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Kholodenko (1999), Epidermal Growth Factor Receptor signalling

August 2006, model of the month by Renaud Schiappa
Original model: BIOMD0000000048

The epidermal growth factor receptor (EGFR) is part of the protein-tyrosine kinase receptor family. It regulates cell growth, survival, proliferation and differentiation. Epidermal growth factor binds to the EGFR, and facilitates receptor dimerization and rapid activation of its intrinsic tyrosine kinase, followed by autophosphorylation of multiple tyrosine residues in the cytoplasmic receptor domain. This tyrosine phosphorylation of EGFR triggers a number of biochemical reactions involving various protein domains (as an example, see Figure 1 for the targets involved in tumor cells [1]). Kholodenko et al developed the first detailed kinetic model of EGF receptor function [2] (a similar model was created in parallel by Bhalla and Iyengar [3]). The authors focus on the activation of the growth factor receptor-binding protein 2 (Grb2), Src homology and collagen domain protein (Shc) and phosholipase C-γ (PLC-γ). Pathways involving Grb2 and Shc lead to the activation of SOS (Son of Sevenless homolog protein, see [4] for a review) and finally expression of Ras protein.

Two other models involving EGFR are in the BioModels Database. Sasagawa et al. [5] (BIOMD0000000049) describes a model which goes further and includes the activation of MAPK cascade and ERK, while the model by Brown et al. [6] (BIOMD0000000033) uses EGF signalling as an example for describing an interesting way of estimating parameters.

Kholodenko et al. tried to understdand the behaviour of the cellular responses to epidermal growth factor by studying experimental data and constructing a computational model. After doing experiments on the cellular response to EGF, the authors created a kinetic model in order to resolve remaining questions (see Figure 2 for the kinetic model). Using the kinetic model, the authors were able to reproduce the results of the experiments. Further analysis of the kinetic model yielded additional insight into the underlying signalling mechanism.

Targets of EGFR involved in tumor cells Kinetic model

Figure 1 - Targets of EGFR involved in tumor cells (reprinted from [1])

Figure 2 - Graph describing the reactions included in the kinetic model of Kholodenko et al.

For example, the authors were able to explain how EGFR responded to the stimulation and why the early peak of the total phosphorylated EGFR was followed by a marked decline. Previously it was thought that a rapid burst of tyrosine phosphorylation of EGFR and/or some cytosolic targets caused the activation of tyrosine phosphatases which caused dephosphorylation of phospho-tyrosine residues on the receptor in a negative feedback loop. By looking at the curves of the EGFR autophosphorylation and dephosphorylation rates, the authors found that while the phosphorylated EGFR was processing its duty cycles (steps 5-20 in Figure 2), the phospho-tyrosine residues occupied by their ligand proteins were protected against dephosphorylation. Therefore the concentration of phosphorylated receptor bound to cytosolic ligand remained constant while the concentration of phosphorylated receptor lacking cytosolic ligand decreased as they were processed by the phosphatases. After the receptors released their cytosolic ligand they were actively dephosphorylated. The rate of dephosphorylation became more important than the tyrosine phosphorylation rate and the level of tyrosine phosphorylated EGFR decreased.

Total Phosphorylation of EGFR

Figure 3 - A result from the Kholodenko et al. model: EGFR phosphorylation as a function of EGF concentration.

The model by Kholodenko et al. was particularly innovating and showed how experimental data and a proper defined kinetic model can interact to yield new answers, and generate new questions and ideas for further experimentation.

Bibliographic References

  1. N. Normanno, A. De Luca, C. Bianco, L. Strizzi, M. Mancino, M. R. Maiello, A. Carotenuto, G. De Feo, F. Caponigro, and D. S. Salomon. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 366(1):2-16, Jan 2006. [PubMed]
  2. B. N. Kholodenko, O. V. Demin, G. Moehren, and J. B. Hoek. Quantification of short term signaling by the epidermal growth factor receptor. J Biol Chem, 274(42):30169-30181, Oct 1999. [PubMed]
  3. U. S. Bhalla and R. Iyengar. Emergent properties of networks of biological signaling pathways. Science, 283(5400):381-387, Jan 1999. [PubMed]
  4. A. Nimnual and D. Bar-Sagi. The two hats of SOS. Sci STKE, 2002(145):PE36, Aug 2002. [PubMed]
  5. S. Sasagawa, Y. Ozaki, K. Fujita, S. Kuroda. Prediction and validation of the distinct dynamics of transient and sustained ERK activation. Nat Cell Biol, 7(4):365-373, Apr 2005. [PubMed]
  6. K. S. Brown and J. P. Sethna. Statistical mechanical approaches to models with many poorly known parameters. Phys Rev E Stat Nonlin Soft Matter Phys. 68(2 Pt 1):021904, Aug 2003. [PubMed]