Kinetic Proofreading Model

  • Byron Goldstein
  • Daniel Coombs
  • James R. Faeder
  • William S. Hlavacek
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 640)


Kinetic proofreading is an intrinsic property of the cell signaling process. It arises as a consequence of the multiple interactions that occur after a ligand triggers a receptor to initiate a signaling cascade and it ensures that false signals do not propagate to completion. In order for an aaive signaling complex to form after a ligand binds to a cell surface receptor, a sequence of binding and phosphorylation events must occur that are rapidly reversed if the ligand dissociates from the receptor. This gives rise to a mechanism by which cells can discriminate among ligands that bind to the same receptor but form ligand-receptor complexes with different lifetimes. We review experiments designed to test for kinetic proofreading and models that exhibit kinetic proofreading.


Bivalent Ligand Reverse Rate Constant High Ligand Concentration Cell Signaling Process FceRI 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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Reth M. Antigen receptor tail clue. Nature 1989; 338:383–384.PubMedCrossRefGoogle Scholar
  2. 2.
    Cambier JC. Antigen and Fc receptor signaling: The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM). J Immunol 1995; 155:3281–2185.PubMedGoogle Scholar
  3. 3.
    Hopfield JJ. Kinetic proofreading: A new mechanism for reducing errors in biosynthetic processes requiring high specificity. Proc Nad Acad Sci USA 1974; 71:4135–4139.CrossRefGoogle Scholar
  4. 4.
    Hopfield JJ, Yamane T, Yue V et al. Direct experimental evidence for kinetic proofreading in amino acylation of tRNAIle. Proc Nad Acad Sci USA 1976; 73:1164–1168.CrossRefGoogle Scholar
  5. 5.
    McKeithan TW. Kinetic Proofreading in T-cell receptor signal-transduction. Proc Natl Acad Sci USA 1995; 92:5042–5046.PubMedCrossRefGoogle Scholar
  6. 6.
    Torigoe C, Inman JK, Metzger H. An unusual mechanism for ligand antagonism. Science 1998; 281:568–572.PubMedCrossRefGoogle Scholar
  7. 7.
    Faeder JR, Hlavacek WS, Reischl I et al. Investigation of early events in FceRI-mediated signaling using a detailed mathematical model. J Immunol 2003; 170:3769–3781.PubMedGoogle Scholar
  8. 8.
    Wbfsy C, Kent UM, Mao SY et al. Kinetics of tyrosine phosphorylation when IgE dimers bind to FcE Receptors on rat basophilic leukemia-cells. J Biol Chem 1995; 270:20264–20272.CrossRefGoogle Scholar
  9. 9.
    Wofsy C, Torigoe C, Kent UM et al. Exploiting the difference between intrinsic and extrinsic kinases: Implications for regulation of signaling by immunoreceptors. J Immunol 1997; 259:5984–5992.Google Scholar
  10. 10.
    Torigoe C, Goldstein B, Wofsy C et al. Shuttling of initiating kinase between discrete aggregates of the high affinity receptor for IgE regulates the cellular response. Proc Natl Acad Sci USA 1997; 94:1372–1377.PubMedCrossRefGoogle Scholar
  11. 11.
    Yamashita T, Mao SY, Metzger H. Aggregation of the high-affinity IgE receptor and enhanced activity of P53/56(Lyn) protcin-tyrosine kinase. Proc Nad Acad of Sci USA 1994; 91:11251–11255.CrossRefGoogle Scholar
  12. 12.
    Vonakis BM, Haleem-Smith H, Benjamin P et al. Interaction between the unphosphorylatcd receptor with high affinity for IgE and Lyn kinase. J Biol Chem 2001; 276:1041–1050.PubMedCrossRefGoogle Scholar
  13. 13.
    Kihara H, Siraganian RP. Src homology 2 domains of Syk and Lyn bind to tyrosine-phosphorylated subunits of the high affinity IgE receptor. J Biol Chem 1994; 269:22427–22432.PubMedGoogle Scholar
  14. 14.
    Chen T, Repetto B, Chizzonite R et al. Interaction of phosphorylated FceRIy immunoglobulin receptor tyrosine activation motif-based peptides with dual and single SH2 domains of p72syk: Assessment of binding parameters and real time binding kinetics. J Biol Chem 1996; 271:25308–25315.PubMedCrossRefGoogle Scholar
  15. 15.
    El-Hillal O, Kurosaki T, Yamamura H et al. Syk kinase activation by a src kinase-initiated activation loop phosphorylation chain reaction. Proc Natl Acad Sci USA 1997; 94:1919–1924.PubMedCrossRefGoogle Scholar
  16. 16.
    Keshvara LM, I saacson CO, Yankee TM et al. Syk-and Lyn-dependcnt phosphorylation of Syk on multiple tyrosines following B-ccU activation includes a site that negatively regulates signaling. J Immunol 1998; 161:5276–5283.PubMedGoogle Scholar
  17. 17.
    Zhang J, Kimura T, Siraganian RP. Mutations in the activation loop tyrosines of protein tyrosine kinase Syk abrogate intracellular signaling but not kinase activity. J Immunol 1998; 161:4366–4374.PubMedGoogle Scholar
  18. 18.
    Siraganian RP, Zhang J, Suzuki K et al. Protein tyrosine kinase Syk in mast cell signaling. Mol Immtmol 2002; 38:1229–1233.CrossRefGoogle Scholar
  19. 19.
    Pribluda VS, Pribluda C, Metzger H. Transphosphorylation as the mechanism by which the high-affinity receptor for IgE is phosphorylated upon aggregation. Proc Natl Acad Sci USA 1994; 91:11246–11250.PubMedCrossRefGoogle Scholar
  20. 20.
    Kent UM, Mao S-Y, Wbfsy C et al. Dynamics of signal transduction after aggregation of cell-surface receptors: Studies on the type I receptor for IgE. Proc Natl Acad Sci USA 1994; 91:3087–3091.PubMedCrossRefGoogle Scholar
  21. 21.
    Bunnell SC, Hong DI, Kardon JR et al. T-cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J Cell Biol 2002; 158:1263–1275.PubMedCrossRefGoogle Scholar
  22. 22.
    Mao SY, Metzger H. Characterization of protein-tyrosine phosphatases that dephosphorylate the high affinity IgE receptor. J Biol Chem 1997; 272:14067–14073.PubMedCrossRefGoogle Scholar
  23. 23.
    Blinov ML, Faeder JR, Goldstein B et al. BioNetGen: Software for rule-based modeling of signaling transduction based on the interactions of molecular domains. Bioinformatics 2004; 20:289–291.CrossRefGoogle Scholar
  24. 24.
    Faeder JR, BUnov ML, Goldstein B et al. Ruled-based modeling of biochemical networks. Complexity 2005; 10:22–41.CrossRefGoogle Scholar
  25. 25.
    Faeder JR, Blinov ML, Goldstein B et al. Combinatorial complexity and dynamical restriction of network flows in signal transduction. Syst Biol 2005; 2:5–15.CrossRefGoogle Scholar
  26. 26.
    Liu Z-J, Haleem-Smith H, Chen H et al. Unexpected signals in a system subject to kinetic proofreading. Proc Natl Acad Sci USA 2001; 98:7289–7294.PubMedCrossRefGoogle Scholar
  27. 27.
    Saitoh S, Arudchandran R, Manetz TS et al. LAT is essential for FceRI-mediated mast cell activation. Immunity 2000; 12:525–535.PubMedCrossRefGoogle Scholar
  28. 28.
    Pierce M, Metzger H. Detergent-resistant microdomains offer no refuge for proteins phophorylated by the IgE receptor. J Biol Chem 2000; 275:34976–34982.CrossRefGoogle Scholar
  29. 29.
    Zhang W, Trible RP, Samelson LE. LAT palmitoylation: Its essential role in membrane microdomain targeting and tyrosine phosphorylation during T-cell activation. Immunity 1988; 9:239–246.CrossRefGoogle Scholar
  30. 30.
    Field KA, Holowka D, Baird B. FceRI-mediated recruitment of p53/56-lyn to detergent-resistant membrane domains accompanies cellular signaling. Proc Natl Acad Sci USA 1995; 92:9201–9205.PubMedCrossRefGoogle Scholar
  31. 31.
    Field KA, Holowka D, Baird B. Compartmentalized activation of the high affinity immunoglobulin E receptor within membrane domains. J Biol Chem 1997; 272:4276–4280.PubMedCrossRefGoogle Scholar
  32. 32.
    Rivera J, Cordero JR, Furumoto Y et al. Macromolecular protein signaling complexes and mast cell responses: A view of the organization of IgE-dependent mast cell signaling. Mol Immunol 2002; 38:1253–1258.PubMedCrossRefGoogle Scholar
  33. 33.
    Wilson BS, Steinberg SL, Liederman K et al. Markers for detergent-resistant lipid rafts occupy distinct and dynamic domains in native membranes. Mol Biol Cell 2004; 15:2580–2592.PubMedCrossRefGoogle Scholar
  34. 34.
    Rosette C, Werlen G, Daniels MA et al. The impact of duration versus extent of TCR occupancy on T-cell activation: A revision of the kinetic proofreading model. Immunity 2001; 15:59–70.PubMedCrossRefGoogle Scholar
  35. 35.
    Eglite S, Morin JM, Metzger H. Sythesis and Secretion of monocyte chemotactic protein-1 stimulated by high affinity receptor for IgE. J Immunol. 2003; 170:2680–2687.PubMedGoogle Scholar
  36. 36.
    Hlavacek WS, Redondo A, Metzger H et al. Kinetic proofreading models for cell signaling predict ways to escape kinetic proofreading. Proc Natl Acad Sci USA 2001; 98:7295–7200.PubMedCrossRefGoogle Scholar
  37. 37.
    Hlavacek WS, Redondo A, Wofsy C et al. Kinetic proofreading in receptor-mediated transduction of cellular signals. Bull Math Biol 2002; 64:887–811.PubMedCrossRefGoogle Scholar
  38. 38.
    Goldstein B, Faeder JR, Hlavacek WS. Mathematical models of immune receptor signaling. Nat Rev Immunol 2004; 4:445–456.PubMedCrossRefGoogle Scholar
  39. 39.
    Coombs D, Goldstein B. T-cell activation: Kinetic proofreading, serial engagement and cell adhesion. J of Computation and Appl Math 2005; 184:121–139.CrossRefGoogle Scholar
  40. 40.
    Krogsgaard M, Li Q.-J, Sumen C et al. Agonist/endogenous peptide-MHC heterodimers drive T-cell activation and sensitivity. Nature 2005; 434:238–243.PubMedCrossRefGoogle Scholar
  41. 41.
    Valitutti S, Muller S, Cella M et al. Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature 1995; 375:148–151.PubMedCrossRefGoogle Scholar
  42. 42.
    Lanzavecchia A, Lezzi G, Viola A. From TCR engagement to T-cell activation: A kinetic view of T-cell behavior. Cell 1999; 96:1–4.Google Scholar
  43. 43.
    van den Berg HA, Rand DA, Burroughs NJ. A reliable and safe T-cell repertoire based on low-affinity T-cell receptors. J Theor Biol 2001; 209:465–486.CrossRefGoogle Scholar
  44. 44.
    Coombs D, Kalergis AM, Nathenson SG et al. Activated TCR remain marked for internalization after dissociation from peptide-MHC. Nature Immunol 2002; 3:926–931.CrossRefGoogle Scholar
  45. 45.
    Wbfsy C, Coombs D, Goldstein B. Calculations show substantial serial engagement of T-cell receptors. Biophys J 2001; 80:606–612.CrossRefGoogle Scholar
  46. 46.
    Kalergis AM, Boucheron N, Doucey M-A et al. Efficient T-cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex. Nature Immunol 2001; 2:229–234.CrossRefGoogle Scholar
  47. 47.
    Gonzalez PA, Carreno LJ, Coombs D et al. Effects of pMHC and TCR dwell time on T-cell activation. Proc Natl Acad Sci USA 2005; 102:4824–4829.PubMedCrossRefGoogle Scholar
  48. 48.
    Holler PD, Kranz DM. Quantitative analysis of the contribution of TCR/pepMHC affinity and CDS to T-cell activation. Immunity 2003; 18:255–264.PubMedCrossRefGoogle Scholar
  49. 49.
    Weber KS, Donermeyer DL, Allen PM et al. Class Il-restricted T-cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc Natl Acad of Sci USA 2005; 102:19033–19038.CrossRefGoogle Scholar
  50. 50.
    Itoh Y, Hemmer B, Martin R et al. Serial TCR engagement and down-modulation by peptide: MHC molecule ligands: Relationship to the quality of individual TCR signaling events. J Immunol 1999; 162:2073–2080.PubMedGoogle Scholar
  51. 51.
    Torigoe C, Song JM, Barisas BG et al. The influence of actin microfilaments on signaling by the receptor with high-affinity for IgE. Mol Immunol 2004; 41:817–829.PubMedCrossRefGoogle Scholar
  52. 52.
    Torigoe C, Facder JR, Oliver JM et al. Kinetic proofreading of ligand-FceRI interactions may persist beyond LAT phosphorylation, J Immunol 2007; 178:3530–3535.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  • Byron Goldstein
    • 1
  • Daniel Coombs
    • 1
  • James R. Faeder
    • 1
  • William S. Hlavacek
    • 1
  1. 1.Theoretical Division, Los Alamos National LaboratoryTheoretical Biology and Biophysics GroupLos AlamosUSA

Personalised recommendations