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Computational Modeling of the Main Signaling Pathways Involved in Mast Cell Activation

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Fc Receptors

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 382))

Abstract

A global and rigorous understanding of the signaling pathways and cross-regulatory processes involved in mast cell activation requires the integration of published information with novel functional datasets into a comprehensive computational model. Based on an exhaustive curation of the existing literature and using the software CellDesigner, we have built and annotated a comprehensive molecular map for the FcεRI signaling network. This map can be used to visualize and interpret high-throughput expression data. Furthermore, leaning on this map and using the logical modeling software GINsim, we have derived a qualitative dynamical model, which recapitulates the most salient features of mast cell activation. The resulting logical model can be used to explore the dynamical properties of the system and its responses to different stimuli, in normal or mutant conditions.

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References

  • Alvarez-Errico D, Lessmann E, Rivera J (2009) Adapters in the organization of mast cell signaling. Immunol Rev 232(1):195–217

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bérenguier D, Chaouiya C, Monteiro PT, Naldi A, Remy E, Thieffry D, Tichit L (2013) Dynamical modeling and analysis of large cellular regulatory networks. Chaos 23(2):025114

    Article  PubMed  Google Scholar 

  • Bonnet E, Calzone L, Rovera D, Stoll G, Barillot E, Zinovyev A (2013) BiNoM 2.0, a Cytoscape plugin for accessing and analyzing pathways using standard systems biology formats. BMC Syst Biol 7:18

    Article  PubMed  PubMed Central  Google Scholar 

  • Bounab Y, Hesse AM, Iannascoli B, Grieco L, Couté Y, Niarakis A, Roncagalli R, Lie E, Lam KP, Demangel C, Thieffry D, Garin J, Malissen B, Daëron M (2013) Proteomic analysis of the SH2domain-containing leukocyte protein of 76 kDa (SLP76) interactome. Mol Cell Proteomics 12:2874–2889

    Article  PubMed  CAS  Google Scholar 

  • Calzone L, Gelay A, Zinovyev A, Radvanyi F, Barillot E (2008) A comprehensive modular map of molecular interactions in RB/E2F pathway. Mol Syst Biol 4:173

    Article  PubMed  PubMed Central  Google Scholar 

  • Caron E, Ghosh S, Matsuoka Y, Ashton-Beaucage D, Therrien M, Lemieux S, Kitano H (2010) A comprehensive map of the mTOR signaling network. Mol Syst Biol 6:453

    Article  PubMed  PubMed Central  Google Scholar 

  • Chaouiya C, Naldi A, Thieffry D (2012) Logical modelling of gene regulatory networks with GINsim. Methods Mol Biol 804:463–479

    Article  PubMed  CAS  Google Scholar 

  • Chaouiya C, Berenguier D, Keating SM, Naldi A, van Iersel MP, Rodriguez N, Dräger A, Büchel F, Cokelaer T, Kowal B, Wicks B, Gonçalves E, Dorier J, Page M, Monteiro PT, von Kamp A, Xenarios I, de Jong H, Hucka M, Klamt S, Thieffry D, Le Novère N, Saez-Rodriguez J, Helikar T (2013) SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools. BMC Syst Biol 7:135

    Article  PubMed  PubMed Central  Google Scholar 

  • Daëron M, Malbec O, Latour S, Arock M, Fridman WH (1995a) Regulation of high-affinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors. J Clin Invest 95(2):577–585

    Google Scholar 

  • Daëron M, Latour S, Malbec O, Espinosa E, Pina P, Pasmans S, Fridman WH (1995b) The same tyrosine-based inhibition motif, in the intracytoplasmic domain of Fc gamma RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation. Immunity 3(5):635–646

    Google Scholar 

  • Funahashi A, Tanimura N, Morohashi M, Kitano H (2003) Cell Designer: a process diagram editor for gene-regulatory and biochemical networks. BIOSILICO 1:159–162

    Article  Google Scholar 

  • Gilfillan AM, Tkaczyk C (2006) Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 6(3):218–230

    Article  PubMed  CAS  Google Scholar 

  • Gilfillan AM, Beaven MA (2011) Regulation of mast cell responses in health and disease. Crit Rev Immunol 31(6):475–529

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Glass L, Siegelmann HT (2010) Logical and symbolic analysis of robust biological dynamics. Curr Opin Genet Dev 20(6):644–649

    Article  PubMed  CAS  Google Scholar 

  • Goldstein B, Faeder JR, Hlavacek WS, Blinov ML, Redondo A, Wofsy C (2002) Modeling the early signaling events mediated by aggregation of FceRI. Mol Immunol 38(16–18):1213–1219

    Article  PubMed  CAS  Google Scholar 

  • Grieco L, Calzone L, Bernard-Pierrot I, Radvanyi F, Kahn-Perlès B, Thieffry D (2013) Integrative modelling of the influence of MAPK network on cancer cell fate decision. PLoS Comput Biol 9:e1003286

    Article  PubMed  PubMed Central  Google Scholar 

  • Helikar T, Kochi N, Kowal B, Dimri M, Naramura M, Raja SM, Band V, Band H, Rogers JA (2013) A comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells. PLoS ONE 8(4):e61757

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hucka M, Finney A, Sauro HM, Bolouri H, Doyle JC, Kitano H, Arkin AP, Bornstein BJ, Bray D, Cornish-Bowden A, Cuellar AA, Dronov S, Gilles ED, Ginkel M, Gor V, Goryanin II, Hedley WJ, Hodgman TC, Hofmeyr JH, Hunter PJ, Juty NS, Kasberger JL, Kremling A, Kummer U, Le Novère N, Loew LM, Lucio D, Mendes P, Minch E, Mjolsness ED, Nakayama Y, Nelson MR, Nielsen PF, Sakurada T, Schaff JC, Shapiro BE, Shimizu TS, Spence HD, Stelling J, Takahashi K, Tomita M, Wagner J, Wang J (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19(4):524–531

    Article  PubMed  CAS  Google Scholar 

  • Iwaki S, Spicka J, Tkaczyk C, Jensen BM, Furumoto Y, Charles N, Kovarova M, Rivera J, Horejsi V, Metcalfe DD, Gilfillan AM (2008) Kit- and Fc epsilonRI-induced differential phosphorylation of the transmembrane adaptor molecule NTAL/LAB/LAT2 allows flexibility in its scaffolding function in mast cells. Cell Signal 20(1):195–205

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jabril-Cuenod B, Zhang C, Scharenberg AM, Paolini R, Numerof R, Beaven MA, Kinet JP (1996) Syk-dependent phosphorylation of Shc. A potential link between FcepsilonRI and the Ras/mitogen-activated protein kinase signaling pathway through SOS and Grb2. J Biol Chem 271(27):16268–16272

    Article  PubMed  CAS  Google Scholar 

  • Joshi-Tope G, Gillespie M, Vastrik I, D’Eustachio P, Schmidt E, de Bono B, Jassal B, Gopinath GR, Wu GR, Matthews L, Lewis S, Birney E, Stein L (2005) Reactome: a knowledgebase of biological pathways. Nucleic Acids Res 33:D428–D432

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kanehisa M, Goto S (2000) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kawakami Y, Kitaura J, Satterthwaite AB, Kato RM, Asai K, Hartman SE, Maeda-Yamamoto M, Lowell CA, Rawlings DJ, Witte ON, Kawakami T (2000) Redundant and opposing functions of two tyrosine kinases, Btk and Lyn, in mast cell activation. J Immunol 165(3):1210–1219

    Article  PubMed  CAS  Google Scholar 

  • Kinet JP (1999) The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu Rev Immunol 17:931–972

    Article  PubMed  CAS  Google Scholar 

  • Klipp E, Liebermeister W, Helbig A, Kowald A, Schaber J (2007) Systems biology standards—the community speaks. Nat Biotech 25:390–391

    Article  CAS  Google Scholar 

  • Kovárová M, Tolar P, Arudchandran R, Dráberová L, Rivera J, Dráber P (2001) Structure-function analysis of Lyn kinase association with lipid rafts and initiation of early signaling events after Fcepsilon receptor I aggregation. Mol Cell Biol 21(24):8318–8328

    Article  PubMed  PubMed Central  Google Scholar 

  • Kraft S, Kinet JP (2007) New developments in FcepsilonRI regulation, function and inhibition. Nat Rev Immunol 7(5):365–378

    Article  PubMed  CAS  Google Scholar 

  • Krull M, Pistor S, Voss N, Kel A, Reuter I, Kronenberg D, Michael H, Schwarzer K, Potapov A, Choi C, Kel-Margoulis O, Wingender E (2006) TRANSPATH: an information resource for storing and visualizing signaling pathways and their pathological aberrations. Nucleic Acids Res 34:D546–D551

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kuperstein I, Cohen DP, Pook S, Viara E, Calzone L, Barillot E, Zinovyev A (2013) NaviCell: a web-based environment for navigation, curation and maintenance of large molecular interaction maps. BMC Syst Biol 7(1):100

    Article  PubMed  PubMed Central  Google Scholar 

  • Le Novere N, Finney A, Hucka M, Bhalla US, Campagne F, Collado-Vides J, Crampin EJ, Halstead M, Klipp E, Mendes P, Nielsen P, Sauro H, Shapiro B, Snoep JL, Spence HD, Wanner BL (2005) Minimum information requested in the annotation of biochemical models (MIRIAM). Nat Biotech 23:1509–1515

    Article  Google Scholar 

  • Liu Q, Sasaki T, Kozieradzki I, Wakeham A, Itie A, Dumont DJ, Penninger JM (1999) SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival. Genes Dev 13(7):786–791

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Malbec O, Fong DC, Turner M, Tybulewicz VL, Cambier JC, Fridman WH, Daëron M (1998) Fc epsilon receptor I-associated lyn-dependent phosphorylation of Fc gamma receptor IIB during negative regulation of mast cell activation. J Immunol 160(4):1647–1658

    PubMed  CAS  Google Scholar 

  • Mendoza L (2006) A network model for the control of the differentiation process in Th cells. Biosystems 84(2):101–114

    Article  PubMed  CAS  Google Scholar 

  • Nag A, Faeder JR, Goldstein B (2010) Shaping the response: the role of FcεRI and Syk expression levels in mast cell signaling. IET Syst Biol 4(6):334–347

    Article  PubMed  PubMed Central  Google Scholar 

  • Naldi A, Berenguier D, Fauré A, Lopez F, Thieffry D, Chaouiya C (2009) Logical modelling of regulatory networks with GINsim 2.3. Biosystems 97(2):134–139

    Article  PubMed  CAS  Google Scholar 

  • Naldi A, Remy E, Thieffry D, Chaouiya C (2011) Dynamically consistent reduction of logical regulatory graphs. Theor Comput Sci 412(21):2207–2218

    Article  Google Scholar 

  • Oda K, Matsuoka Y, Funahashi A, Kitano H (2005) A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol 1(2005):0010

    PubMed  Google Scholar 

  • Saez-Rodriguez J, Mirschel S, Hemenway R, Klamt S, Gilles ED, Ginkel M (2006) Visual setup of logical models of signaling and regulatory networks with ProMoT. BMC Bioinformatics 7:506

    Article  PubMed  PubMed Central  Google Scholar 

  • Saez-Rodriguez J, Simeoni L, Lindquist JA, Hemenway R, Bommhardt U, Arndt B, Haus UU, Weismantel R, Gilles ED, Klamt S, Schraven B (2007) A logical model provides insights into T cell receptor signaling. PLoS Comput Biol 3(8):e163

    Article  PubMed  PubMed Central  Google Scholar 

  • Saitoh S, Arudchandran R, Manetz TS, Zhang W, Sommers CL, Love PE, Rivera J, Samelson LE (2000) LAT is essential for Fc(epsilon)RI-mediated mast cell activation. Immunity 12(5):525–535

    Article  PubMed  CAS  Google Scholar 

  • Samaga R, Saez-Rodriguez J, Alexopoulos LG, Sorger PK, Klamt S (2009) The logic of EGFR/ErbB signaling: theoretical properties and analysis of high-throughput data. PLoS Comput Biol 5(8):e1000438

    Article  PubMed  PubMed Central  Google Scholar 

  • Sahin O, Fröhlich H, Löbke C, Korf U, Burmester S, Majety M, Mattern J, Schupp I, Chaouiya C, Thieffry D, Poustka A, Wiemann S, Beissbarth T, Arlt D (2009) Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance. BMC Syst Biol 3:1

    Article  PubMed  PubMed Central  Google Scholar 

  • Setoguchi R, Kinashi T, Sagara H, Hirosawa K, Takatsu K (1998) Defective degranulation and calcium mobilization of bone-marrow derived mast cells from Xid and Btk-deficient mice. Immunol Lett 64(2–3):109–118

    Article  PubMed  CAS  Google Scholar 

  • Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Simon M, Vanes L, Geahlen RL, Tybulewicz VL (2005) Distinct roles for the linker region tyrosines of Syk in FcepsilonRI signaling in primary mast cells. J Biol Chem 280(6):4510–4517

    Article  PubMed  CAS  Google Scholar 

  • Thieffry D (2007) Dynamical roles of biological regulatory circuits. Brief Bioinform 8:220–225

    Article  PubMed  CAS  Google Scholar 

  • Tůmová M, Koffer A, Simíček M, Dráberová L, Dráber P (2010) The transmembrane adaptor protein NTAL signals to mast cell cytoskeleton via the small GTPase Rho. Eur J Immunol 40(11):3235–3245

    Article  PubMed  Google Scholar 

  • Young RM, Holowka D, Baird B (2003) A lipid raft environment enhances Lyn kinase activity by protecting the active site tyrosine from dephosphorylation. J Biol Chem 278(23):20746–20752

    Article  PubMed  CAS  Google Scholar 

  • Zhu M, Liu Y, Koonpaew S, Granillo O, Zhang W (2004) Positive and negative regulation of FcepsilonRI-mediated signaling by the adaptor protein LAB/NTAL. J Exp Med 200(8):991–1000

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zinovyev A, Viara E, Calzone L, Barillot E (2008) BiNoM: a Cytoscape plugin for manipulating and analyzing biological networks. Bioinformatics 24(6):876–877

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This project was supported by the ANR through the MI2 project iSa and by the proteomics ProFI infrastructure, as well as by the French excellence initiatives MemoLife LabEx and PSL* IdEx.

Author information

Authors and Affiliations

  1. Institut de Biologie de l’ENS (IBENS), Ecole Normale Supérieure, Paris, France

    Anna Niarakis, Luca Grieco & Denis Thieffry

  2. INSERM, U1024, Paris, France

    Anna Niarakis, Luca Grieco & Denis Thieffry

  3. CNRS, UMR 8197, Paris, France

    Anna Niarakis, Luca Grieco & Denis Thieffry

  4. Unité d’Allergologie Moléculaire et Cellulaire, Département d’Immunologie, Institut Pasteur, Paris, France

    Yacine Bounab

  5. Centre d’Immunologie de Marseille-Luminy (CIML), Université Aix Marseille, Marseille, France

    Romain Roncagalli & Bernard Malissen

  6. INSERM, UMS20, Paris, France

    Yacine Bounab

  7. INSERM, U1104, Marseille, France

    Romain Roncagalli & Bernard Malissen

  8. CNRS, UMR7280, Marseille, France

    Romain Roncagalli & Bernard Malissen

  9. Laboratoire de Biologie à Grande Echelle, CEA, IRTSV, Grenoble, France

    Anne-Marie Hesse & Jérôme Garin

  10. INSERM, U1038, Grenoble, France

    Anne-Marie Hesse & Jérôme Garin

  11. Laboratoire de Biologie à Grande Echelle, Université de Grenoble Alpes, iRTSV, Grenoble, France

    Anne-Marie Hesse & Jérôme Garin

  12. Institut Pasteur, Paris, France

    Marc Daëron

  13. Inserm, U1104, Centre d’Immunologie de Marseille-Luminy, Marseille, France

    Marc Daëron

Authors
  1. Anna Niarakis
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  2. Yacine Bounab
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  3. Luca Grieco
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  4. Romain Roncagalli
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  5. Anne-Marie Hesse
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  6. Jérôme Garin
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  7. Bernard Malissen
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  8. Marc Daëron
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  9. Denis Thieffry
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Corresponding author

Correspondence to Denis Thieffry .

Editor information

Editors and Affiliations

  1. Institut Pasteur, Paris, France

    Marc Daeron

  2. Department of Biology, Institute of Genetics, University of Erlangen-Nürnberg, Erlangen, Germany

    Falk Nimmerjahn

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Niarakis, A. et al. (2014). Computational Modeling of the Main Signaling Pathways Involved in Mast Cell Activation. In: Daeron, M., Nimmerjahn, F. (eds) Fc Receptors. Current Topics in Microbiology and Immunology, vol 382. Springer, Cham. https://doi.org/10.1007/978-3-319-07911-0_4

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