Signals and Systems: Towards a Systems Biology of Signal Transduction

Systems biology seeks to understand how the behavior of cells and organisms arises from the collective interactions of their component molecules. I will discuss how signal transduction- the process by which cells sense and respond to external signals - is being reconsidered from a systems perspective. This relies on ideas and concepts from the physical sciences coupled to new experimental strategies. I will outline some of the challenges through work in our laboratory on epidermal growth factor signalling.

[1]  R. Macnab,et al.  The gradient-sensing mechanism in bacterial chemotaxis. , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Quake,et al.  Microfluidic Large-Scale Integration , 2002, Science.

[3]  Chi-Ying F. Huang,et al.  Ultrasensitivity in the mitogen-activated protein kinase cascade. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  S. Raghavachari,et al.  A Unified Model of the Presynaptic and Postsynaptic Changes During LTP at CA1 Synapses , 2006, Science's STKE.

[5]  Jeffrey C Way,et al.  Designing biological systems. , 2007, Genes & development.

[6]  H. Kacser,et al.  The control of flux. , 1995, Biochemical Society transactions.

[7]  Lea Sistonen,et al.  Multisite phosphorylation provides sophisticated regulation of transcription factors. , 2002, Trends in biochemical sciences.

[8]  S. Quake,et al.  Dissecting biological “dark matter” with single-cell genetic analysis of rare and uncultivated TM7 microbes from the human mouth , 2007, Proceedings of the National Academy of Sciences.

[9]  Andre Levchenko,et al.  Comment on "Oscillations in NF-κB Signaling Control the Dynamics of Gene Expression" , 2005, Science.

[10]  H. Berg,et al.  Transient response to chemotactic stimuli in Escherichia coli. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Piston,et al.  Fluorescent protein FRET: the good, the bad and the ugly. , 2007, Trends in biochemical sciences.

[12]  A. Hodgkin,et al.  A quantitative description of membrane current and its application to conduction and excitation in nerve , 1952, The Journal of physiology.

[13]  Vivien A. Casagrande,et al.  Biophysics of Computation: Information Processing in Single Neurons , 1999 .

[14]  Marta Cascante,et al.  Bistability from double phosphorylation in signal transduction , 2006, The FEBS journal.

[15]  O. Griesbeck,et al.  Live-cell transforms between Ca2+ transients and FRET responses for a troponin-C-based Ca2+ sensor. , 2007, Biophysical journal.

[16]  B. Imperiali,et al.  Chemical approaches for investigating phosphorylation in signal transduction networks. , 2005, Trends in cell biology.

[17]  P. Pellicena,et al.  Processive Phosphorylation of p130Cas by Src Depends on SH3-Polyproline Interactions* , 2001, The Journal of Biological Chemistry.

[18]  S. Leibler,et al.  Bacterial Persistence as a Phenotypic Switch , 2004, Science.

[19]  Ertugrul M. Ozbudak,et al.  Multistability in the lactose utilization network of Escherichia coli , 2004, Nature.

[20]  Wei Chen,et al.  Differential regulation and properties of MAPKs , 2007, Oncogene.

[21]  M. Freeman,et al.  Cell determination strategies in the Drosophila eye. , 1997, Development.

[22]  K. Ferrell,et al.  HIV-1 Tat Inhibits the 20 S Proteasome and Its 11 S Regulator-mediated Activation* , 1997, The Journal of Biological Chemistry.

[23]  Ann M Stock,et al.  Histidine kinases and response regulator proteins in two-component signaling systems. , 2001, Trends in biochemical sciences.

[24]  Howard C. Berg,et al.  E. coli in Motion , 2003 .

[25]  P. Dempsey,et al.  Control of ErbB signaling through metalloprotease mediated ectodomain shedding of EGF-like factors , 2006, Growth factors.

[26]  E. Kandel The Molecular Biology of Memory Storage: A Dialog Between Genes and Synapses , 2004, Bioscience reports.

[27]  Ivan Mijakovic,et al.  The Serine/Threonine/Tyrosine Phosphoproteome of the Model Bacterium Bacillus subtilis*S , 2007, Molecular & Cellular Proteomics.

[28]  J. Lisman,et al.  The molecular basis of CaMKII function in synaptic and behavioural memory , 2002, Nature Reviews Neuroscience.

[29]  J. Monod,et al.  Teleonomic mechanisms in cellular metabolism, growth, and differentiation. , 1961, Cold Spring Harbor symposia on quantitative biology.

[30]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

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

[32]  N. Normanno,et al.  Epidermal growth factor receptor (EGFR) signaling in cancer. , 2006, Gene.

[33]  T. Pawson,et al.  Assembly of Cell Regulatory Systems Through Protein Interaction Domains , 2003, Science.

[34]  A. Ullrich,et al.  The discovery of receptor tyrosine kinases: targets for cancer therapy , 2004, Nature Reviews Cancer.

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

[36]  B. Palsson,et al.  The model organism as a system: integrating 'omics' data sets , 2006, Nature Reviews Molecular Cell Biology.

[37]  T. Höfer,et al.  Versatile regulation of multisite protein phosphorylation by the order of phosphate processing and protein–protein interactions , 2007, The FEBS journal.

[38]  G. Whitesides,et al.  Soft lithography in biology and biochemistry. , 2001, Annual review of biomedical engineering.

[39]  Yuhai Tu,et al.  Perfect and near-perfect adaptation in a model of bacterial chemotaxis. , 2002, Biophysical journal.

[40]  J. Doyle,et al.  Robust perfect adaptation in bacterial chemotaxis through integral feedback control. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[42]  U. Alon,et al.  Robustness in bacterial chemotaxis , 2022 .

[43]  P. Shapiro,et al.  Tyrosine-Phosphorylated Extracellular Signal–Regulated Kinase Associates with the Golgi Complex during G2/M Phase of the Cell Cycle , 2001, The Journal of cell biology.

[44]  Ann M Stock,et al.  Two-component signal transduction. , 2000, Annual review of biochemistry.

[45]  William Thies,et al.  Abstraction layers for scalable microfluidic biocomputing , 2008, Natural Computing.

[46]  D. Koshland Bacterial chemotaxis in relation to neurobiology. , 1980, Annual review of neuroscience.

[47]  Peter J. Verveer,et al.  EGFR activation coupled to inhibition of tyrosine phosphatases causes lateral signal propagation , 2003, Nature Cell Biology.

[48]  Jerome T. Mettetal,et al.  Cellular asymmetry and individuality in directional sensing. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[49]  E. Krebs Protein phosphorylation and cellular regulation I , 1993 .

[50]  P. Swain,et al.  Stochastic Gene Expression in a Single Cell , 2002, Science.

[51]  S. Quake,et al.  Monolithic microfabricated valves and pumps by multilayer soft lithography. , 2000, Science.

[52]  F. Crick Neurobiology: Memory and molecular turnover , 1984, Nature.

[53]  Marc W Kirschner,et al.  The Meaning of Systems Biology , 2005, Cell.

[54]  J. Ferrell,et al.  Bistability in the JNK cascade , 2001, Current Biology.

[55]  E. Kandel The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses , 2001, Science.

[56]  Uri Alon,et al.  Dynamics of the p53-Mdm2 feedback loop in individual cells , 2004, Nature Genetics.

[57]  Thomas Höfer,et al.  Allosteric regulation of the transcription factor NFAT1 by multiple phosphorylation sites: a mathematical analysis. , 2003, Journal of molecular biology.

[58]  Pablo A. Iglesias,et al.  MAPK-mediated bimodal gene expression and adaptive gradient sensing in yeast , 2007, Nature.

[59]  Rustem F. Ismagilov,et al.  Dynamics of Drosophila embryonic patterning network perturbed in space and time using microfluidics , 2005, Nature.

[60]  R. Levi‐montalcini The nerve growth factor: Thirty-five years later , 1987, Bioscience reports.

[61]  Julio Saez-Rodriguez,et al.  Flexible informatics for linking experimental data to mathematical models via DataRail , 2008, Bioinform..

[62]  A. Cornish-Bowden Fundamentals of Enzyme Kinetics , 1979 .

[63]  W. S. Hlavacek,et al.  A network model of early events in epidermal growth factor receptor signaling that accounts for combinatorial complexity. , 2006, Bio Systems.

[64]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[65]  M. Mann,et al.  Phosphotyrosine interactome of the ErbB-receptor kinase family , 2005, Molecular systems biology.

[66]  James E. Ferrell,et al.  Mechanistic Studies of the Dual Phosphorylation of Mitogen-activated Protein Kinase* , 1997, The Journal of Biological Chemistry.

[67]  Robert J Coffey,et al.  EGF receptor ligands. , 2003, Experimental cell research.

[68]  B. Kholodenko,et al.  Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses , 2007, Molecular systems biology.

[69]  Jeremy Gunawardena,et al.  The geometry of multisite phosphorylation. , 2008, Biophysical journal.

[70]  J. Gunawardena Multisite protein phosphorylation makes a good threshold but can be a poor switch. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[71]  C. Pesce,et al.  Regulated cell-to-cell variation in a cell-fate decision system , 2005, Nature.

[72]  R. Stein,et al.  Evolutionary Analysis of the ErbB Receptor and Ligand Families , 2000, Journal of Molecular Evolution.

[73]  Joseph Schlessinger,et al.  Ligand-Induced, Receptor-Mediated Dimerization and Activation of EGF Receptor , 2002, Cell.

[74]  D. Lauffenburger,et al.  Receptors: Models for Binding, Trafficking, and Signaling , 1993 .

[75]  James E. Ferrell,et al.  The JNK Cascade as a Biochemical Switch in Mammalian Cells Ultrasensitive and All-or-None Responses , 2003, Current Biology.

[76]  R. Seger,et al.  Detection of partially phosphorylated forms of ERK by monoclonal antibodies reveals spatial regulation of ERK activity by phosphatases , 2000, FEBS letters.

[77]  Oliver Hobert,et al.  MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[78]  Kit-Yi Leung,et al.  Novel Phosphorylation Sites in Tau from Alzheimer Brain Support a Role for Casein Kinase 1 in Disease Pathogenesis* , 2007, Journal of Biological Chemistry.

[79]  R Y Tsien,et al.  Genetically encoded fluorescent reporters of protein tyrosine kinase activities in living cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

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

[81]  G. Carpenter,et al.  EPIDERMAL GROWTH FACTOR * , 1982, The Journal of biological chemistry.

[82]  Madhusudan Natarajan,et al.  A global analysis of cross-talk in a mammalian cellular signalling network , 2006, Nature Cell Biology.

[83]  M. Fischbach,et al.  “Oncogenic Shock”: Explaining Oncogene Addiction through Differential Signal Attenuation , 2006, Clinical Cancer Research.

[84]  J. Massagué TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[85]  H. Lane,et al.  ERBB receptors and cancer: the complexity of targeted inhibitors , 2005, Nature Reviews Cancer.

[86]  Jeremy Gunawardena,et al.  Programming with models: modularity and abstraction provide powerful capabilities for systems biology , 2009, Journal of The Royal Society Interface.

[87]  F. Crick Memory and molecular turnover. , 1984, Nature.

[88]  K. Carraway,et al.  Ligand discrimination by ErbB receptors: differential signaling through differential phosphorylation site usage , 2000, Oncogene.

[89]  Aaas News,et al.  Book Reviews , 1893, Buffalo Medical and Surgical Journal.

[90]  Adam A. Friedman,et al.  A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling , 2006, Nature.

[91]  Erin K O'Shea,et al.  Partially Phosphorylated Pho4 Activates Transcription of a Subset of Phosphate-Responsive Genes , 2003, PLoS biology.

[92]  Yu Zhao,et al.  The Mechanism of Dephosphorylation of Extracellular Signal-regulated Kinase 2 by Mitogen-activated Protein Kinase Phosphatase 3* , 2001, The Journal of Biological Chemistry.

[93]  C. Clevenger Signal transduction. , 2003, Breast disease.

[94]  J. Lisman A mechanism for memory storage insensitive to molecular turnover: a bistable autophosphorylating kinase. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[95]  Antje J Baeumner,et al.  Recirculating, passive micromixer with a novel sawtooth structure. , 2006, Lab on a chip.