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. 2002 Jun;82(6):2928–2933. doi: 10.1016/S0006-3495(02)75633-6

The role of proofreading in signal transduction specificity.

Peter S Swain 1, Eric D Siggia 1
PMCID: PMC1302080  PMID: 12023215

Abstract

Many intracellular signaling proteins such as MAP kinases and transcription factors require multiple covalent modifications before activating downstream targets. This property suggests that signaling pathways are organized to facilitate proofreading, which expends energy to enhance the specificity of the pathway for the appropriate effector. Focusing on MAP kinases, we show that each phosphorylation of the kinase can act as an independent specificity test for that kinase. This is independent of whether MAP kinase activation is distributive, processive, or confined to a protein scaffold. We also highlight the importance of phosphatases in developing and maintaining specificity. Support for our proposals can be drawn from the existing literature.

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Selected References

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  1. Anderson N. G., Maller J. L., Tonks N. K., Sturgill T. W. Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase. Nature. 1990 Feb 15;343(6259):651–653. doi: 10.1038/343651a0. [DOI] [PubMed] [Google Scholar]
  2. Bagowski C. P., Ferrell J. E., Jr Bistability in the JNK cascade. Curr Biol. 2001 Aug 7;11(15):1176–1182. doi: 10.1016/s0960-9822(01)00330-x. [DOI] [PubMed] [Google Scholar]
  3. Bhalla U. S., Iyengar R. Emergent properties of networks of biological signaling pathways. Science. 1999 Jan 15;283(5400):381–387. doi: 10.1126/science.283.5400.381. [DOI] [PubMed] [Google Scholar]
  4. Burack W. R., Sturgill T. W. The activating dual phosphorylation of MAPK by MEK is nonprocessive. Biochemistry. 1997 May 20;36(20):5929–5933. doi: 10.1021/bi970535d. [DOI] [PubMed] [Google Scholar]
  5. Canagarajah B. J., Khokhlatchev A., Cobb M. H., Goldsmith E. J. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell. 1997 Sep 5;90(5):859–869. doi: 10.1016/s0092-8674(00)80351-7. [DOI] [PubMed] [Google Scholar]
  6. Dérijard B., Raingeaud J., Barrett T., Wu I. H., Han J., Ulevitch R. J., Davis R. J. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682–685. doi: 10.1126/science.7839144. [DOI] [PubMed] [Google Scholar]
  7. Ferrell J. E., Jr, Bhatt R. R. Mechanistic studies of the dual phosphorylation of mitogen-activated protein kinase. J Biol Chem. 1997 Jul 25;272(30):19008–19016. doi: 10.1074/jbc.272.30.19008. [DOI] [PubMed] [Google Scholar]
  8. Ferrell J. E., Jr, Machleder E. M. The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science. 1998 May 8;280(5365):895–898. doi: 10.1126/science.280.5365.895. [DOI] [PubMed] [Google Scholar]
  9. Ferrell J. E., Jr Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs. Trends Biochem Sci. 1996 Dec;21(12):460–466. doi: 10.1016/s0968-0004(96)20026-x. [DOI] [PubMed] [Google Scholar]
  10. Garrington T. P., Johnson G. L. Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol. 1999 Apr;11(2):211–218. doi: 10.1016/s0955-0674(99)80028-3. [DOI] [PubMed] [Google Scholar]
  11. Goldberg J. Decoding of sorting signals by coatomer through a GTPase switch in the COPI coat complex. Cell. 2000 Mar 17;100(6):671–679. doi: 10.1016/s0092-8674(00)80703-5. [DOI] [PubMed] [Google Scholar]
  12. Hopfield J. J. Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity. Proc Natl Acad Sci U S A. 1974 Oct;71(10):4135–4139. doi: 10.1073/pnas.71.10.4135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Huang C. Y., Ferrell J. E., Jr Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10078–10083. doi: 10.1073/pnas.93.19.10078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Janknecht R., Hunter T. Convergence of MAP kinase pathways on the ternary complex factor Sap-1a. EMBO J. 1997 Apr 1;16(7):1620–1627. doi: 10.1093/emboj/16.7.1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Madhani H. D., Styles C. A., Fink G. R. MAP kinases with distinct inhibitory functions impart signaling specificity during yeast differentiation. Cell. 1997 Nov 28;91(5):673–684. doi: 10.1016/s0092-8674(00)80454-7. [DOI] [PubMed] [Google Scholar]
  16. Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
  17. McKeithan T. W. Kinetic proofreading in T-cell receptor signal transduction. Proc Natl Acad Sci U S A. 1995 May 23;92(11):5042–5046. doi: 10.1073/pnas.92.11.5042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ninio J. Kinetic amplification of enzyme discrimination. Biochimie. 1975;57(5):587–595. doi: 10.1016/s0300-9084(75)80139-8. [DOI] [PubMed] [Google Scholar]
  19. Noguchi K., Kitanaka C., Yamana H., Kokubu A., Mochizuki T., Kuchino Y. Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase. J Biol Chem. 1999 Nov 12;274(46):32580–32587. doi: 10.1074/jbc.274.46.32580. [DOI] [PubMed] [Google Scholar]
  20. Pulido R., Zúiga A., Ullrich A. PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J. 1998 Dec 15;17(24):7337–7350. doi: 10.1093/emboj/17.24.7337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pulverer B. J., Kyriakis J. M., Avruch J., Nikolakaki E., Woodgett J. R. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991 Oct 17;353(6345):670–674. doi: 10.1038/353670a0. [DOI] [PubMed] [Google Scholar]
  22. Schaeffer H. J., Catling A. D., Eblen S. T., Collier L. S., Krauss A., Weber M. J. MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science. 1998 Sep 11;281(5383):1668–1671. doi: 10.1126/science.281.5383.1668. [DOI] [PubMed] [Google Scholar]
  23. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000 Oct 13;103(2):211–225. doi: 10.1016/s0092-8674(00)00114-8. [DOI] [PubMed] [Google Scholar]
  24. Zhan X. L., Deschenes R. J., Guan K. L. Differential regulation of FUS3 MAP kinase by tyrosine-specific phosphatases PTP2/PTP3 and dual-specificity phosphatase MSG5 in Saccharomyces cerevisiae. Genes Dev. 1997 Jul 1;11(13):1690–1702. doi: 10.1101/gad.11.13.1690. [DOI] [PubMed] [Google Scholar]
  25. Zheng C. F., Guan K. L. Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues. EMBO J. 1994 Mar 1;13(5):1123–1131. doi: 10.1002/j.1460-2075.1994.tb06361.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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