Noise in cellular signaling pathways: causes and effects.

Noise caused by stochastic fluctuations in genetic circuits (transcription and translation) is now appreciated as a central aspect of cell function and phenotypic behavior. Noise has also been detected in signaling networks, but the origin of this noise and how it shapes cellular outcomes remain poorly understood. Here, we argue that noise in signaling networks results from the intrinsic promiscuity of protein-protein interactions (PPIs), and that this noise has shaped cellular signal transduction. Features promoted by the presence of this molecular signaling noise include multimerization and clustering of signaling components, pleiotropic effects of gross changes in protein concentration, and a probabilistic rather than a linear view of signal propagation.

[1]  A. Barabasi,et al.  An empirical framework for binary interactome mapping , 2008, Nature Methods.

[2]  Hyeong Jun An,et al.  Estimating the size of the human interactome , 2008, Proceedings of the National Academy of Sciences.

[3]  L. Castagnoli,et al.  Protein Interaction Networks by Proteome Peptide Scanning , 2004, PLoS biology.

[4]  A. Oudenaarden,et al.  Cellular Decision Making and Biological Noise: From Microbes to Mammals , 2011, Cell.

[5]  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.

[6]  R. Bansal,et al.  Phosphorylation and lipid raft association of fibroblast growth factor receptor‐2 in oligodendrocytes , 2009, Glia.

[7]  Leo Goodstadt,et al.  Eukaryotic domain evolution inferred from genome comparisons. , 2003, Current opinion in genetics & development.

[8]  Luisa Montecchi-Palazzi,et al.  Selectivity and promiscuity in the interaction network mediated by protein recognition modules , 2004, FEBS letters.

[9]  Sompop Bencharit,et al.  Structural and evolutionary division of phosphotyrosine binding (PTB) domains. , 2005, Journal of molecular biology.

[10]  Paul J. Choi,et al.  Quantifying E. coli Proteome and Transcriptome with Single-Molecule Sensitivity in Single Cells , 2010, Science.

[11]  I. Ispolatov,et al.  Binding properties and evolution of homodimers in protein–protein interaction networks , 2005, Nucleic acids research.

[12]  M. Elowitz,et al.  Functional roles for noise in genetic circuits , 2010, Nature.

[13]  S. Li Specificity and versatility of SH3 and other proline-recognition domains: structural basis and implications for cellular signal transduction. , 2005, The Biochemical journal.

[14]  Cem Elbi,et al.  FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. , 2008, Cancer research.

[15]  Gary D. Bader,et al.  Bayesian Modeling of the Yeast SH3 Domain Interactome Predicts Spatiotemporal Dynamics of Endocytosis Proteins , 2009, PLoS biology.

[16]  D. Kern,et al.  Dynamic personalities of proteins , 2007, Nature.

[17]  S. Arold How focal adhesion kinase achieves regulation by linking ligand binding, localization and action. , 2011, Current opinion in structural biology.

[18]  Michael Liss,et al.  Identification of preferred protein interactions by phage‐display of the human Src homology‐3 proteome , 2006, EMBO reports.

[19]  Young-Joon Kim,et al.  Stochastic and Regulatory Role of Chromatin Silencing in Genomic Response to Environmental Changes , 2008, PloS one.

[20]  Derek Toomre,et al.  Spatial control of EGF receptor activation by reversible dimerization on living cells , 2010, Nature.

[21]  Leslie M Loew,et al.  Molecular machines or pleiomorphic ensembles: signaling complexes revisited , 2009, Journal of biology.

[22]  Eivind Almaas,et al.  Genetic noise control via protein oligomerization , 2008, BMC Systems Biology.

[23]  Erich E. Wanker,et al.  UniHI 4: new tools for query, analysis and visualization of the human protein–protein interactome , 2008, Nucleic Acids Res..

[24]  J. Ladbury,et al.  Searching for specificity in SH domains. , 2000, Chemistry & biology.

[25]  Ben S. Wittner,et al.  A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations , 2010, Cell.

[26]  Roger B. Sidje,et al.  Stochastic analysis of the VEGF receptor response curve , 2007 .

[27]  I. Nemenman,et al.  Information Transduction Capacity of Noisy Biochemical Signaling Networks , 2011, Science.

[28]  J. Ladbury,et al.  Specificity is complex and time consuming: mutual exclusivity in tyrosine kinase-mediated signaling. , 2003, Accounts of chemical research.

[29]  A. Barabasi,et al.  Interactome Networks and Human Disease , 2011, Cell.

[30]  S. Arold,et al.  Nef-Induced Major Histocompatibility Complex Class I Down-Regulation Is Functionally Dissociated from Its Virion Incorporation, Enhancement of Viral Infectivity, and CD4 Down-Regulation , 2000, Journal of Virology.

[31]  J. Schlessinger,et al.  Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[32]  Emmanuel D. Levy,et al.  How Perfect Can Protein Interactomes Be? , 2009, Science Signaling.

[33]  B. Walker,et al.  HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes , 1998, Nature.

[34]  Claude Desplan,et al.  Stochasticity and Cell Fate , 2008, Science.

[35]  S. Arold,et al.  Energetics of Src homology domain interactions in receptor tyrosine kinase-mediated signaling. , 2011, Methods in enzymology.

[36]  Paul J. Choi,et al.  Quantifying E. coli Proteome and Transcriptome with Single-molecule Sensitivity in Single Cells , 2011 .

[37]  N. Saijo,et al.  AZD2171 Shows Potent Antitumor Activity Against Gastric Cancer Over-Expressing Fibroblast Growth Factor Receptor 2/Keratinocyte Growth Factor Receptor , 2007, Clinical Cancer Research.

[38]  S. Fumagalli,et al.  Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division. , 1995, Science.

[39]  Mario Stevenson,et al.  SH3-mediated Hck Tyrosine Kinase Activation and Fibroblast Transformation by the Nef Protein of HIV-1* , 1997, The Journal of Biological Chemistry.

[40]  Zhaohui S. Qin,et al.  A Global Protein Kinase and Phosphatase Interaction Network in Yeast , 2010, Science.

[41]  Karen M Page,et al.  Mathematical models of the VEGF receptor and its role in cancer therapy , 2007, Journal of The Royal Society Interface.

[42]  Toby J Gibson,et al.  Cell regulation: determined to signal discrete cooperation. , 2009, Trends in biochemical sciences.

[43]  B. Mayer,et al.  SH3 domains: complexity in moderation. , 2001, Journal of cell science.

[44]  Emmanuel D Levy,et al.  Signaling Through Cooperation , 2010, Science.

[45]  Karen M Page,et al.  Stochastic models of receptor oligomerization by bivalent ligand , 2006, Journal of The Royal Society Interface.

[46]  L. Hood,et al.  Gene expression dynamics in the macrophage exhibit criticality , 2008, Proceedings of the National Academy of Sciences.

[47]  J. Ladbury,et al.  Direct binding of Grb2 SH3 domain to FGFR2 regulates SHP2 function. , 2010, Cellular signalling.

[48]  A. Gavin,et al.  SnapShot: Protein-Protein Interaction Networks , 2011, Cell.