Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

MAPK Interacting Protein Kinase 1 and 2 (Mnk1 and Mnk2)

  • Sonali JoshiEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101722


Historical Background

The MAPK interacting protein kinases 1 and 2 were identified as a part of a screen to identify novel proteins that can be phosphorylated by extracellular regulated kinase (Erk) (Fukunaga and Hunter 1997). This screen identified Mnk1 as an Erk2 substrate. Additionally Mnk1 was found to be phosphorylated by the p38 MAPK and the Erk kinase but not by c-Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK) (Fukunaga and Hunter 1997). Stimulation with 12-O-tetradecanoylphorbol-13-acetate, fetal calf serum, anisomycin, UV irradiation, tumor necrosis factor-alpha, interleukin-1beta, or osmotic shock also resulted in phosphorylation of Mnk1 in an Erk and/or p38-dependent manner (Fukunaga and Hunter 1997). Another study utilizing a two-hybrid screen approach to identify novel Erk2 substrates identified Mnk1 as an Erk2 target (Waskiewicz et al. 1997...
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  1. Altman JK, Glaser H, Sassano A, Joshi S, Ueda T, Watanabe-Fukunaga R, et al. Negative regulatory effects of Mnk kinases in the generation of chemotherapy-induced antileukemic responses. Mol Pharmacol. 2010;78:778–84. doi:10.1124/mol.110.064642.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bell JB, Eckerdt FD, Alley K, Magnusson LP, Hussain H, Bi Y, et al. MNK inhibition disrupts mesenchymal glioma stem cells and prolongs survival in a mouse model of glioblastoma. Mol Cancer Res: MCR. 2016;14:984–93. doi:10.1158/1541-7786.MCR-16-0172.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Brown MC, Bryant JD, Dobrikova EY, Shveygert M, Bradrick SS, Chandramohan V, et al. Induction of viral, 7-methyl-guanosine cap-independent translation and oncolysis by mitogen-activated protein kinase-interacting kinase-mediated effects on the serine/arginine-rich protein kinase. J Virol. 2014;88:13135–48. doi:10.1128/JVI.01883-14.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Buxade M, Parra JL, Rousseau S, Shpiro N, Marquez R, Morrice N, et al. The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1. Immunity. 2005;23:177–89. doi:10.1016/j.immuni.2005.06.009.CrossRefPubMedGoogle Scholar
  5. Buxade M, Morrice N, Krebs DL, Proud CG. The PSF.p54nrb complex is a novel Mnk substrate that binds the mRNA for tumor necrosis factor alpha. J Biol Chem. 2008;283:57–65. doi:10.1074/jbc.M705286200.CrossRefPubMedGoogle Scholar
  6. Fukunaga R, Hunter T. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J. 1997;16:1921–33. doi:10.1093/emboj/16.8.1921.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Gorentla BK, Krishna S, Shin J, Inoue M, Shinohara ML, Grayson JM, et al. Mnk1 and 2 are dispensable for T cell development and activation but important for the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 2013;190:1026–37. doi:10.4049/jimmunol.1200026.CrossRefPubMedGoogle Scholar
  8. Goto S, Yao Z, Proud CG. The C-terminal domain of Mnk1a plays a dual role in tightly regulating its activity. Biochem J. 2009;423:279–90. doi:10.1042/BJ20090228.CrossRefPubMedGoogle Scholar
  9. Grund EM, Spyropoulos DD, Watson DK, Muise-Helmericks RC. Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells. J Biol Chem. 2005;280:4772–8. doi:10.1074/jbc.M408356200.CrossRefPubMedGoogle Scholar
  10. Grzmil M, Seebacher J, Hess D, Behe M, Schibli R, Moncayo G, et al. Inhibition of MNK pathways enhances cancer cell response to chemotherapy with temozolomide and targeted radionuclide therapy. Cell Signal. 2016;28:1412–21. doi:10.1016/j.cellsig.2016.06.005.CrossRefPubMedGoogle Scholar
  11. Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988;241:42–52.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Imataka H, Olsen HS, Sonenberg N. A new translational regulator with homology to eukaryotic translation initiation factor 4G. EMBO J. 1997;16:817–25. doi:10.1093/emboj/16.4.817.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Jauch R, Jakel S, Netter C, Schreiter K, Aicher B, Jackle H, et al. Crystal structures of the Mnk2 kinase domain reveal an inhibitory conformation and a zinc binding site. Structure. 2005;13:1559–68. doi:10.1016/j.str.2005.07.013.CrossRefPubMedGoogle Scholar
  14. Jauch R, Cho MK, Jakel S, Netter C, Schreiter K, Aicher B, et al. Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment. EMBO J. 2006;25:4020–32. doi:10.1038/sj.emboj.7601285.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Johnson LN, Noble ME, Owen DJ. Active and inactive protein kinases: structural basis for regulation. Cell. 1996;85:149–58.CrossRefPubMedGoogle Scholar
  16. Joshi S, Platanias LC. Mnk kinases in cytokine signaling and regulation of cytokine responses. Biomol Concepts. 2012;3:127–39. doi:10.1515/bmc-2011-0057.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Joshi S, Kaur S, Redig AJ, Goldsborough K, David K, Ueda T, et al. Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses. Proc Natl Acad Sci U S A. 2009;106:12097–102. doi:10.1073/pnas.0900562106.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Joshi S, Sharma B, Kaur S, Majchrzak B, Ueda T, Fukunaga R, et al. Essential role for Mnk kinases in type II interferon (IFNgamma) signaling and its suppressive effects on normal hematopoiesis. J Biol Chem. 2011;286:6017–26. doi:10.1074/jbc.M110.197921.CrossRefPubMedGoogle Scholar
  19. Koromilas AE, Lazaris-Karatzas A, Sonenberg N. mRNAs containing extensive secondary structure in their 5′ non-coding region translate efficiently in cells overexpressing initiation factor eIF-4E. EMBO J. 1992;11:4153–8.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Kosciuczuk EM, Saleiro D, Kroczynska B, Beauchamp EM, Eckerdt F, Blyth GT, et al. Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo. Blood. 2016;128:410–4. doi:10.1182/blood-2016-02-698704.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kwegyir-Afful AK, Bruno RD, Purushottamachar P, Murigi FN, Njar VC. Galeterone and VNPT55 disrupt Mnk-eIF4E to inhibit prostate cancer cell migration and invasion. FEBS J. 2016. doi:10.1111/febs.13895.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Laan M, Lotvall J, Chung KF, Linden A. IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases. Br J Pharmacol. 2001;133:200–6. doi:10.1038/sj.bjp.0704063.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Li Y, Yue P, Deng X, Ueda T, Fukunaga R, Khuri FR, et al. Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E. Neoplasia. 2010;12:848–55.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Ling J, Morley SJ, Traugh JA. Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2. EMBO J. 2005;24:4094–105. doi:10.1038/sj.emboj.7600868.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Maruoka S, Hashimoto S, Gon Y, Takeshita I, Horie T. PAF-induced RANTES production by human airway smooth muscle cells requires both p38 MAP kinase and Erk. Am J Respir Crit Care Med. 2000;161:922–9. doi:10.1164/ajrccm.161.3.9906059.CrossRefPubMedGoogle Scholar
  26. Noubade R, Krementsov DN, Del Rio R, Thornton T, Nagaleekar V, Saligrama N, et al. Activation of p38 MAPK in CD4 T cells controls IL-17 production and autoimmune encephalomyelitis. Blood. 2011;118:3290–300. doi:10.1182/blood-2011-02-336552.CrossRefPubMedPubMedCentralGoogle Scholar
  27. O’Loghlen A, Gonzalez VM, Pineiro D, Perez-Morgado MI, Salinas M, Martin ME. Identification and molecular characterization of Mnk1b, a splice variant of human MAP kinase-interacting kinase Mnk1. Exp Cell Res. 2004;299:343–55. doi:10.1016/j.yexcr.2004.06.006.CrossRefPubMedGoogle Scholar
  28. O’Loghlen A, Gonzalez VM, Jurado T, Salinas M, Martin ME. Characterization of the activity of human MAP kinase-interacting kinase Mnk1b. Biochim Biophys Acta. 2007;1773:1416–27. doi:10.1016/j.bbamcr.2007.05.009.CrossRefPubMedGoogle Scholar
  29. Orton KC, Ling J, Waskiewicz AJ, Cooper JA, Merrick WC, Korneeva NL, et al. Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. J Biol Chem. 2004;279:38649–57. doi:10.1074/jbc.M407337200.CrossRefPubMedGoogle Scholar
  30. Parra JL, Buxade M, Proud CG. Features of the catalytic domains and C termini of the MAPK signal-integrating kinases Mnk1 and Mnk2 determine their differing activities and regulatory properties. J Biol Chem. 2005;280:37623–33. doi:10.1074/jbc.M508356200.CrossRefPubMedGoogle Scholar
  31. Parra-Palau JL, Scheper GC, Wilson ML, Proud CG. Features in the N and C termini of the MAPK-interacting kinase Mnk1 mediate its nucleocytoplasmic shuttling. J Biol Chem. 2003;278:44197–204. doi:10.1074/jbc.M302398200.CrossRefPubMedGoogle Scholar
  32. Proud CG. Mnks, eIF4E phosphorylation and cancer. Biochim Biophys Acta. 2015;1849:766–73. doi:10.1016/j.bbagrm.2014.10.003.CrossRefPubMedGoogle Scholar
  33. Pyronnet S, Imataka H, Gingras AC, Fukunaga R, Hunter T, Sonenberg N. Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E. EMBO J. 1999;18:270–9. doi:10.1093/emboj/18.1.270.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Ramalingam S, Gediya L, Kwegyir-Afful AK, Ramamurthy VP, Purushottamachar P, Mbatia H, et al. First MNKs degrading agents block phosphorylation of eIF4E, induce apoptosis, inhibit cell growth, migration and invasion in triple negative and Her2-overexpressing breast cancer cell lines. Oncotarget. 2014;5:530–43. doi:10.18632/oncotarget.1528.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Rowlett RM, Chrestensen CA, Nyce M, Harp MG, Pelo JW, Cominelli F, et al. MNK kinases regulate multiple TLR pathways and innate proinflammatory cytokines in macrophages. Am J Physiol Gastrointest Liver Physiol. 2008;294:G452–9. doi:10.1152/ajpgi.00077.2007.CrossRefPubMedGoogle Scholar
  36. Scheper GC, Proud CG. Does phosphorylation of the cap-binding protein eIF4E play a role in translation initiation? Eur J Biochem. 2002;269:5350–9.CrossRefPubMedGoogle Scholar
  37. Scheper GC, Morrice NA, Kleijn M, Proud CG. The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells. Mol Cell Biol. 2001;21:743–54. doi:10.1128/MCB.21.3.743-754.2001.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Scheper GC, Parra JL, Wilson M, Van Kollenburg B, Vertegaal AC, Han ZG, et al. The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization. Mol Cell Biol. 2003;23:5692–705.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Shi Y, Frost P, Hoang B, Yang Y, Fukunaga R, Gera J, et al. MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells. Oncogene. 2013;32:190–7. doi:10.1038/onc.2012.43.CrossRefPubMedGoogle Scholar
  40. Shveygert M, Kaiser C, Bradrick SS, Gromeier M. Regulation of eukaryotic initiation factor 4E (eIF4E) phosphorylation by mitogen-activated protein kinase occurs through modulation of Mnk1-eIF4G interaction. Mol Cell Biol. 2010;30:5160–7. doi:10.1128/MCB.00448-10.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Slentz-Kesler K, Moore JT, Lombard M, Zhang J, Hollingsworth R, Weiner MP. Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta. Genomics. 2000;69:63–71. doi:10.1006/geno.2000.6299.CrossRefPubMedGoogle Scholar
  42. Sonenberg N, Rupprecht KM, Hecht SM, Shatkin AJ. Eukaryotic mRNA cap binding protein: purification by affinity chromatography on sepharose-coupled m7GDP. Proc Natl Acad Sci U S A. 1979;76:4345–9.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Ueda T, Watanabe-Fukunaga R, Fukuyama H, Nagata S, Fukunaga R. Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Mol Cell Biol. 2004;24:6539–49. doi:10.1128/MCB.24.15.6539-6549.2004.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Ueda T, Sasaki M, Elia AJ, Chio II, Hamada K, Fukunaga R, et al. Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development. Proc Natl Acad Sci U S A. 2010;107:13984–90. doi:10.1073/pnas.1008136107.CrossRefPubMedPubMedCentralGoogle Scholar
  45. van der Velden AW, Thomas AA. The role of the 5′ untranslated region of an mRNA in translation regulation during development. Int J Biochem Cell Biol. 1999;31:87–106.CrossRefPubMedGoogle Scholar
  46. Wang X, Flynn A, Waskiewicz AJ, Webb BL, Vries RG, Baines IA, et al. The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways. J Biol Chem. 1998;273:9373–7.CrossRefPubMedGoogle Scholar
  47. Waskiewicz AJ, Flynn A, Proud CG, Cooper JA. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 1997;16:1909–20. doi:10.1093/emboj/16.8.1909.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Waskiewicz AJ, Johnson JC, Penn B, Mahalingam M, Kimball SR, Cooper JA. Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo. Mol Cell Biol. 1999;19:1871–80.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular and Cellular OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA