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Huang and Ferrell (1996), MAPK ultrasensitivity

June 2006, model of the month by Nicolas Le Novère
Original model: BIOMD0000000009

Many biological systems respond non-linearly to an effector. When one plots the response toward the logarithm of increasing signal intensity, this translates into a "sigmoid" curve with a slope at the inflexion point larger than one. Since the 1960s and the development of the allosteric theory [1], it was assumed that such an ultrasensitivity, observed in an increasing number of molecular systems, was due to positive cooperativities and oligomeric complexes. In the early 1980s, Albert Goldbeter and Daniel Koshland presented an alternative mechanism, based on a cascade of covalent modifications in the absence of cooperativity [2, 3]. This proved to be visionary, since the discovery of such an ultra-sensitive cascade in living cells only came almost a decade later, with the deciphering of the MAP kinase cascade.

Mitogen Activating Protein Kinases (MAPKs) are kinases initialy identified as activated by signals regulating cell cycle. However, it has now been shown that they are regulating gene expression in a larger variety of biological processes such as cell differentiation, cell survival/apoptosis, adaptation to drugs etc. The initial signal comes from the plasma membrane, while the last member of the cascade can enter the nucleus.

We had to wait for another half-decade before the first kinetic model of MAP kinase cascade was designed by Chi-Ying Huang and James Ferrell, based on experimental data and estimated constants [4].

Reaction graph of Huang and Ferrell 1996

The model was based on elementary steps, where all the associations, dissociations and conversions were represented, rather than a non-linear scheme such as Michaelis-Menten, where only conversions would be represented (For an in-depth discussion on the two approaches applied to MAPK models, see [5]). It comprised 20 reactions and 22 molecular species (see BIOMD0000000009). Contrarily to most of its followers, the model was not based on the cascade Raf/MEK1/ERK but on the cascade MOS/MEK1/P42 of Xenopus oocyte


The authors varied all the concentrations and the Michaelis constants of all the enzymes without modifying the main result: The Hill-coefficient of activation of MAPK is always greater than that of MAPKK, itself greater than that of MAPKKK. The double phosphorylation of MAPKK and MAPK was shown to increase the non-linearity of response.

Ultrasensitivity generated by the phosphorylation cascade

Most of the current models of MAP kinase cascade, as well as the derived model including the cascade, stem from the model of Huang and Ferrell. This pionneer position has been emphasised by Bhalla and colleagues in a reconstruction of the history of MAP kinase models [6].

History of the MAPK cascade models

Bibliographic References

  1. J. Monod, J. Wyman, and J. P. Changeux. On the nature of allosteric transitions: a plausible model. J Mol Biol, 12:88-118, May 1965. [PubMed]
  2. A. Goldbeter and D. E. Koshland. An amplified sensitivity arising from covalent modification in biological systems. Proc Natl Acad Sci USA, 78(11):6840-6844, Nov 1981. [PubMed]
  3. A. Goldbeter and D. E. Koshland. Ultrasensitivity in biochemical systems controlled by covalent modification. Interplay between zero-order and multistep effects. J Biol Chem, 259(23):14441-14447, Dec 1984. [PubMed]
  4. C. Y. Huang and J. E. Ferrell. Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA, 93(19):10087-10083. Sep 1996.[PubMed]
  5. N. I. Markevich, J. B. Hoek, and Boris N Kholodenko. Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. J Cell Biol, 164(3):353-359, Feb 2004. [PubMed]
  6. S. J. Vayttaden, S. M. Ajay, and U. S. Bhalla. A spectrum of models of signaling pathways. Chembiochem, 5(10):1365-1374, Oct 2004. [PubMed]