Skip to main content
SpringerLink
Log in

Sensitivity and specificity amplification in signal transduction

  • Review Article
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Gurdon, J. B., Lemaire, P., and Kato, K. (1993) Community effects and related phenomena in development. Cell 75, 831–834.

    Article  PubMed  CAS  Google Scholar 

  2. Pitcher, J. A., Freedman, N. J., and Lefkowitz, R. J. (1998) G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–692.

    Article  PubMed  CAS  Google Scholar 

  3. Schlessinger, J. (2000) Cell signaling by receptor tyrosine kinases. Cell 103, 211–225.

    Article  PubMed  CAS  Google Scholar 

  4. Bourne, H. R. (1997) How receptors talk to trimeric G proteins. Curr. Opin. Cell. Biol. 9, 134–142.

    Article  PubMed  CAS  Google Scholar 

  5. Cohen, P. (1992) Signal integration at the level of protein kinases, protein phosphatases and their substrates. Trends Biochem. Sci. 17, 408–413.

    Article  PubMed  CAS  Google Scholar 

  6. Pawson, T. and Nash, P. (2000) Protein-protein interactions define specificity in signal transduction. Genes. Dev. 14, 1027–1047.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  8. Bar-Sagi, D. and Hall, A. (2000) Ras and Rho GTPases: a family reunion. Cell 103, 227–238.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  10. Gilman, A. G. (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem 56, 615–649.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  18. Karin, M. (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J. Biol. Chem. 270, 16483–16486.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  20. Koshland, D. E., Jr. (1998) The era of pathway quantification. Science 280, 852–853.

    Article  PubMed  Google Scholar 

  21. Swain, P. S. and Siggia, E. D. (2002) The role of proofreading in signal transduction specificity. Biophys. J. 82, 2928–2933.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  28. Bagowski, C. P. and Ferrell, J. E., Jr. (2001) Bistability in the JNK cascade. Curr. Biol. 11, 1176–1182.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  30. Qian, H. (2003) Thermodynamic and kinetic analysis of sensitivity amplification in biological signal transduction. Biophys. Chem., in press.

  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.

    Article  PubMed  CAS  Google Scholar 

  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. Donovan, S., Shannon, K. M., and Bollag, G. (2002) GTPase activating proteins: critical regulators of intracellular signaling. Biochim. Biophys. Acta 1602, 23–45.

    PubMed  CAS  Google Scholar 

  34. Zhang, F. L. and Casey, P. J. (1996) Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem. 65, 241–269.

    Article  PubMed  CAS  Google Scholar 

  35. Elion, E. A. (2001) The Ste5p scaffold. J. Cell. Sci. 114, 3967–3978.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  37. Morrison, D. K. (2001) KSR: a MAPK scaffold of the Ras pathway? J. Cell. Sci. 114, 1609–1612.

    PubMed  CAS  Google Scholar 

  38. Raabe, T. and Rapp, U. R. (2002) KSR—a regulator and scaffold protein of the MAPK pathway. Sci. STKE 2002, PE28.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  54. Ferrell, J. E., Jr. (2000) What do scaffold proteins really do? Sci. STKE 2000, PE1.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  59. Ninio, J. (1975) Kinetic amplification of enzyme discrimination. Biochimie 57, 587–595.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 73104, Oklahoma City, OK

    Guangpu Li

  2. Department of Applied Mathematics, University of Washington, 98195, Seattle, WA

    Hong Qian

Authors
  1. Guangpu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guangpu Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, G., Qian, H. Sensitivity and specificity amplification in signal transduction. Cell Biochem Biophys 39, 45–59 (2003). https://doi.org/10.1385/CBB:39:1:45

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/CBB:39:1:45

Index Entries

Search

Navigation