Encyclopedia of Signaling Molecules

Living Edition
| Editors: Sangdun Choi

ERK1 and ERK2

  • Roser Buscà
  • Jacques Pouysségur
  • Philippe Lenormand
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-6438-9_470-1

Synonyms

Historical Background

The transmission of extracellular signals to intracellular targets is mediated by a network of signaling pathways. The ERK signaling cascade is a central regulator to a large number of cellular processes such as proliferation, differentiation, and migration; it is also one of the most studied pathways. The kinases ERK1 and ERK2 are activated by MEK kinase in the signaling cascade Ras/Raf/MEK/ERK, and then they phosphorylate protein substrates on serine and threonine residues.

Several years prior to ERK1 and ERK2 cloning, respectively, in 1990 and 1991 (Boulton et al. 1991), the close correlation between mitogen activation and the increased double phosphorylation of two proteins of 41 and 43 kDa on a phospho-tyrosine residue...

Keywords

Noonan Syndrome ERK1 Protein Cell Cycle Entry Effector Kinase Anthrax Lethal Toxin 
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.
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References

  1. Albeck JG, Mills GB, Brugge JS. Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals. Mol Cell. 2013;49:249–61. doi:10.1016/j.molcel.2012.11.002.CrossRefPubMedGoogle Scholar
  2. Boulton TG, Nye SH, Robbins DJ, Ip NY, Radziejewska E, Morgenbesser SD, et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991;65:663–75.CrossRefPubMedGoogle Scholar
  3. Brunet A, Roux D, Lenormand P, Dowd S, Keyse S, Pouyssegur J. Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry. EMBO J. 1999;18:664–74.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Busca R, Christen R, Lovern M, Clifford AM, Yue JX, Goss GG, et al. ERK1 and ERK2 present functional redundancy in tetrapods despite higher evolution rate of ERK1. BMC Evol Biol. 2015;15:179. doi:10.1186/s12862-015-0450-x.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Busca R, Pouyssegur J, Lenormand P. ERK1 and ERK2 map kinases: specific roles or functional redundancy? Front Cell Dev Biol. 2016;4:53. doi:10.3389/fcell.2016.00053.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death – apoptosis, autophagy and senescence. FEBS J. 2010;277:2–21.CrossRefPubMedGoogle Scholar
  7. Campbell JD, Alexandrov A, Kim J, Wala J, Berger AH, Pedamallu CS, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet. 2016;48:607–16. doi:10.1038/ng.3564.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chambard JC, Lefloch R, Pouyssegur J, Lenormand P. ERK implication in cell cycle regulation. Biochim Biophys Acta. 2007;1773:1299–310.CrossRefPubMedGoogle Scholar
  9. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky Jr WE, et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009;41:544–52.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dhomen N, Reis-Filho JS, da Rocha DS, Hayward R, Savage K, Delmas V, et al. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009;15:294–303.CrossRefPubMedGoogle Scholar
  11. Duesbery NS, Webb CP, Leppla SH, Gordon VM, Klimpel KR, Copeland TD, et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor [see comments]. Science. 1998;280:734–7.CrossRefPubMedGoogle Scholar
  12. Ebisuya M, Kondoh K, Nishida E. The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity. J Cell Sci. 2005;118:2997–3002.CrossRefPubMedGoogle Scholar
  13. Ercan D, Xu C, Yanagita M, Monast CS, Pratilas CA, Montero J, et al. Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov. 2012;2:934–47. doi:10.1158/2159-8290.CD-12-0103.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Frémin C, Saba-El-Leil MK, Lévesque K, Ang S-L, Meloche S. Functional redundancy of ERK1 and ERK2 MAP kinases during development. Cell Rep. 2015;12(6):913–21.Google Scholar
  15. Hu S, Xie Z, Onishi A, Yu X, Jiang L, Lin J, et al. Profiling the human protein-DNA interactome reveals ERK2 as a transcriptional repressor of interferon signaling. Cell. 2009;139:610–22.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Jha S, Morris EJ, Hruza A, Mansueto MS, Schroeder GK, Arbanas J, et al. Dissecting therapeutic resistance to ERK inhibition. Mol Cancer Ther. 2016;15:548–59. doi:10.1158/1535-7163.MCT-15-0172.CrossRefPubMedGoogle Scholar
  17. Kelleher 3rd RJ, Govindarajan A, Jung HY, Kang H, Tonegawa S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell. 2004;116:467–79.CrossRefPubMedGoogle Scholar
  18. Kidger AM, Keyse SM. The regulation of oncogenic Ras/ERK signalling by dual-specificity mitogen activated protein kinase phosphatases (MKPs). Semin Cell Dev Biol. 2016;50:125–32. doi:10.1016/j.semcdb.2016.01.009.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Lee T, Hoofnagle AN, Kabuyama Y, Stroud J, Min X, Goldsmith EJ, et al. Docking motif interactions in MAP kinases revealed by hydrogen exchange mass spectrometry. Mol Cell. 2004;14:43–55.CrossRefPubMedGoogle Scholar
  20. Lenormand P, Sardet C, Pagès G, L'Allemain G, Brunet A, Pouysségur J. Growth factors induce nuclear translocation of MAP kinases (p42maPk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J Cell Biol. 1993;122:1079–89.CrossRefPubMedGoogle Scholar
  21. Lidke DS, Huang F, Post JN, Rieger B, Wilsbacher J, Thomas JL, et al. ERK nuclear translocation is dimerization-independent but controlled by the rate of phosphorylation. J Biol Chem. 2010;285:3092–4102.CrossRefPubMedGoogle Scholar
  22. Murphy LO, Blenis J. MAPK signal specificity: the right place at the right time. Trends Biochem Sci. 2006;31:268–75.CrossRefPubMedGoogle Scholar
  23. Pages G, Lenormand P, L'Allemain G, Chambard JC, Meloche S, Pouyssegur J. Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci U S A. 1993;90:8319–23.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A. 2009;106:4519–24.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355–69. doi:10.1146/annurev-genom-091212-153523.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Roskoski Jr R. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012;66:105–43. doi:10.1016/j.phrs.2012.04.005.CrossRefPubMedGoogle Scholar
  27. Saba-El-Leil MK, Fremin C, Meloche S. Redundancy in the world of MAP kinases: all for one. Front Cell Dev Biol. 2016;4:67. doi:10.3389/fcell.2016.00067.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Samuels IS, Karlo JC, Faruzzi AN, Pickering K, Herrup K, Sweatt JD, et al. Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function. J Neurosci. 2008;28:6983–95.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Shai A, Dankort D, Juan J, Green S, McMahon M. TP53 silencing bypasses growth arrest of BRAFV600E-induced lung tumor cells in a two-switch model of lung tumorigenesis. Cancer Res. 2015;75:3167–80. doi:10.1158/0008-5472.CAN-14-3701.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Torii S, Yamamoto T, Tsuchiya Y, Nishida E. ERK MAP kinase in G cell cycle progression and cancer. Cancer Sci. 2006;97:697–702. doi:10.1111/j.1349-7006.2006.00244.x.CrossRefPubMedGoogle Scholar
  31. Uehling DE, Harris PA. Recent progress on MAP kinase pathway inhibitors. Bioorg Med Chem Lett. 2015;25:4047–56. doi:10.1016/j.bmcl.2015.07.093.CrossRefPubMedGoogle Scholar
  32. von Kriegsheim A, Baiocchi D, Birtwistle M, Sumpton D, Bienvenut W, Morrice N, et al. Cell fate decisions are specified by the dynamic ERK interactome. Nat Cell Biol. 2009;11:1458–64. doi:10.1038/ncb1994.CrossRefGoogle Scholar
  33. Yamamoto T, Ebisuya M, Ashida F, Okamoto K, Yonehara S, Nishida E. Continuous ERK activation downregulates antiproliferative genes throughout G1 phase to allow cell-cycle progression. Curr Biol. 2006;16:1171–82.CrossRefPubMedGoogle Scholar
  34. Yazicioglu MN, Goad DL, Ranganathan A, Whitehurst AW, Goldsmith EJ, Cobb MH. Mutations in ERK2 binding sites affect nuclear entry. J Biol Chem. 2007;282:28759–67.CrossRefPubMedGoogle Scholar
  35. Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors. 2006;24:21–44.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2016

Authors and Affiliations

  • Roser Buscà
    • 1
  • Jacques Pouysségur
    • 1
    • 2
  • Philippe Lenormand
    • 1
  1. 1.Institute for Research on Cancer and Ageing of Nice (IRCAN), CNRS UMR7284, INSERMUniversity of Nice-Sophia AntipolisNiceFrance
  2. 2.Centre Scientifique de Monaco (CSM)MonacoMonaco