Advertisement

ERK Signaling pp 409-432 | Cite as

Dissecting Cell-Fate Determination Through Integrated Mathematical Modeling of the ERK/MAPK Signaling Pathway

  • Sung-Young Shin
  • Lan K. NguyenEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1487)

Abstract

The past three decades have witnessed an enormous progress in the elucidation of the ERK/MAPK signaling pathway and its involvement in various cellular processes. Because of its importance and complex wiring, the ERK pathway has been an intensive subject for mathematical modeling, which facilitates the unraveling of key dynamic properties and behaviors of the pathway. Recently, however, it became evident that the pathway does not act in isolation but closely interacts with many other pathways to coordinate various cellular outcomes under different pathophysiological contexts. This has led to an increasing number of integrated, large-scale models that link the ERK pathway to other functionally important pathways. In this chapter, we first discuss the essential steps in model development and notable models of the ERK pathway. We then use three examples of integrated, multipathway models to investigate how crosstalk of ERK signaling with other pathways regulates cell-fate decision-making in various physiological and disease contexts. Specifically, we focus on ERK interactions with the phosphoinositide-3 kinase (PI3K), c-Jun N-terminal kinase (JNK), and β-adrenergic receptor (β-AR) signaling pathways. We conclude that integrated modeling in combination with wet-lab experimentation have been and will be instrumental in gaining an in-depth understanding of ERK signaling in multiple biological contexts.

Key words

ERK/MAPK signaling pathway Mathematical modeling Systems analysis Cell-fate determination Functional switch Apoptosis Proliferation Cell survival 

References

  1. 1.
    Kolch W (2002) Ras/Raf signalling and emerging pharmacotherapeutic targets. Expert Opin Pharmacother 3:709–718CrossRefPubMedGoogle Scholar
  2. 2.
    Kolch W (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6:827–837CrossRefPubMedGoogle Scholar
  3. 3.
    Shin SY, Rath O, Choo SM et al (2009) Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway. J Cell Sci 122:425–435CrossRefPubMedGoogle Scholar
  4. 4.
    Wellbrock C, Karasarides M, Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5:875–885CrossRefPubMedGoogle Scholar
  5. 5.
    Dong C, Waters SB, Holt KH et al (1996) SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways. J Biol Chem 271:6328–6332CrossRefGoogle Scholar
  6. 6.
    Dumaz N, Marais R (2005) Raf phosphorylation: one step forward and two steps back. Mol Cell 17:164–166PubMedGoogle Scholar
  7. 7.
    Yeung K, Seitz T, Li S et al (1999) Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401:173–177CrossRefPubMedGoogle Scholar
  8. 8.
    Orton RJ, Sturm OE, Vyshemirsky V et al (2005) Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway. Biochem J 392:249–261CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Romano D, Nguyen LK, Matallanas D et al (2014) Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling. Nat Cell Biol 16:673–684CrossRefPubMedGoogle Scholar
  10. 10.
    Nguyen LK, Kholodenko BN (2016) Feedback regulation in cell signalling: lessons for cancer therapeutics. Semin Cell Dev Biol 50:85–94CrossRefPubMedGoogle Scholar
  11. 11.
    Nguyen LK, Cavadas MA, Scholz CC et al (2015) A dynamic model of the hypoxia-inducible factor 1a (HIF-1a) network. J Cell Sci 128:422CrossRefPubMedGoogle Scholar
  12. 12.
    Nguyen LK (2015) Dynamics of ubiquitin-mediated signalling: insights from mathematical modelling and experimental studies. Brief Bioinform 17(3):479–493CrossRefPubMedGoogle Scholar
  13. 13.
    Kolch W, Halasz M, Granovskaya M et al (2015) The dynamic control of signal transduction networks in cancer cells. Nat Rev Cancer 15:515–527CrossRefPubMedGoogle Scholar
  14. 14.
    Nguyen LK, Kolch W, Kholodenko BN (2013) When ubiquitination meets phosphorylation: a systems biology perspective of EGFR/MAPK signalling. Cell Commun Signal 11:52CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kholodenko BN, Hancock JF, Kolch W (2010) Signalling ballet in space and time. Nat Rev Mol Cell Biol 11:414–426CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Borisov N, Aksamitiene E, Kiyatkin A et al (2009) Systems-level interactions between insulin-EGF networks amplify mitogenic signaling. Mol Syst Biol 5:256CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Won JK, Yang HW, Shin SY et al (2012) The crossregulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor. J Mol Cell Biol 4:153–163CrossRefPubMedGoogle Scholar
  18. 18.
    Shin SY, Rath O, Zebisch A et al (2010) Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition. Cancer Res 70:6715–6724CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lee HS, Hwang CY, Shin SY et al (2014) MLK3 is part of a feedback mechanism that regulates different cellular responses to reactive oxygen species. Sci Signal 7(328):52CrossRefGoogle Scholar
  20. 20.
    Shin SY, Kim T, Lee HS et al (2014) The switching role of beta-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes. Nat Commun 5:5777CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hoops S, Sahle S, Gauges R et al (2006) COPASI—a COmplex PAthway SImulator. Bioinformatics 22:3067–3074CrossRefPubMedGoogle Scholar
  22. 22.
    Takahashi K, Ishikawa N, Sadamoto Y et al (2003) E-Cell 2: multi-platform E-cell simulation system. Bioinformatics 19:1727–1729CrossRefPubMedGoogle Scholar
  23. 23.
    Neves SR (2012) Modeling of spatially-restricted intracellular signaling. Wiley Interdiscip Rev Syst Biol Med 4:103–115CrossRefPubMedGoogle Scholar
  24. 24.
    Funahashi A, Matsuoka Y, Akiya J et al (2008) Cell designer 3.5: a versatile modeling tool for biochemical networks. Proc IEEE 96(8):1254–1265CrossRefGoogle Scholar
  25. 25.
    Chelliah V, Juty N, Ajmera I et al (2015) BioModels: ten-year anniversary. Nucleic Acids Res 43(Database issue):D542–D548CrossRefPubMedGoogle Scholar
  26. 26.
    Huang CY, Ferrell JE Jr (1996) Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A 93:10078–10083CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kholodenko BN, Demin OV, Moehren G et al (1999) Quantification of short term signaling by the epidermal growth factor receptor. J Biol Chem 274:30169–30181CrossRefPubMedGoogle Scholar
  28. 28.
    Kholodenko BN (2000) Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. Eur J Biochem 267:1583–1588CrossRefPubMedGoogle Scholar
  29. 29.
    Shankaran H, Ippolito DL, Chrisler WB et al (2009) Rapid and sustained nuclear-cytoplasmic ERK oscillations induced by epidermal growth factor. Mol Syst Biol 5:332CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Brightman FA, Fell DA (2000) Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cells. FEBS Lett 482:169–174CrossRefPubMedGoogle Scholar
  31. 31.
    Schoeberl B, Eichler-Jonsson C, Gilles ED et al (2002) Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Nat Biotechnol 20:370–375CrossRefPubMedGoogle Scholar
  32. 32.
    Kulasiri D, Nguyen LK, Samarasinghe S et al (2008) A review of systems biology perspective on genetic regulatory networks with examples. Curr Bioinformatics 3:29CrossRefGoogle Scholar
  33. 33.
    Saucerman JJ, McCulloch AD (2004) Mechanistic systems models of cell signaling networks: a case study of myocyte adrenergic regulation. Prog Biophys Mol Biol 85:261–278CrossRefPubMedGoogle Scholar
  34. 34.
    Cho KH, Shin SY, Kim H-W et al (2003) Mathematical modeling of the influence of RKIP on the ERK signaling pathway. In: Priami C (ed) Computational methods in systems biology, vol 2602, Springer. New York, NY, pp 127–141CrossRefGoogle Scholar
  35. 35.
    Briggs GE (1925) A further note on the kinetics of enzyme action. Biochem J 19:1037–1038CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Briggs GE, Haldane JB (1925) A note on the kinetics of enzyme action. Biochem J 19:338–339CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Schauer M, Heinrich R (1983) Quasi-steady-state approximation in the mathematical modeling of biochemical reaction networks. Math Biosci 65:155–170CrossRefGoogle Scholar
  38. 38.
    Lee E, Salic A, Kruger R et al (2003) The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol 1(1):E10CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Strebel O (2013) A preprocessing method for parameter estimation in ordinary differential equations. Chaos Solitons Fractals 57:93–104CrossRefGoogle Scholar
  40. 40.
    Peifer M, Timmer J (2007) Parameter estimation in ordinary differential equations for biochemical processes using the method of multiple shooting. IET Syst Biol 1:78–88CrossRefPubMedGoogle Scholar
  41. 41.
    Aksamitiene E, Kiyatkin A, Kholodenko BN (2012) Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem Soc Trans 40:139–146CrossRefPubMedGoogle Scholar
  42. 42.
    Sebastian S, Settleman J, Reshkin SJ et al (2006) The complexity of targeting EGFR signalling in cancer: from expression to turnover. Biochim Biophys Acta 1766:120–139PubMedGoogle Scholar
  43. 43.
    Kiyatkin A, Aksamitiene E, Markevich NI et al (2006) Scaffolding protein Grb2-associated binder 1 sustains epidermal growth factor-induced mitogenic and survival signaling by multiple positive feedback loops. J Biol Chem 281:19925–19938CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gu H, Neel BG (2003) The “Gab” in signal transduction. Trends Cell Biol 13:122–130CrossRefPubMedGoogle Scholar
  45. 45.
    Weng LP, Smith WM, Brown JL et al (2001) PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. Hum Mol Genet 10:605–616CrossRefPubMedGoogle Scholar
  46. 46.
    Stoker AW (2005) Protein tyrosine phosphatases and signalling. J Endocrinol 185:19–33CrossRefPubMedGoogle Scholar
  47. 47.
    Asante-Appiah E, Kennedy BP (2003) Protein tyrosine phosphatases: the quest for negative regulators of insulin action. Am J Physiol Endocrinol Metab 284:E663–E670CrossRefPubMedGoogle Scholar
  48. 48.
    Lehar J, Krueger A, Zimmermann G et al (2008) High-order combination effects and biological robustness. Mol Syst Biol 4:215CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36:320–328CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Veal EA, Day AM, Morgan BA (2007) Hydrogen peroxide sensing and signaling. Mol Cell 26:1–14CrossRefPubMedGoogle Scholar
  51. 51.
    Chen J, Chen JK, Harris RC (2012) Angiotensin II induces epithelial-to-mesenchymal transition in renal epithelial cells through reactive oxygen species/Src/caveolin-mediated activation of an epidermal growth factor receptor-extracellular signal-regulated kinase signaling pathway. Mol Cell Biol 32:981–991CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Shen HM, Liu ZG (2006) JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radic Biol Med 40:928–939CrossRefPubMedGoogle Scholar
  53. 53.
    Masuda K, Katagiri C, Nomura M et al (2010) MKP-7, a JNK phosphatase, blocks ERK-dependent gene activation by anchoring phosphorylated ERK in the cytoplasm. Biochem Biophys Res Commun 393:201–206CrossRefPubMedGoogle Scholar
  54. 54.
    Gallo KA, Johnson GL (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3:663–672CrossRefPubMedGoogle Scholar
  55. 55.
    Chadee DN, Kyriakis JM (2004) A novel role for mixed lineage kinase 3 (MLK3) in B-Raf activation and cell proliferation. Cell Cycle 3:1227–1229CrossRefPubMedGoogle Scholar
  56. 56.
    Chadee DN, Kyriakis JM (2004) MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. Nat Cell Biol 6:770–776CrossRefPubMedGoogle Scholar
  57. 57.
    Martin KR, Barrett JC (2002) Reactive oxygen species as double-edged swords in cellular processes: low-dose cell signaling versus high-dose toxicity. Hum Exp Toxicol 21:71–75CrossRefPubMedGoogle Scholar
  58. 58.
    Communal C, Singh K, Sawyer DB et al (1999) Opposing effects of beta(1)- and beta(2)-adrenergic receptors on cardiac myocyte apoptosis : role of a pertussis toxin-sensitive G protein. Circulation 100:2210–2212CrossRefPubMedGoogle Scholar
  59. 59.
    Chesley A, Lundberg MS, Asai T et al (2000) The beta(2)-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through G(i)-dependent coupling to phosphatidylinositol 3′'-kinase. Circ Res 87:1172–1179CrossRefPubMedGoogle Scholar
  60. 60.
    Green SA, Holt BD, Liggett SB (1992) Beta 1- and beta 2-adrenergic receptors display subtype-selective coupling to Gs. Mol Pharmacol 41:889–893PubMedGoogle Scholar
  61. 61.
    Berlot CH, Bourne HR (1992) Identification of effector-activating residues of Gs alpha. Cell 68:911–922CrossRefPubMedGoogle Scholar
  62. 62.
    Gardner LA, Delos Santos NM, Matta SG et al (2004) Role of the cyclic AMP-dependent protein kinase in homologous resensitization of the beta1-adrenergic receptor. J Biol Chem 279:21135–21143CrossRefPubMedGoogle Scholar
  63. 63.
    Martin NP, Whalen EJ, Zamah MA et al (2004) PKA-mediated phosphorylation of the beta1-adrenergic receptor promotes Gs/Gi switching. Cell Signal 16:1397–1403CrossRefPubMedGoogle Scholar
  64. 64.
    Hawes BE, Luttrell LM, van Biesen T et al (1996) Phosphatidylinositol 3-kinase is an early intermediate in the G beta gamma-mediated mitogen-activated protein kinase signaling pathway. J Biol Chem 271:12133–12136CrossRefPubMedGoogle Scholar
  65. 65.
    Yehia G, Schlotter F, Razavi R et al (2001) Mitogen-activated protein kinase phosphorylates and targets inducible cAMP early repressor to ubiquitin-mediated destruction. J Biol Chem 276:35272–35279CrossRefPubMedGoogle Scholar
  66. 66.
    Xing J, Ginty DD, Greenberg ME (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273:959–963CrossRefPubMedGoogle Scholar
  67. 67.
    Tomita H, Nazmy M, Kajimoto K et al (2003) Inducible cAMP early repressor (ICER) is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to beta-adrenergic receptor stimulation. Circ Res 93:12–22CrossRefPubMedGoogle Scholar
  68. 68.
    Communal C, Singh K, Pimentel DR et al (1998) Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation 98:1329–1334CrossRefPubMedGoogle Scholar
  69. 69.
    Henaff M, Hatem SN, Mercadier JJ (2000) Low catecholamine concentrations protect adult rat ventricular myocytes against apoptosis through cAMP-dependent extracellular signal-regulated kinase activation. Mol Pharmacol 58:1546–1553PubMedGoogle Scholar
  70. 70.
    Imahashi K, Schneider MD, Steenbergen C et al (2004) Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res 95:734–741CrossRefPubMedGoogle Scholar
  71. 71.
    Rose BA, Force T, Wang Y (2010) Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev 90:1507–1546CrossRefPubMedGoogle Scholar
  72. 72.
    McCubrey JA, Steelman LS, Chappell WH et al (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773:1263–1284CrossRefPubMedGoogle Scholar
  73. 73.
    Fischer HP (2008) Mathematical modeling of complex biological systems: from parts lists to understanding systems behavior. Alcohol Res Health 31:49–59PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular Biology, School of Biomedical SciencesMonash UniversityClaytonAustralia
  2. 2.Biomedicine Discovery InstituteMonash UniversityClaytonAustralia

Personalised recommendations