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

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.

[1]  M. Rubin,et al.  Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. , 2003, Journal of the National Cancer Institute.

[2]  Kwang-Hyun Cho,et al.  Optimal sampling time selection for parameter estimation in dynamic pathway modeling. , 2004, Bio Systems.

[3]  飯倉 洋治,et al.  ヒト好塩基球のシグナル伝達機構(Extracellular Signal-Regulated Kinase の役割の解明) , 2000 .

[4]  M. R. Osborne,et al.  Parameter estimation of ordinary differential equations , 2005 .

[5]  Karin Oien,et al.  Reduction of Raf-1 Kinase Inhibitor Protein Expression Correlates with Breast Cancer Metastasis , 2005, Clinical Cancer Research.

[6]  B. Kholodenko,et al.  Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades , 2004, The Journal of cell biology.

[7]  F. Holstege,et al.  Specific inhibition of gene expression using a stably integrated, inducible small‐interfering‐RNA vector , 2003, EMBO reports.

[8]  Athanasios Kehagias,et al.  Genetic Algorithm in Parameter Estimation of Nonlinear Dynamic Systems , 1998, PPSN.

[9]  Muffy Calder,et al.  When kinases meet mathematics: the systems biology of MAPK signalling , 2005, FEBS letters.

[10]  W. Kolch,et al.  Raf kinase inhibitor protein regulation of raf and MAPK signaling. , 2006, Methods in enzymology.

[11]  M Gyllenberg,et al.  Parameter identification in dynamical models of anaerobic waste water treatment. , 2002, Mathematical biosciences.

[12]  R. Seger,et al.  The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions , 2006, Growth factors.

[13]  P. Bastiaens,et al.  Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate , 2007, Nature Cell Biology.

[14]  W. Kolch,et al.  Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  T. Pawson,et al.  Mutational activation of c-raf-1 and definition of the minimal transforming sequence , 1990, Molecular and cellular biology.

[16]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[17]  W. Kolch,et al.  Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP , 1999, Nature.

[18]  J. Pessin,et al.  SOS Phosphorylation and Disassociation of the Grb2-SOS Complex by the ERK and JNK Signaling Pathways (*) , 1996, The Journal of Biological Chemistry.

[19]  E. Gilles,et al.  Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors , 2002, Nature Biotechnology.

[20]  Kwang-Hyun Cho,et al.  Mathematical Modeling of the Influence of RKIP on the ERK Signaling Pathway , 2003, CMSB.

[21]  A. Bosserhoff,et al.  Reduction in Raf Kinase Inhibitor Protein Expression Is Associated with Increased Ras-Extracellular Signal-Regulated Kinase Signaling in Melanoma Cell Lines , 2004, Cancer Research.

[22]  Kwang-Hyun Cho,et al.  Investigations Into the Analysis and Modeling of the TNFα-Mediated NF-κB-Signaling Pathway , 2003 .

[23]  B. Aggarwal,et al.  RKIP Sensitizes Prostate and Breast Cancer Cells to Drug-induced Apoptosis* , 2004, Journal of Biological Chemistry.

[24]  J. Hancock,et al.  Activation of the MAPK module from different spatial locations generates distinct system outputs. , 2008, Molecular biology of the cell.

[25]  B. Kholodenko,et al.  Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. , 2000, European journal of biochemistry.

[26]  W. Kolch.  Coordinating ERK/MAPK signalling through scaffolds and inhibitors , 2005, Nature Reviews Molecular Cell Biology.

[27]  W. Kolch,et al.  Mechanism of Suppression of the Raf/MEK/Extracellular Signal-Regulated Kinase Pathway by the Raf Kinase Inhibitor Protein , 2000, Molecular and Cellular Biology.

[28]  E. Eves,et al.  Activation of Raf-1 Signaling by Protein Kinase C through a Mechanism Involving Raf Kinase Inhibitory Protein* , 2003, The Journal of Biological Chemistry.

[29]  W. Kolch.  Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. , 2000, The Biochemical journal.

[30]  E. Keller,et al.  The role of Raf kinase inhibitor protein (RKIP) in health and disease. , 2004, Biochemical pharmacology.

[31]  Tianhai Tian,et al.  Plasma membrane nanoswitches generate high-fidelity Ras signal transduction , 2007, Nature Cell Biology.

[32]  Ryoichiro Kageyama,et al.  FGF induces oscillations of Hes1 expression and Ras/ERK activation , 2008, Current Biology.

[33]  A. Pellicer,et al.  Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. , 2003, Nature.

[34]  Marcel Salathé,et al.  Signal transduction networks: topology, response and biochemical processes. , 2006, Journal of theoretical biology.

[35]  W. Kolch,et al.  Mechanism of inhibition of Raf-1 by protein kinase A , 1994, Molecular and cellular biology.

[36]  F Khorasheh,et al.  Application of direct search optimization for pharmacokinetic parameter estimation. , 1999, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[37]  J. Timmer,et al.  Identification of nucleocytoplasmic cycling as a remote sensor in cellular signaling by databased modeling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Julian Downward,et al.  EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2 , 1997, Oncogene.

[39]  Kwang-Hyun Cho,et al.  Investigations into the analysis and modeling of the TNF alpha-mediated NF-kappa B-signaling pathway. , 2003, Genome research.

[40]  K. Guan,et al.  Desensitization of Ras Activation by a Feedback Disassociation of the SOS-Grb2 Complex (*) , 1995, The Journal of Biological Chemistry.

[41]  J. Pessin,et al.  Insulin-stimulated disassociation of the SOS-Grb2 complex , 1995, Molecular and cellular biology.

[42]  R. Wetzker,et al.  Ras activation in response to phorbol ester proceeds independently of the EGFR via an unconventional nucleotide-exchange factor system in COS-7 cells. , 2006, The Biochemical journal.

[43]  J. Ferrell.  Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. , 2002, Current opinion in cell biology.

[44]  Oliver E. Sturm,et al.  Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway. , 2005, The Biochemical journal.

[45]  Shinya Kuroda,et al.  Prediction and validation of the distinct dynamics of transient and sustained ERK activation , 2005, Nature Cell Biology.

[46]  Walter Kolch,et al.  Ras/Raf signalling and emerging pharmacotherapeutic targets , 2002, Expert opinion on pharmacotherapy.

[47]  Tom V. Mathew.  Genetic Algorithm , 2022 .

[48]  Richard Marais,et al.  The RAF proteins take centre stage , 2004, Nature Reviews Molecular Cell Biology.

[49]  C. Chu,et al.  Sustained extracellular signal‐regulated kinase activation by 6‐hydroxydopamine: implications for Parkinson's disease , 2001, Journal of neurochemistry.

[50]  D. Fell,et al.  Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cells , 2000, FEBS letters.

[51]  Seon Ki Park,et al.  Parameter estimation using the genetic algorithm and its impact on quantitative precipitation forecast , 2006 .

[52]  Carmen G. Moles,et al.  Parameter estimation in biochemical pathways: a comparison of global optimization methods. , 2003, Genome research.

[53]  G. Johnson,et al.  Measuring activation of kinases in mitogen-activated protein kinase regulatory network. , 1994, Methods in enzymology.

[54]  J. Olefsky,et al.  Negative Feedback Regulation and Desensitization of Insulin- and Epidermal Growth Factor-stimulated p21ras Activation (*) , 1995, The Journal of Biological Chemistry.

[55]  J. Timmer,et al.  Parameter estimation in ordinary differential equations for biochemical processes using the method of multiple shooting. , 2007, IET systems biology.

[56]  J. Parsons,et al.  Mitogen-Activated Protein Kinase Feedback Phosphorylation Regulates MEK1 Complex Formation and Activation during Cellular Adhesion , 2004, Molecular and Cellular Biology.

[57]  Peter J. Cullen,et al.  Phospholipase Cγ activates Ras on the Golgi apparatus by means of RasGRP1 , 2003, Nature.