Cell Biochemistry and Biophysics

, Volume 39, Issue 1, pp 45–59 | Cite as

Sensitivity and specificity amplification in signal transduction

Review Article

Abstract

Intracellular signal transduction pathways transmit signals from the cell surface to various intracellular destinations, such as cytoskeleton and nucleus through a cascade of protein-protein interactions and activation events, leading to phenotypic changes such as cell proliferation, differentiation, and death. Over the past two decades, numerous signaling proteins and signal transduction pathways have been discovered and characterized. There are two major classes of signaling proteins: phosphoproteins (e.g., mitogen-activated protein kinases) and guanosine triphosphatases (GTPases; e.g., Ras and G proteins). They both function as molecular switches by addition and removal of one or more high-energy phosphate groups. This review discusses developments that seek to quantify the signal transduction processes with kinetic analysis and mathematical modeling of the signaling phosphoproteins and GTPases. These studies have provided insights into the sensitivity and specificity amplification of biological signals in integrated systems.

Index Entries

Signal transduction phosphorylation kinase phosphatase MAPK GTP hydrolysis GTPase G protein Ras kinetics mathematical modeling 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gurdon, J. B., Lemaire, P., and Kato, K. (1993) Community effects and related phenomena in development. Cell 75, 831–834.PubMedCrossRefGoogle Scholar
  2. 2.
    Pitcher, J. A., Freedman, N. J., and Lefkowitz, R. J. (1998) G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–692.PubMedCrossRefGoogle Scholar
  3. 3.
    Schlessinger, J. (2000) Cell signaling by receptor tyrosine kinases. Cell 103, 211–225.PubMedCrossRefGoogle Scholar
  4. 4.
    Bourne, H. R. (1997) How receptors talk to trimeric G proteins. Curr. Opin. Cell. Biol. 9, 134–142.PubMedCrossRefGoogle Scholar
  5. 5.
    Cohen, P. (1992) Signal integration at the level of protein kinases, protein phosphatases and their substrates. Trends Biochem. Sci. 17, 408–413.PubMedCrossRefGoogle Scholar
  6. 6.
    Pawson, T. and Nash, P. (2000) Protein-protein interactions define specificity in signal transduction. Genes. Dev. 14, 1027–1047.PubMedGoogle Scholar
  7. 7.
    Widmann, C., Gibson, S., Jarpe, M. B., and Johnson, G. L. (1999) Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol. Rev. 79, 143–180.PubMedGoogle Scholar
  8. 8.
    Bar-Sagi, D. and Hall, A. (2000) Ras and Rho GTPases: a family reunion. Cell 103, 227–238.PubMedCrossRefGoogle Scholar
  9. 9.
    Bourne, H. R., Sanders, D. A., and McCormick, F. (1990) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348, 125–132.PubMedCrossRefGoogle Scholar
  10. 10.
    Gilman, A. G. (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem 56, 615–649.PubMedCrossRefGoogle Scholar
  11. 11.
    Egan, S. E., Giddings, B. W., Brooks, M. W., Buday, L., Sizeland, A. M., and Weinberg, R. A. (1993) Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363, 45–51.PubMedCrossRefGoogle Scholar
  12. 12.
    Boriack-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D., and Kuriyan, J. (1998) The structural basis of the activation of Ras by Sos. Nature 394, 337–343.PubMedCrossRefGoogle Scholar
  13. 13.
    Moodie, S. A., Willumsen, B. M., Weber, M. J., and Wolfman, A. (1993) Complexes of Ras-GTP with Raf-1 and mitogen-activated protein kinase. Science 260, 1658–1661.PubMedCrossRefGoogle Scholar
  14. 14.
    van Aelst, L., Barr, M., Marcus, S., Polverino, A., and Wigler, M. (1993) Complex formation between RAS and RAF and other protein kinases. Proc. Natl. Acad. Sci. USA 90, 6213–6217.PubMedCrossRefGoogle Scholar
  15. 15.
    Vojtek, A. B., Hollenberg, S. M., and Cooper, J. A. (1993) Mammalian ras interacts directly with the serine/threonine kinase raf. Cell 74, 205–214.PubMedCrossRefGoogle Scholar
  16. 16.
    Warne, P. H., Viciana, P. R., and Downward, J. (1993) Direct interaction of Ras and the aminoterminal region of Raf-1 in vitro. Nature 364, 352–355.PubMedCrossRefGoogle Scholar
  17. 17.
    Khokhlatchev, A. V., Canagarajah, B., Wilsbacher, J., Robinson, M., Atkinson, M., Goldsmith, E., and Cobb, M. H. (1998) Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell 93, 605–615.PubMedCrossRefGoogle Scholar
  18. 18.
    Karin, M. (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J. Biol. Chem. 270, 16483–16486.PubMedGoogle Scholar
  19. 19.
    Waskiewicz, A. J. and Cooper, J. A. (1995) Mitogen and stress response pathways: MAP kinase cascades and phosphatase regulation in mammals and yeast. Curr. Opin. Cell. Biol. 7, 798–805.PubMedCrossRefGoogle Scholar
  20. 20.
    Koshland, D. E., Jr. (1998) The era of pathway quantification. Science 280, 852–853.PubMedCrossRefGoogle Scholar
  21. 21.
    Swain, P. S. and Siggia, E. D. (2002) The role of proofreading in signal transduction specificity. Biophys. J. 82, 2928–2933.PubMedCrossRefGoogle Scholar
  22. 22.
    Ferrell, J. E., Jr., and Machleder, E. M. (1998) The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science 280, 895–898.PubMedCrossRefGoogle Scholar
  23. 23.
    Bhalla, U. S., Ram, P. T., and Iyengar, R. (2002) MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 297, 1018–1023.PubMedCrossRefGoogle Scholar
  24. 24.
    Goldbeter, A. and Koshland, D. E., Jr. (1981) An amplified sensitivity arising from covalent modification in biological systems. Proc. Natl. Acad. Sci. USA 78, 6840–6844.PubMedCrossRefGoogle Scholar
  25. 25.
    Baldwin, J. and Chothia, C. (1979) Haemoglobin: the structural changes related to ligand binding and its allosteric mechanism. J. Mol. Biol. 129, 175–220.PubMedCrossRefGoogle Scholar
  26. 26.
    Gelin, B. R., Lee, A. W., and Karplus, M. (1983) Hemoglobin tertiary structural change on ligand binding. Its role in the co-operative mechanism. J. Mol. Biol. 171, 489–559.PubMedCrossRefGoogle Scholar
  27. 27.
    Ferrell, J. E., Jr. (2002) Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr. Opin. Cell. Biol. 14, 140–148.PubMedCrossRefGoogle Scholar
  28. 28.
    Bagowski, C. P. and Ferrell, J. E., Jr. (2001) Bistability in the JNK cascade. Curr. Biol. 11, 1176–1182.PubMedCrossRefGoogle Scholar
  29. 29.
    Berg, O. G., Paulsson, J., and Ehrenberg, M. (2000) Fluctuations and quality of control in biological cells: zero-order ultrasensitivity reinvestigated. Biophys. J. 79, 1228–1236.PubMedGoogle Scholar
  30. 30.
    Qian, H. (2003) Thermodynamic and kinetic analysis of sensitivity amplification in biological signal transduction. Biophys. Chem., in press.Google Scholar
  31. 31.
    Hopfield, J. J. (1980) The energy relay: a proofreading scheme based on dynamic cooperativity and lacking all characteristic symptoms of kinetic proofreading in DNA replication and protein synthesis. Proc. Natl. Acad. Sci. USA 77, 5248–5252.PubMedCrossRefGoogle Scholar
  32. 32.
    Wittinghofer, A. (2000) The functioning of molecular switches in three dimensions, in GTPases (Hall, A., ed.). Oxford University Press, NY, pp. 244–310.Google Scholar
  33. 33.
    Donovan, S., Shannon, K. M., and Bollag, G. (2002) GTPase activating proteins: critical regulators of intracellular signaling. Biochim. Biophys. Acta 1602, 23–45.PubMedGoogle Scholar
  34. 34.
    Zhang, F. L. and Casey, P. J. (1996) Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem. 65, 241–269.PubMedCrossRefGoogle Scholar
  35. 35.
    Elion, E. A. (2001) The Ste5p scaffold. J. Cell. Sci. 114, 3967–3978.PubMedGoogle Scholar
  36. 36.
    Choi, K. Y., Satterberg, B., Lyons, D. M., and Elion, E. A. (1994) Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Cell 78, 499–512.PubMedCrossRefGoogle Scholar
  37. 37.
    Morrison, D. K. (2001) KSR: a MAPK scaffold of the Ras pathway? J. Cell. Sci. 114, 1609–1612.PubMedGoogle Scholar
  38. 38.
    Raabe, T. and Rapp, U. R. (2002) KSR—a regulator and scaffold protein of the MAPK pathway. Sci. STKE 2002, PE28.Google Scholar
  39. 39.
    Schaeffer, H. J., Catling, A. D., Eblen, S. T., Collier, L. S., Krauss, A., and Weber, M. J. (1998) MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 281, 1668–1671.PubMedCrossRefGoogle Scholar
  40. 40.
    Kornfeld, K., Hom, D. B., and Horvitz, H. R. (1995) The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell 83, 903–913.PubMedCrossRefGoogle Scholar
  41. 41.
    Sundaram, M. and Han, M. (1995) The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Cell 83, 889–901.PubMedCrossRefGoogle Scholar
  42. 42.
    Therrien, M., Chang, H. C., Solomon, N. M., Karim, F. D., Wassarman, D. A., and Rubin, G. M. (1995) KSR, a novel protein kinase required for RAS signal transduction. Cell 83, 879–888.PubMedCrossRefGoogle Scholar
  43. 43.
    Jacobs, D., Glossip, D., Xing, H., Muslin, A. J., and Kornfeld, K. (1999) Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 13, 163–175.PubMedCrossRefGoogle Scholar
  44. 44.
    Stewart, S., Sundaram, M., Zhang, Y., Lee, J., Han, M., and Guan, K. L. (1999) Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization. Mol. Cell. Biol. 19, 5523–5534.PubMedGoogle Scholar
  45. 45.
    Therrien, M., Michaud, N. R., Rubin, G. M., and Morrison, D. K. (1996) KSR modulates signal propagation within the MAPK cascade. Genes Dev. 10, 2684–2695.PubMedCrossRefGoogle Scholar
  46. 46.
    Yu, W., Fantl, W. J., Harrowe, G., and Williams, L. T. (1998). Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK. Curr. Biol. 8, 56–64.PubMedCrossRefGoogle Scholar
  47. 47.
    Roy, F., Laberge, G., Douziech, M., Ferland-McCollough, D., and Therrien, M. (2002) KSR is a scaffold required for activation of the ERK/MAPK module. Genes Dev. 16, 427–438.PubMedCrossRefGoogle Scholar
  48. 48.
    Nguyen, A., Burack, W. R., Stock, J. L., et al. (2002) Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Mol. Cell. Biol. 22, 3035–3045.PubMedCrossRefGoogle Scholar
  49. 49.
    Joneson, T., Fulton, J. A., Volle, D. J., Chaika, O. V., Bar-Sagi, D., and Lewis, R. E. (1998) Kinase suppressor of Ras inhibits the activation of extracellular ligand-regulated (ERK) mitogen-activated protein (MAP) kinase by growth factors, activated Ras, and Ras effectors. J. Biol. Chem. 273, 7743–7748.PubMedCrossRefGoogle Scholar
  50. 50.
    Whitmarsh, A. J., Kuan, C. Y., Kennedy, N. J. et al. (2001) Requirement of the JIP1 scaffold protein for stress-induced JNK activation. Genes Dev. 15, 2421–2432.PubMedCrossRefGoogle Scholar
  51. 51.
    Yasuda, J., Whitmarsh, A. J., Cavanagh, J., Sharma, M., and Davis, R. J. (1999) The JIP group of mitogen-activated protein kinase scaffold proteins. Mol. Cell. Biol. 19, 7245–7254.PubMedGoogle Scholar
  52. 52.
    Bray, D. and Lay, S. (1997) Computer-based analysis of the binding steps in protein complex formation. Proc. Natl. Acad. Sci. USA. 94, 13493–13498.PubMedCrossRefGoogle Scholar
  53. 53.
    Levchenko, A., Bruck, J. and Sternberg, P. W. (2000) Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties. Proc. Natl. Acad. Sci. USA. 97, 5818–5823.PubMedCrossRefGoogle Scholar
  54. 54.
    Ferrell, J. E., Jr. (2000) What do scaffold proteins really do? Sci. STKE 2000, PE1.Google Scholar
  55. 55.
    Yablonski, D., Marbach, I. and Levitzki, A. (1996) Dimerization of Ste5, a mitogen-activated protein kinase cascade scaffold protein, is required for signal transduction. Proc. Natl. Acad. Sci. USA. 93, 13864–13869.PubMedCrossRefGoogle Scholar
  56. 56.
    Derijard, B., Raingeaud, J., Barrett, T., Wu, I. H., Han, J., Ulevitch, R. J. and Davis, R. J. (1995) Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science 267, 682–685.PubMedCrossRefGoogle Scholar
  57. 57.
    Madhani, H. D., Styles, C. A. and Fink, G. R. (1997) MAP kinases with distinct inhibitory functions impart signaling specificity during yeast differentiation. Cell 91, 673–684.PubMedCrossRefGoogle Scholar
  58. 58.
    Hopfield, J. J. (1974) Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity. Proc. Natl. Acad. Sci. USA. 71, 4135–4139.PubMedCrossRefGoogle Scholar
  59. 59.
    Ninio, J. (1975) Kinetic amplification of enzyme discrimination. Biochimie 57, 587–595.PubMedCrossRefGoogle Scholar
  60. 60.
    Chong, H., Lee, J. and Guan, K. L. (2001) Positive and negative regulation of Raf kinase activity and function by phosphorylation. Embo J. 20, 3716–3727.PubMedCrossRefGoogle Scholar
  61. 61.
    Li, G. and Qian, H. (2002) Kinetic timing: a novel mechanism that improves the accuracy of GTPase timers in endosome fusion and other biological processes. Traffic 3, 249–255.PubMedCrossRefGoogle Scholar
  62. 62.
    Neal, S. E., Eccleston, J. F. and Webb, M. R. (1990) Hydrolysis of GTP by p21NRAS, the NRAS protooncogene product, is accompanied by a conformational change in the wildtype protein: use of a single fluorescent probe at the catalytic site. Proc. Natl. Acad. Sci. USA. 87, 3562–3565.PubMedCrossRefGoogle Scholar
  63. 63.
    Hu, J. S. and Redfield, A. G. (1997) Conformational and dynamic differences between N-ras P21 bound to GTPgammaS and to GMPPNP as studied by NMR. Biochemistry 36, 5045–5052.PubMedCrossRefGoogle Scholar
  64. 64.
    Gideon, P., John, J., Frech, M., Lautwein, A., Clark, R., Scheffler, J. E. and Wittinghofer, A. (1992) Mutational and kinetic analyses of the GTPase-activating protein (GAP)-p21 interaction: the C-terminal domain of GAP is not sufficient for full activity. Mol. Cell. Biol. 12, 2050–2056.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Oklahoma Health Sciences CenterOklahoma City
  2. 2.Department of Applied MathematicsUniversity of WashingtonSeattle

Personalised recommendations