Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Shin Yasuda
  • Hiroko Sugiura
  • Kanato YamagataEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_574


Historical Background

Polymyxin B sensitivity (PBS) 2, a yeast homolog of mitogen-activated protein kinase kinase 3 (Mek3), was originally cloned (in 1987) as a gene that conferred polymyxin B resistance to yeast cells (Boguslawski and Polazzi 1987). The amino acid sequence of the PBS2 gene product showed strong homology to the serine/threonine protein kinase family (Boguslawski and Polazzi 1987). In 1993, it was shown that PBS2 and its downstream HOG1 genes, which code for a Mek3 homologue and a p38 mitogen-activated protein kinase (MAPK) homologue, respectively, are necessary for yeast cells to grow at high osmolarity (Brewster et al. 1993). Two years after that study, Mek3 was first amplified by degenerative PCR as a human homolog of yeast PBS2, and overexpression of...

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This work was partly supported by KAKENHIs (20591426 to SY, 21500332 to HS, and 20300135 to KY) and the Naito Foundation (to KY).


  1. Boguslawski G, Polazzi JO. Complete nucleotide sequence of a gene conferring polymyxin B resistance on yeast: similarity of the predicted polypeptide to protein kinases. Proc Natl Acad Sci USA. 1987;84:5848–52.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Brewster JL, de Valoir T, Dwyer ND, Winter E, Gustin MC. An osmosensing signal transduction pathway in yeast. Science. 1993;259:1760–3.CrossRefPubMedGoogle Scholar
  3. Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010;429:403–17.CrossRefGoogle Scholar
  4. Dang A, Frost JA, Cobb MH. The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells. J Biol Chem. 1998;273:19909–13.CrossRefPubMedGoogle Scholar
  5. Derijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ, Davis RJ. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995;267:682–5.CrossRefPubMedGoogle Scholar
  6. Edlund S, Lee SY, Grimsby S, Zhang S, Aspenstrom P, Heldin CH, Landstrom M. Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis. Mol Cell Biol. 2005;25:1475–88.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Enslen H, Brancho DM, Davis RJ. Molecular determinants that mediate selective activation of p38 MAP kinase isoforms. EMBO J. 2000;19:1301–11.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Fukuda K, Tesch GH, Yap FY, Forbes JM, Flavell RA, Davis RJ, Nikolic-Paterson DJ. MKK3 signalling plays an essential role in leukocyte-mediated pancreatic injury in the multiple low-dose streptozotocin model. Lab Investig. 2008;88:398–407.CrossRefPubMedGoogle Scholar
  9. Greenblatt MB, Shim JH, Zou W, Sitara D, Schweitzer M, Hu D, Lotinun S, Sano Y, Baron R, Park JM, et al. The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J Clin Invest. 2010;120:2457–73.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 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
  11. Hitti E, Iakovleva T, Brook M, Deppenmeier S, Gruber AD, Radzioch D, Clark AR, Blackshear PJ, Kotlyarov A, Gaestel M. Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol Cell Biol. 2006;26:2399–407.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Inoue T, Boyle DL, Corr M, Hammaker D, Davis RJ, Flavell RA, Firestein GS. Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis. Proc Natl Acad Sci USA. 2006;103:5484–9.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Jin K, Lim S, Mercer SE, Friedman E. The survival kinase Mirk/dyrk1B is activated through Rac1-MKK3 signaling. J Biol Chem. 2005;280:42097–105.CrossRefPubMedGoogle Scholar
  14. Kobayashi M, Nagata S, Iwasaki T, Yanagihara K, Saitoh I, Karouji Y, Ihara S, Fukui Y. Dedifferentiation of adenocarcinomas by activation of phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA. 1999;96:4874–9.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Linares JF, Duran A, Reina-Campos M, Aza-Blanc P, Campos A, Moscat J, Diaz-Meco MT. Amino acid activation of mTORC1 by a PB1-domain-driven kinase complex cascade. Cell Rep. 2015;12:1339–52.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Ma FY, Tesch GH, Flavell RA, Davis RJ, Nikolic-Paterson DJ. MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney. Am J Physiol Ren Physiol. 2007;293:F1556–63.CrossRefGoogle Scholar
  17. Mukherjee S, Keitany G, Li Y, Wang Y, Ball HL, Goldsmith EJ, Orth K. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science. 2006;312:1211–4.CrossRefPubMedGoogle Scholar
  18. Prickett TD, Brautigan DL. Cytokine activation of p38 MAPK and apoptosis is opposed by alpha-4 targeting of PP2A for site-specific dephosphorylation of MEK3. Mol Cell Biol. 2007;27:4217–27.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Stein B, Brady H, Yang MX, Young DB, Barbosa MS. Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. J Biol Chem. 1996;271:11427–33.CrossRefPubMedGoogle Scholar
  20. Yasuda S, Tanaka H, Sugiura H, Okamura K, Sakaguchi T, Tran U, Takemiya T, Mizoguchi A, Yagita Y, Sakurai T, et al. Activity-induced protocadherin arcadlin regulates dendritic spine number by triggering N-cadherin endocytosis via TAO2beta and p38 MAP kinases. Neuron. 2007;56:456–71.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Yasuda S, Sugiura H, Yamagata K. Mek3. UCSD-Nature Molecule Pages. 2009.  https://doi.org/10.1038/mp.a001507.01

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Synaptic Plasticity ProjectTokyo Metropolitan Institute of Medical ScienceSetagaya, TokyoJapan
  2. 2.Department of PharmacologyShukutoku UniversityChibaJapan