Advertisement

Receptor Dynamics in Signaling

  • Verena Becker
  • Jens Timmer
  • Ursula Klingmüller
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 736)

Abstract

Reliable inter- and intracellular communication is central to both the development and the integrity of multicellular organisms. Key mediators of these processes are cell surface receptors that perceive and convert extracellular cues to trigger intracellular signaling networks and ultimately a phenotypic response. Deregulation of signal transduction leads to a variety of diseases, and aberrations in receptor proteins are very common in various cancer types. Therefore, cell surface receptors have been established as major targets in drug discovery. However, in order to efficiently apply therapeutics, it is crucial to gain knowledge about design principles of receptor signaling. In this chapter, we will discuss signal transduction at the receptor level for examples from different receptor classes.

Keywords

Epidermal Growth Factor Receptor Cytokine Receptor Epidermal Growth Factor Receptor Signaling EpoR Expression EpoR Signaling 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by the Helmholtz Alliance on Systems Biology (SBCancer) (VB, JT, UK), the German Federal Ministry of Education and Research (BMBF)-funded MedSys-Network LungSys (JT, UK), and the Excellence Initiative of the German Federal and State Governments (EXC 294) (JT).

References

  1. 1.
    Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5(12):993–996PubMedCrossRefGoogle Scholar
  2. 2.
    Kitano H (2002) Computational systems biology. Nature 420(6912):206–210PubMedCrossRefGoogle Scholar
  3. 3.
    Butcher EC, Berg EL, Kunkel EJ (2004) Systems biology in drug discovery. Nat Biotechnol 22(10):1253–1259PubMedCrossRefGoogle Scholar
  4. 4.
    Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J (2006) Cancer: a systems biology disease. Biosystems 83(2–3):81–90PubMedCrossRefGoogle Scholar
  5. 5.
    Wiley HS, Cunningham DD (1981) A steady state model for analyzing the cellular binding, internalization and degradation of polypeptide ligands. Cell 25(2):433–440PubMedCrossRefGoogle Scholar
  6. 6.
    Wiley HS, Shvartsman SY, Lauffenburger DA (2003) Computational modeling of the EGF–receptor system: a paradigm for systems biology. Trends Cell Biol 13(1):43–50PubMedCrossRefGoogle Scholar
  7. 7.
    Vilar JM, Jansen R, Sander C (2006) Signal processing in the TGF-beta superfamily ligand-receptor network. PLoS Comput Biol 2(1):e3PubMedCrossRefGoogle Scholar
  8. 8.
    Becker V, Schilling M, Bachmann J, Baumann U, Raue A, Maiwald T, Timmer J, Klingmüller U (2010) Covering a broad dynamic range: information processing at the erythropoietin receptor. Science 328(5984):1404–1408PubMedCrossRefGoogle Scholar
  9. 9.
    Baker SJ, Rane SG, Reddy EP (2007) Hematopoietic cytokine receptor signaling. Oncogene 26(47):6724–6737PubMedCrossRefGoogle Scholar
  10. 10.
    O’Shea JJ, Murray PJ (2008) Cytokine signaling modules in inflammatory responses. Immunity 28(4):477–487PubMedCrossRefGoogle Scholar
  11. 11.
    Longmore GD, Lodish HF (1991) An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: a cytokine receptor superfamily oncogene. Cell 67(6): 1089–1102PubMedCrossRefGoogle Scholar
  12. 12.
    Arcasoy MO, Degar BA, Harris KW, Forget BG (1997) Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene. Blood 89(12):4628–4635PubMedGoogle Scholar
  13. 13.
    Forbes LV, Gale RE, Pizzey A, Pouwels K, Nathwani A, Linch DC (2002) An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia. Oncogene 21(39):5981–5989PubMedCrossRefGoogle Scholar
  14. 14.
    Ding J, Komatsu H, Wakita A, Kato-Uranishi M, Ito M, Satoh A, Tsuboi K, Nitta M, Miyazaki H, Iida S, Ueda R (2004) Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 103(11):4198–4200PubMedCrossRefGoogle Scholar
  15. 15.
    James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434(7037):1144–1148PubMedCrossRefGoogle Scholar
  16. 16.
    Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L, Ariola C, Fodale V, Clappier E, Paoloni F, Martinelli S, Fragale A, Sanchez M, Tavolaro S, Messina M, Cazzaniga G, Camera A, Pizzolo G, Tornesello A, Vignetti M, Battistini A, Cave H, Gelb BD, Renauld JC, Biondi A, Constantinescu SN, Foa R, Tartaglia M (2008) Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med 205(4):751–758PubMedCrossRefGoogle Scholar
  17. 17.
    Richmond TD, Chohan M, Barber DL (2005) Turning cells red: signal transduction mediated by erythropoietin. Trends Cell Biol 15(3):146–155PubMedCrossRefGoogle Scholar
  18. 18.
    Wu H, Liu X, Jaenisch R, Lodish HF (1995) Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 83(1):59–67PubMedCrossRefGoogle Scholar
  19. 19.
    Livnah O, Stura EA, Middleton SA, Johnson DL, Jolliffe LK, Wilson IA (1999) Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 283(5404):987–990PubMedCrossRefGoogle Scholar
  20. 20.
    Yoshimura A, D’Andrea AD, Lodish HF (1990) Friend spleen focus-forming virus glycoprotein gp55 interacts with the erythropoietin receptor in the endoplasmic reticulum and affects receptor metabolism. Proc Natl Acad Sci USA 87(11):4139–4143PubMedCrossRefGoogle Scholar
  21. 21.
    Neumann D, Wikström L, Watowich SS, Lodish HF (1993) Intermediates in degradation of the erythropoietin receptor accumulate and are degraded in lysosomes. J Biol Chem 268(18):13639–13649PubMedGoogle Scholar
  22. 22.
    Hilton DJ, Watowich SS, Murray PJ, Lodish HF (1995) Increased cell surface expression and enhanced folding in the endoplasmic reticulum of a mutant erythropoietin receptor. Proc Natl Acad Sci USA 92(1):190–194PubMedCrossRefGoogle Scholar
  23. 23.
    Ketteler R, Heinrich AC, Offe JK, Becker V, Cohen J, Neumann D, Klingmüller U (2002) A functional green fluorescent protein-erythropoietin receptor despite physical separation of JAK2 binding site and tyrosine residues. J Biol Chem 277(29):26547–26552PubMedCrossRefGoogle Scholar
  24. 24.
    Becker V, Sengupta D, Ketteler R, Ullmann GM, Smith JC, Klingmüller U (2008) Packing density of the erythropoietin receptor transmembrane domain correlates with amplification of biological responses. Biochemistry 47(45):11771–11782PubMedCrossRefGoogle Scholar
  25. 25.
    Walrafen P, Verdier F, Kadri Z, Chretien S, Lacombe C, Mayeux P (2005) Both proteasomes and lysosomes degrade the activated erythropoietin receptor. Blood 105(2):600–608PubMedCrossRefGoogle Scholar
  26. 26.
    Gross AW, Lodish HF (2006) Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem 281(4):2024–2032PubMedCrossRefGoogle Scholar
  27. 27.
    Behar M, Hao N, Dohlman HG, Elston TC (2008) Dose-to-duration encoding and signaling beyond saturation in intracellular signaling networks. PLoS Comput Biol 4(10):e1000197PubMedCrossRefGoogle Scholar
  28. 28.
    Wang X, Lupardus P, Laporte SL, Garcia KC (2009) Structural biology of shared cytokine receptors. Annu Rev Immunol 27:29–60PubMedCrossRefGoogle Scholar
  29. 29.
    Shankaran H, Wiley HS, Resat H (2007) Receptor downregulation and desensitization enhance the information processing ability of signalling receptors. BMC Syst Biol 1:48PubMedCrossRefGoogle Scholar
  30. 30.
    Shankaran H, Resat H, Wiley HS (2007) Cell surface receptors for signal transduction and ligand transport: a design principles study. PLoS Comput Biol 3(6):e101PubMedCrossRefGoogle Scholar
  31. 31.
    Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134PubMedCrossRefGoogle Scholar
  32. 32.
    Lamorte L, Park M (2001) The receptor tyrosine kinases: role in cancer progression. Surg Oncol Clin N Am 10(2):271–288, viiiGoogle Scholar
  33. 33.
    Grimminger F, Schermuly RT, Ghofrani HA (2010) Targeting non-malignant disorders with tyrosine kinase inhibitors. Nat Rev Drug Discov 9(12):956–970PubMedCrossRefGoogle Scholar
  34. 34.
    Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298(5600):1912–1934PubMedCrossRefGoogle Scholar
  35. 35.
    Holbro T, Hynes NE (2004) ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol 44:195–217PubMedCrossRefGoogle Scholar
  36. 36.
    Wells A, Welsh JB, Lazar CS, Wiley HS, Gill GN, Rosenfeld MG (1990) Ligand-induced transformation by a noninternalizing epidermal growth factor receptor. Science 247(4945):962–964PubMedCrossRefGoogle Scholar
  37. 37.
    Wiley HS, Herbst JJ, Walsh BJ, Lauffenburger DA, Rosenfeld MG, Gill GN (1991) The role of tyrosine kinase activity in endocytosis, compartmentation, and down-regulation of the epidermal growth factor receptor. J Biol Chem 266(17):11083–11094PubMedGoogle Scholar
  38. 38.
    Decker SJ (1990) Epidermal growth factor and transforming growth factor-alpha induce differential processing of the epidermal growth factor receptor. Biochem Biophys Res Commun 166(2):615–621PubMedCrossRefGoogle Scholar
  39. 39.
    French AR, Tadaki DK, Niyogi SK, Lauffenburger DA (1995) Intracellular trafficking of epidermal growth factor family ligands is directly influenced by the pH sensitivity of the receptor/ligand interaction. J Biol Chem 270(9):4334–4340PubMedCrossRefGoogle Scholar
  40. 40.
    Reddy CC, Wells A, Lauffenburger DA (1998) Comparative mitogenic potencies of EGF and TGF alpha and their dependence on receptor-limitation versus ligand-limitation. Med Biol Eng Comput 36(4):499–507PubMedCrossRefGoogle Scholar
  41. 41.
    Reddy CC, Niyogi SK, Wells A, Wiley HS, Lauffenburger DA (1996) Engineering epidermal growth factor for enhanced mitogenic potency. Nat Biotechnol 14(13):1696–1699PubMedCrossRefGoogle Scholar
  42. 42.
    Sarkar CA, Lowenhaupt K, Horan T, Boone TC, Tidor B, Lauffenburger DA (2002) Rational cytokine design for increased lifetime and enhanced potency using pH-activated “histidine switching”. Nat Biotechnol 20(9):908–913PubMedCrossRefGoogle Scholar
  43. 43.
    Fallon EM, Liparoto SF, Lee KJ, Ciardelli TL, Lauffenburger DA (2000) Increased endosomal sorting of ligand to recycling enhances potency of an interleukin-2 analog. J Biol Chem 275(10):6790–6797PubMedCrossRefGoogle Scholar
  44. 44.
    Stoscheck CM, Carpenter G (1984) Down regulation of epidermal growth factor receptors: direct demonstration of receptor degradation in human fibroblasts. J Cell Biol 98(3): 1048–1053PubMedCrossRefGoogle Scholar
  45. 45.
    Moustakas A, Heldin CH (2009) The regulation of TGFbeta signal transduction. Development 136(22):3699–3714PubMedCrossRefGoogle Scholar
  46. 46.
    Ikushima H, Miyazono K (2010) TGF-beta signalling: a complex web in cancer progression. Nat Rev Cancer 10(6):415–424PubMedCrossRefGoogle Scholar
  47. 47.
    Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL (2003) Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol 5(5):410–421PubMedCrossRefGoogle Scholar
  48. 48.
    Mitchell H, Choudhury A, Pagano RE, Leof EB (2004) Ligand-dependent and -independent transforming growth factor-beta receptor recycling regulated by clathrin-mediated endocytosis and Rab11. Mol Biol Cell 15(9):4166–4178PubMedCrossRefGoogle Scholar
  49. 49.
    Zuo W, Chen YG (2009) Specific activation of mitogen-activated protein kinase by transforming growth factor-beta receptors in lipid rafts is required for epithelial cell plasticity. Mol Biol Cell 20(3):1020–1029PubMedCrossRefGoogle Scholar
  50. 50.
    Zi Z, Klipp E (2007) Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway. PLoS One 2(9):e936PubMedCrossRefGoogle Scholar
  51. 51.
    Miaczynska M, Pelkmans L, Zerial M (2004) Not just a sink: endosomes in control of signal transduction. Curr Opin Cell Biol 16(4):400–406PubMedCrossRefGoogle Scholar
  52. 52.
    Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, Di Fiore PP, Polo S (2005) Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci USA 102(8):2760–2765PubMedCrossRefGoogle Scholar
  53. 53.
    Rappoport JZ, Simon SM (2009) Endocytic trafficking of activated EGFR is AP-2 dependent and occurs through preformed clathrin spots. J Cell Sci 122(Pt 9):1301–1305PubMedCrossRefGoogle Scholar
  54. 54.
    Palmer MJ, Mahajan VS, Trajman LC, Irvine DJ, Lauffenburger DA, Chen J (2008) Interleukin-7 receptor signaling network: an integrated systems perspective. Cell Mol Immunol 5(2):79–89PubMedCrossRefGoogle Scholar
  55. 55.
    Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC (2000) Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem 275(12):8806–8811PubMedCrossRefGoogle Scholar
  56. 56.
    Guo A, Villen J, Kornhauser J, Lee KA, Stokes MP, Rikova K, Possemato A, Nardone J, Innocenti G, Wetzel R, Wang Y, MacNeill J, Mitchell J, Gygi SP, Rush J, Polakiewicz RD, Comb MJ (2008) Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci USA 105(2):692–697PubMedCrossRefGoogle Scholar
  57. 57.
    Jänne PA, Gray N, Settleman J (2009) Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov 8(9):709–723PubMedCrossRefGoogle Scholar
  58. 58.
    Lappano R, Maggiolini M (2011) G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov 10(1):47–60PubMedCrossRefGoogle Scholar
  59. 59.
    Breslauer DN, Lee PJ, Lee LP (2006) Microfluidics-based systems biology. Mol BioSyst 2(2):97–112PubMedCrossRefGoogle Scholar
  60. 60.
    Wang CJ, Levchenko A (2009) Microfluidics technology for systems biology research. Meth Mol Biol 500:203–219CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Verena Becker
    • 1
    • 2
  • Jens Timmer
    • 3
  • Ursula Klingmüller
    • 1
    • 2
  1. 1.Division Systems Biology of Signal TransductionDKFZ-ZMBH Alliance, German Cancer Research CenterHeidelbergGermany
  2. 2.Bioquant, Heidelberg UniversityHeidelbergGermany
  3. 3.BIOSS Centre for Biological Signalling Studies, Freiburg Institute for Advanced Studies, Institute of Physics, Center for Systems BiologyUniversity of FreiburgFreiburgGermany

Personalised recommendations