Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 21 December 2010
Vol. 3, Issue 153, p. ra90
[DOI: 10.1126/scisignal.2001212]


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

Oliver E. Sturm1*{dagger}, Richard Orton1*{ddagger}, Joan Grindlay2*, Marc Birtwistle3, Vladislav Vyshemirsky1§, David Gilbert1||, Muffy Calder1, Andrew Pitt4, Boris Kholodenko3, and Walter Kolch3,5

1 Department of Computing Science, University of Glasgow, Glasgow G12 8QQ, UK.
2 Signalling and Proteomics Laboratory, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
3 Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
4 Sir Henry Wellcome Functional Genomics Facility, University of Glasgow, Glasgow G12 8QQ, UK.
5 Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

* These authors contributed equally to this work.

{dagger} Present address: Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38104, USA.

{ddagger} Present address: Comparative Epidemiology Group, Faculty of Veterinary Medicine, University of Glasgow, Glasgow G61 1QH, UK.

§ Present address: Department of Mathematics and Statistics, University of Strathclyde, Glasgow G1 1XH, UK.

|| Present address: School of Information Systems, Computing and Mathematics, Brunel University, Uxbridge, Middlesex UB8 3PH, UK.

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.

¶ To whom correspondence should be addressed. E-mail: walter.kolch{at}

Citation: O. E. Sturm, R. Orton, J. Grindlay, M. Birtwistle, V. Vyshemirsky, D. Gilbert, M. Calder, A. Pitt, B. Kholodenko, W. Kolch, The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier. Sci. Signal. 3, ra90 (2010).

Read the Full Text

Strong negative feedback from Erk to Raf confers robustness to MAPK signalling.
R. Fritsche-Guenther, F. Witzel, A. Sieber, R. Herr, N. Schmidt, S. Braun, T. Brummer, C. Sers, and N. Bluthgen (2014)
Mol Syst Biol 7, 489
   Abstract »    Full Text »    PDF »
Data-driven modeling reconciles kinetics of ERK phosphorylation, localization, and activity states.
S. Ahmed, K. G. Grant, L. E. Edwards, A. Rahman, M. Cirit, M. B. Goshe, and J. M. Haugh (2014)
Mol Syst Biol 10, 718
   Abstract »    Full Text »    PDF »
Network quantification of EGFR signaling unveils potential for targeted combination therapy.
B. Klinger, A. Sieber, R. Fritsche-Guenther, F. Witzel, L. Berry, D. Schumacher, Y. Yan, P. Durek, M. Merchant, R. Schafer, et al. (2014)
Mol Syst Biol 9, 673
   Abstract »    Full Text »    PDF »
Molecular Pathways: Response and Resistance to BRAF and MEK Inhibitors in BRAFV600E Tumors.
M. D. Thakur and D. D. Stuart (2014)
Clin. Cancer Res. 20, 1074-1080
   Abstract »    Full Text »    PDF »
Small G Proteins Rac1 and Ras Regulate Serine/Threonine Protein Phosphatase 5 (PP5){middle dot}Extracellular Signal-Regulated Kinase (ERK) Complexes Involved in the Feedback Regulation of Raf1.
M. D. Mazalouskas, R. Godoy-Ruiz, D. J. Weber, D. B. Zimmer, R. E. Honkanen, and B. E. Wadzinski (2014)
J. Biol. Chem. 289, 4219-4232
   Abstract »    Full Text »    PDF »
Nested autoinhibitory feedbacks alter the resistance of homeostatic adaptive biochemical networks.
J. Schaber, A. Lapytsko, and D. Flockerzi (2014)
J R Soc Interface 11, 20130971
   Abstract »    Full Text »    PDF »
Information transfer by leaky, heterogeneous, protein kinase signaling systems.
M. Voliotis, R. M. Perrett, C. McWilliams, C. A. McArdle, and C. G. Bowsher (2014)
PNAS 111, E326-E333
   Abstract »    Full Text »    PDF »
From Bench to Bedside: Lessons Learned in Translating Preclinical Studies in Cancer Drug Development.
C. H. Lieu, A.-C. Tan, S. Leong, J. R. Diamond, and S. G. Eckhardt (2013)
J Natl Cancer Inst 105, 1441-1456
   Abstract »    Full Text »    PDF »
Systems medicine: helping us understand the complexity of disease.
D. Vandamme, W. Fitzmaurice, B. Kholodenko, and W. Kolch (2013)
QJM 106, 891-895
   Abstract »    Full Text »    PDF »
Unintentional Weakness of Cancers: The MEK-ERK Pathway as a Double-Edged Sword.
K. Suda and T. Mitsudomi (2013)
Mol. Cancer Res. 11, 1125-1128
   Abstract »    Full Text »    PDF »
Negative feedback self-regulation contributes to robust and high-fidelity transmembrane signal transduction.
M. A. Serrano, M. Jurado, and R. Reigada (2013)
J R Soc Interface 10, 20130581
   Abstract »    Full Text »    PDF »
Complexity of Receptor Tyrosine Kinase Signal Processing.
N. Volinsky and B. N. Kholodenko (2013)
Cold Spring Harb Perspect Biol 5, a009043
   Abstract »    Full Text »    PDF »
Signaling to Extracellular Signal-regulated Kinase from ErbB1 Kinase and Protein Kinase C: FEEDBACK, HETEROGENEITY, AND GATING.
R. M. Perrett, R. C. Fowkes, C. J. Caunt, K. Tsaneva-Atanasova, C. G. Bowsher, and C. A. McArdle (2013)
J. Biol. Chem. 288, 21001-21014
   Abstract »    Full Text »    PDF »
Receptor Tyrosine Kinases Fall into Distinct Classes Based on Their Inferred Signaling Networks.
J. P. Wagner, A. Wolf-Yadlin, M. Sevecka, J. K. Grenier, D. E. Root, D. A. Lauffenburger, and G. MacBeath (2013)
Science Signaling 6, ra58
   Abstract »    Full Text »    PDF »
Relief of Feedback Inhibition of HER3 Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in BRAF-Mutant Thyroid Carcinomas.
C. Montero-Conde, S. Ruiz-Llorente, J. M. Dominguez, J. A. Knauf, A. Viale, E. J. Sherman, M. Ryder, R. A. Ghossein, N. Rosen, and J. A. Fagin (2013)
Cancer Discovery 3, 520-533
   Abstract »    Full Text »    PDF »
Ultrasensitive response motifs: basic amplifiers in molecular signalling networks.
Q. Zhang, S. Bhattacharya, and M. E. Andersen (2013)
Open Bio 3, 130031
   Abstract »    Full Text »    PDF »
Systems pharmacology of the nerve growth factor pathway: use of a systems biology model for the identification of key drug targets using sensitivity analysis and the integration of physiology and pharmacology.
N. Benson, T. Matsuura, S. Smirnov, O. Demin, H. M. Jones, P. Dua, and P. H. van der Graaf (2013)
Interface Focus 3, 20120071
   Abstract »    Full Text »    PDF »
ERK-Mediated Phosphorylation of Fibroblast Growth Factor Receptor 1 on Ser777 Inhibits Signaling.
M. Zakrzewska, E. M. Haugsten, B. Nadratowska-Wesolowska, A. Oppelt, B. Hausott, Y. Jin, J. Otlewski, J. Wesche, and A. Wiedlocha (2013)
Science Signaling 6, ra11
   Abstract »    Full Text »    PDF »
The Temporal Pattern of Stimulation Determines the Extent and Duration of MAPK Activation in a Caenorhabditis elegans Sensory Neuron.
T. Tomida, S. Oda, M. Takekawa, Y. Iino, and H. Saito (2012)
Science Signaling 5, ra76
   Abstract »    Full Text »    PDF »
The Response of Cancers to BRAF Inhibition Underscores the Importance of Cancer Systems Biology.
E. C. Stites (2012)
Science Signaling 5, pe46
   Abstract »    Full Text »    PDF »
Multiple protein kinases influence the redistribution of fission yeast Clp1/Cdc14 phosphatase upon genotoxic stress.
M. R. Broadus and K. L. Gould (2012)
Mol. Biol. Cell 23, 4118-4128
   Abstract »    Full Text »    PDF »
Combined computational and experimental analysis reveals mitogen-activated protein kinase-mediated feedback phosphorylation as a mechanism for signaling specificity.
N. Hao, N. Yildirim, M. J. Nagiec, S. C. Parnell, B. Errede, H. G. Dohlman, and T. C. Elston (2012)
Mol. Biol. Cell 23, 3899-3910
   Abstract »    Full Text »    PDF »
Kinase-Impaired BRAF Mutations in Lung Cancer Confer Sensitivity to Dasatinib.
B. Sen, S. Peng, X. Tang, H. S. Erickson, H. Galindo, T. Mazumdar, D. J. Stewart, I. Wistuba, and F. M. Johnson (2012)
Science Translational Medicine 4, 136ra70
   Abstract »    Full Text »    PDF »
Computational Approaches for Analyzing Information Flow in Biological Networks.
B. Kholodenko, M. B. Yaffe, and W. Kolch (2012)
Science Signaling 5, re1
   Abstract »    Full Text »    PDF »
Quantifying Crosstalk Among Interferon-{gamma}, Interleukin-12, and Tumor Necrosis Factor Signaling Pathways Within a TH1 Cell Model.
D. J. Klinke II, N. Cheng, and E. Chambers (2012)
Science Signaling 5, ra32
   Abstract »    Full Text »    PDF »
Signalling in space and time: systems dynamics of intracellular communication.
S. Tzlil and R. Kuruvilla (2011)
EMBO Rep. 12, 877-879
   Full Text »    PDF »
Resistance to MEK Inhibitors: Should We Co-Target Upstream?.
P. I. Poulikakos and D. B. Solit (2011)
Science Signaling 4, pe16
   Abstract »    Full Text »    PDF »
Raf Family Kinases: Old Dogs Have Learned New Tricks.
D. Matallanas, M. Birtwistle, D. Romano, A. Zebisch, J. Rauch, A. von Kriegsheim, and W. Kolch (2011)
Genes & Cancer 2, 232-260
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882