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First published online January 21, 2009
doi: 10.1242/10.1242/jcs.036319

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Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway

Sung-Young Shin^1,*, Oliver Rath^2,*, Sang-Mok Choo³, Frances Fee², Brian McFerran^2,, Walter Kolch^2,4, and Kwang-Hyun Cho^1,

¹ Department of Bio and Brain Engineering and KI for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
² Beatson Institute for Cancer Research, Cancer Research UK, Glasgow, UK
³ School of Electrical Engineering, University of Ulsan, Ulsan, Korea
⁴ Institute of Biomedical and Life Science, University of Glasgow, Glasgow, UK

Authors for correspondence (e-mails: ckh{at}kaist.ac.kr; w.kolch{at}beatson.gla.ac.uk)

Accepted 12 October 2008

The Ras-Raf-MEK-ERK pathway (or ERK pathway) is an important signal transduction system involved in the control of cell proliferation, survival and differentiation. However, the dynamic regulation of the pathway by positive- and negative-feedback mechanisms, in particular the functional role of Raf kinase inhibitor protein (RKIP) are still incompletely understood. RKIP is a physiological endogenous inhibitor of MEK phosphorylation by Raf kinases, but also participates in a positive-feedback loop in which ERK can inactivate RKIP. The aim of this study was to elucidate the hidden dynamics of these feedback mechanisms and to identify the functional role of RKIP through combined efforts of biochemical experiments and in silico simulations based on an experimentally validated mathematical model. We show that the negative-feedback loop from ERK to SOS plays a crucial role in generating an oscillatory behavior of ERK activity. The positive-feedback loop in which ERK functionally inactivates RKIP also enhances the oscillatory activation pattern of ERK. However, RKIP itself has an important role in inducing a switch-like behavior of MEK activity. When overexpressed, RKIP also causes delayed and reduced responses of ERK. Thus, positive- and negative-feedback loops and RKIP work together to shape the response pattern and dynamical characteristics of the ERK pathway.

Key words: Systems biology, ERK signaling pathway, RKIP, Feedback regulation, Dynamics, Mathematical modeling

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