiers
MAP Kinase Signaling System
Feedback
Phosphotransferases
Extracellular Signal-Regulated MAP Kinases
Chemical activation
Kinetics
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Mitogens
Linearization
Pharmaceutical Preparations
Protein Kinases
Amplification
Stabilization
Switches
Networks (circuits)

Keywords

  • animals
  • butadienes
  • cell membrane
  • extracellular signal-regulated MAP kinases
  • physiological feedback
  • flow cytometry
  • guanine nucleotide exchange factors
  • guanosine triphosphate
  • immunoblotting
  • immunoprecipitation
  • indoles
  • kinetics
  • MAP kinase kinase kinases
  • metabolic networks and pathways
  • mice
  • theoretical models
  • NIH 3T3 cells
  • nitriles
  • phosphorylation
  • quinazolines
  • signal transduction
  • ras proteins

Cite this

Sturm, O. E., Orton, R., Grindlay, J., Birtwistle, M., Vyshemirsky, V., Gilbert, D., ... Kolch, W. (2010). The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. Science Signaling, 3(153), ra90. https://doi.org/10.1126/scisignal.2001212
Sturm, Oliver E. ; Orton, Richard ; Grindlay, Joan ; Birtwistle, Marc ; Vyshemirsky, Vladislav ; Gilbert, David ; Calder, Muffy ; Pitt, Andrew ; Kholodenko, Boris ; Kolch, Walter. / The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. In: Science Signaling. 2010 ; Vol. 3, No. 153. pp. ra90.
@article{17264d6f0fe14e23a93147f4a38b7f74,
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.",
keywords = "animals, butadienes, cell membrane, extracellular signal-regulated MAP kinases, physiological feedback, flow cytometry, guanine nucleotide exchange factors, guanosine triphosphate, immunoblotting, immunoprecipitation, indoles, kinetics, MAP kinase kinase kinases, metabolic networks and pathways, mice, theoretical models, NIH 3T3 cells, nitriles, phosphorylation, quinazolines, signal transduction, ras proteins",
author = "Sturm, {Oliver E.} and Richard Orton and Joan Grindlay and Marc Birtwistle and Vladislav Vyshemirsky and David Gilbert and Muffy Calder and Andrew Pitt and Boris Kholodenko and Walter Kolch",
year = "2010",
month = "12",
day = "21",
doi = "10.1126/scisignal.2001212",
language = "English",
volume = "3",
pages = "ra90",
journal = "Science Signaling",
issn = "1945-0877",
publisher = "American Association for the Advancement of Science",
number = "153",

}

Sturm, OE, Orton, R, Grindlay, J, Birtwistle, M, Vyshemirsky, V, Gilbert, D, Calder, M, Pitt, A, Kholodenko, B & Kolch, W 2010, 'The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier' Science Signaling, vol. 3, no. 153, pp. ra90. https://doi.org/10.1126/scisignal.2001212

The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. / Sturm, Oliver E.; Orton, Richard; Grindlay, Joan; Birtwistle, Marc; Vyshemirsky, Vladislav; Gilbert, David; Calder, Muffy; Pitt, Andrew; Kholodenko, Boris; Kolch, Walter.

In: Science Signaling, Vol. 3, No. 153, 21.12.2010, p. ra90.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier

AU - Sturm, Oliver E.

AU - Orton, Richard

AU - Grindlay, Joan

AU - Birtwistle, Marc

AU - Vyshemirsky, Vladislav

AU - Gilbert, David

AU - Calder, Muffy

AU - Pitt, Andrew

AU - Kholodenko, Boris

AU - Kolch, Walter

PY - 2010/12/21

Y1 - 2010/12/21

N2 - 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.

AB - 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.

KW - animals

KW - butadienes

KW - cell membrane

KW - extracellular signal-regulated MAP kinases

KW - physiological feedback

KW - flow cytometry

KW - guanine nucleotide exchange factors

KW - guanosine triphosphate

KW - immunoblotting

KW - immunoprecipitation

KW - indoles

KW - kinetics

KW - MAP kinase kinase kinases

KW - metabolic networks and pathways

KW - mice

KW - theoretical models

KW - NIH 3T3 cells

KW - nitriles

KW - phosphorylation

KW - quinazolines

KW - signal transduction

KW - ras proteins

UR - http://www.scopus.com/inward/record.url?scp=78650635354&partnerID=8YFLogxK

U2 - 10.1126/scisignal.2001212

DO - 10.1126/scisignal.2001212

M3 - Article

VL - 3

SP - ra90

JO - Science Signaling

T2 - Science Signaling

JF - Science Signaling

SN - 1945-0877

IS - 153

ER -

Sturm OE, Orton R, Grindlay J, Birtwistle M, Vyshemirsky V, Gilbert D et al. The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. Science Signaling. 2010 Dec 21;3(153):ra90. https://doi.org/10.1126/scisignal.2001212