Dynamical Analysis of Cellular Signal Transduction Pathways with Nonlinear Systems Perspectives

비선형시스템 관점으로부터 세포 신호전달경로의 동역학 분석

  • 김현우 (울산대학교 전기전자정보시스템공학부) ;
  • 조광현 (서울대학교 의과대학 의학과 및 서울대학교 생명공학공동연구원)
  • Published : 2004.12.01


Extracellular signal-regulated kinase (ERK) signaling pathway is one of the mitogen-activated protein kinase (MAPK) signal transduction pathways. This pathway is known as pivotal in many signaling networks that govern proliferation, differentiation and cell survival. The ERK signaling pathway comprises positive and negative feedback loops, depending on whether the terminal kinase stimulates or inhibits the activation of the initial level. In this paper, we attempt to model the ERK pathway by considering both of the positive and negative feedback mechanisms based on Michaelis-Menten kinetics. In addition, we propose a fraction ratio model based on the mass action law. We first develop a mathematical model of the ERK pathway with fraction ratios. Secondly, we analyze the dynamical properties of the fraction ratio model based on simulation studies. Furthermore, we propose a concept of an inhibitor, catalyst, and substrate (ICS) controller which regulates the inhibitor, catalyst, and substrate concentrations of the ERK signal transduction pathway. The ICS controller can be designed through dynamical analysis of the ERK signaling transduction pathway within limited concentration ranges.


  1. S. Arimoto, 'Linear controllable systems,' Nature, vol. 135, pp. 18-27, July, 1990
  2. B. Schoeberl, C. Eichler-Jonsson, E. D. Gilles, and G. Muller, 'Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors,' Nature Biotechnology, vol. 20, pp. 370-375, Apr., 2002
  3. U. S. Bhalla and R. Iyengar, 'Emergent properties of networks of biological signaling pathways,' Science, vol. 283, pp. 381-387, Jan., 1999
  4. K.-H. Cho, S.-Y. Shin, H.-W. Kim, O. Wolkenhauer, B. McFerran, and W. Kolch, Computational methods in systems biology, Berlin: Springer-Verlag, pp. 127-141,2003
  5. K. Yeung, T. Seitz, S. Li, P. Janosch, B. McFerran, C. Kaiser, F. Fee, K. D. Katsanakis, D. W. Rose, H. Mischak, J. M. Sedivy, and W. Kolch, 'Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP,' Nature, vol. 401, pp. 173-177, Sep., 1999
  6. B. N. Kholodenko, 'Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades,' Eur. J. Biochem., vol. 267, pp. 1583-1588, Mar., 2000
  7. F. A. Brightman and D. A. Fell, 'Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cells,' FEBS Lett., vol. 482, pp. 169-174, Oct., 2000
  8. W. Kolch, 'Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions,' Biochem. J., vol. 351, pp. 289-305, Oct., 2000
  9. K. Yeung, P, Janosch, B. McFerran, D. W. Rose, H. Mischak, J. M. Sedivy, and W. Kolch, 'Mechanism of suppression of the Raf/MEK/Extracellular signal-regulated kinase pathway by the Raf kinase inhibitor protein,' Mol. Cell. Biol., vol. 20, no. 9, pp. 3079-3085, May, 2000
  10. A. S. Dhillon, S. Meikle, Z. Yazici, M. Eulitz, and W. Kolch, 'Regulation of Raf-1 activation and signalling by dephosphorylation,' EMBO J., vol. 21, pp. 64-71, Jan., 2002
  11. E. Kerkhoff and U. R. Rapp, 'The Ras-Raf relationship: an unfinished puzzle,' Advan. Enzyme Regul., vol. 41, pp. 261-267, 2001
  12. B. N. Kholodenko, A. Kiyatkin, F. J. Bruggeman, E. Sontag, H. V. Westerhoff, and J. B. Hoek, 'Untangling the wires: a strategy to trace functional interactions in signaling and gene networks,' PNAS, vol. 99, no. 20, pp. 12841-12846, Oct., 2002
  13. A. R. Asthagiri and D. A. Lauffenburger, 'A computational study of feedback effects on signal dynamics in a mitogen-activated protein kinase (MAPK) pathway model,' Biotechnol. Prog., vol. 17, pp. 227-239, Mar., 2001
  14. B. C. Kuo and F. Golnaraghi, Automatic Control Systems, N.J.: John Wiley & Sons, 2003