Fuzzy Logic Analysis of Kinase Pathway Crosstalk in TNF/EGF/Insulin-Induced Signaling

When modeling cell signaling networks, a balance must be struck between mechanistic detail and ease of interpretation. In this paper we apply a fuzzy logic framework to the analysis of a large, systematic dataset describing the dynamics of cell signaling downstream of TNF, EGF, and insulin receptors in human colon carcinoma cells. Simulations based on fuzzy logic recapitulate most features of the data and generate several predictions involving pathway crosstalk and regulation. We uncover a relationship between MK2 and ERK pathways that might account for the previously identified pro-survival influence of MK2. We also find unexpected inhibition of IKK following EGF treatment, possibly due to down-regulation of autocrine signaling. More generally, fuzzy logic models are flexible, able to incorporate qualitative and noisy data, and powerful enough to produce quantitative predictions and new biological insights about the operation of signaling networks.

[1]  L. Hood,et al.  Highly accurate two-gene classifier for differentiating gastrointestinal stromal tumors and leiomyosarcomas , 2007, Proceedings of the National Academy of Sciences.

[2]  Hidde de Jong,et al.  Modeling and Simulation of Genetic Regulatory Systems: A Literature Review , 2002, J. Comput. Biol..

[3]  E. Lam,et al.  FOXO transcription factors: key regulators of cell fate. , 2006, Biochemical Society transactions.

[4]  E. Wimmer,et al.  MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network , 2022 .

[5]  S. Huang,et al.  Shape-dependent control of cell growth, differentiation, and apoptosis: switching between attractors in cell regulatory networks. , 2000, Experimental cell research.

[6]  Tiegang Liu,et al.  Smooth muscle alpha-actin expression and myofibroblast differentiation by TGFbeta are dependent upon MK2. , 2007, Journal of cellular biochemistry.

[7]  J. Collins,et al.  Large-Scale Mapping and Validation of Escherichia coli Transcriptional Regulation from a Compendium of Expression Profiles , 2007, PLoS biology.

[8]  A. Hoffmann,et al.  The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. , 2002, Science.

[9]  Magnus Bosse,et al.  Regulation of Raf-Akt Cross-talk , 2002, The Journal of Biological Chemistry.

[10]  D. Lauffenburger,et al.  A Compendium of Signals and Responses Triggered by Prodeath and Prosurvival Cytokines*S , 2005, Molecular & Cellular Proteomics.

[11]  U. Bhalla,et al.  Complexity in biological signaling systems. , 1999, Science.

[12]  Jehoshua Bruck,et al.  Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Alan V. Oppenheim,et al.  Modeling cellular signal processing using interacting Markov chains , 2003, 2003 IEEE International Conference on Acoustics, Speech, and Signal Processing, 2003. Proceedings. (ICASSP '03)..

[14]  Prahlad T. Ram,et al.  MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network , 2002, Science.

[15]  Lotfi A. Zadeh,et al.  Fuzzy logic = computing with words , 1996, IEEE Trans. Fuzzy Syst..

[16]  J. Ricort,et al.  Growth factor-specific regulation of insulin receptor substrate-1 expression in MCF-7 breast carcinoma cells: effects on the insulin-like growth factor signaling pathway. , 2003, Endocrinology.

[17]  Mark von Zastrow,et al.  Signal transduction and endocytosis: close encounters of many kinds , 2002, Nature Reviews Molecular Cell Biology.

[18]  Amit Bhaya,et al.  Evolving fuzzy rules to model gene expression , 2007, Biosyst..

[19]  Steffen Klamt,et al.  A Logical Model Provides Insights into T Cell Receptor Signaling , 2007, PLoS Comput. Biol..

[20]  L. Cantley,et al.  ERK Negatively Regulates the Epidermal Growth Factor-mediated Interaction of Gab1 and the Phosphatidylinositol 3-Kinase* , 2002, The Journal of Biological Chemistry.

[21]  Arup K Chakraborty,et al.  In silico models for cellular and molecular immunology: successes, promises and challenges , 2003, Nature Immunology.

[22]  D. Lauffenburger,et al.  Physicochemical modelling of cell signalling pathways , 2006, Nature Cell Biology.

[23]  Yuhong Yang,et al.  Information Theory, Inference, and Learning Algorithms , 2005 .

[24]  Michael Karin,et al.  The IKK NF-kappa B system: a treasure trove for drug development. , 2004, Nature reviews. Drug discovery.

[25]  Adam A. Margolin,et al.  Reverse engineering cellular networks , 2006, Nature Protocols.

[26]  P. Leder,et al.  The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. , 1998, Immunity.

[27]  Keith A. Luhrs,et al.  The “Fuzzy Logic” of the Death-Inducing Signaling Complex in Lymphocytes , 2003, Journal of Clinical Immunology.

[28]  Madalena Chaves,et al.  Robustness and fragility of Boolean models for genetic regulatory networks. , 2005, Journal of theoretical biology.

[29]  Rency S Varghese,et al.  Increasing the efficiency of fuzzy logic-based gene expression data analysis. , 2003, Physiological genomics.

[30]  R. Milo,et al.  Oscillations and variability in the p53 system , 2006, Molecular systems biology.

[31]  I. Nemenman,et al.  Optimal Signal Processing in Small Stochastic Biochemical Networks , 2006, PloS one.

[32]  Denis Thieffry,et al.  Genetic control of flower morphogenesis in Arabidopsis thaliana: a logical analysis , 1999, Bioinform..

[33]  D. Lauffenburger,et al.  Computational modeling of the EGF-receptor system: a paradigm for systems biology. , 2003, Trends in cell biology.

[34]  Nir Friedman,et al.  Inferring Cellular Networks Using Probabilistic Graphical Models , 2004, Science.

[35]  Tiegang Liu,et al.  Smooth muscle α‐actin expression and myofibroblast differentiation by TGFβ are dependent upon MK2 , 2007 .

[36]  Roland Eils,et al.  Inferring genetic regulatory logic from expression data , 2005, Bioinform..

[37]  A. Pardee,et al.  Epidermal growth factor-induced nuclear factor kappa B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Hoffmann,et al.  The I (cid:1) B –NF-(cid:1) B Signaling Module: Temporal Control and Selective Gene Activation , 2022 .

[39]  Boris N Kholodenko,et al.  Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops* , 2006, Journal of Biological Chemistry.

[40]  William J. Bosl,et al.  Systems biology by the rules: hybrid intelligent systems for pathway modeling and discovery , 2007, BMC Systems Biology.

[41]  H. Othmer,et al.  The topology of the regulatory interactions predicts the expression pattern of the segment polarity genes in Drosophila melanogaster. , 2003, Journal of theoretical biology.

[42]  D. Lauffenburger,et al.  A Systems Model of Signaling Identifies a Molecular Basis Set for Cytokine-Induced Apoptosis , 2005, Science.

[43]  David J. C. MacKay,et al.  Information Theory, Inference, and Learning Algorithms , 2004, IEEE Transactions on Information Theory.

[44]  D. Pe’er,et al.  Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data , 2003, Nature Genetics.

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

[46]  Ron Shamir,et al.  A Probabilistic Methodology for Integrating Knowledge and Experiments on Biological Networks , 2006, J. Comput. Biol..

[47]  Jian Gong,et al.  Modeling gene expression networks using fuzzy logic , 2005, IEEE Transactions on Systems, Man, and Cybernetics, Part B (Cybernetics).

[48]  Richard C Zangar,et al.  Induced Autocrine Signaling through the Epidermal Growth Factor Receptor Contributes to the Response of Mammary Epithelial Cells to Tumor Necrosis Factor α* , 2004, Journal of Biological Chemistry.

[49]  Kevin A Janes,et al.  A biological approach to computational models of proteomic networks. , 2006, Current opinion in chemical biology.

[50]  Andrew A. Quong,et al.  Linear fuzzy gene network models obtained from microarray data by exhaustive search , 2004, BMC Bioinformatics.

[51]  Q. Ouyang,et al.  The yeast cell-cycle network is robustly designed. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[52]  K. Sachs,et al.  Causal Protein-Signaling Networks Derived from Multiparameter Single-Cell Data , 2005, Science.

[53]  J. Blenis,et al.  ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions , 2004, Microbiology and Molecular Biology Reviews.

[54]  Michio Sugeno,et al.  A fuzzy-logic-based approach to qualitative modeling , 1993, IEEE Trans. Fuzzy Syst..

[55]  Ilya Shmulevich,et al.  In silico microdissection of microarray data from heterogeneous cell populations , 2005, BMC Bioinformatics.

[56]  D. di Bernardo,et al.  How to infer gene networks from expression profiles , 2007, Molecular systems biology.

[57]  Gasper Tkacik,et al.  Information capacity of genetic regulatory elements. , 2007, Physical review. E, Statistical, nonlinear, and soft matter physics.

[58]  U. Alon.  Biological Networks: The Tinkerer as an Engineer , 2003, Science.

[59]  Michael Hucka,et al.  A Correction to the Review Titled "Rules for Modeling Signal-Transduction Systems" by W. S. Hlavacek et al. , 2006, Science's STKE.

[60]  D. Lauffenburger,et al.  The Response of Human Epithelial Cells to TNF Involves an Inducible Autocrine Cascade , 2006, Cell.

[61]  Debajit K. Biswas,et al.  Epidermal growth factor-induced nuclear factor κB activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells , 2000 .

[62]  S. Schmid,et al.  Control of EGF Receptor Signaling by Clathrin-Mediated Endocytosis , 1996, Science.

[63]  J. Stelling,et al.  Ensemble modeling for analysis of cell signaling dynamics , 2007, Nature Biotechnology.

[64]  E. Davidson,et al.  Genomic cis-regulatory logic: experimental and computational analysis of a sea urchin gene. , 1998, Science.

[65]  Stefan Grimm,et al.  The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal , 1998 .

[66]  L Glass,et al.  Co-operative components, spatial localization and oscillatory cellular dynamics. , 1972, Journal of theoretical biology.

[67]  Michael B. Yaffe,et al.  Data-driven modelling of signal-transduction networks , 2006, Nature Reviews Molecular Cell Biology.