Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi

Erk3 and Erk4

Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_542

Synonyms

Historical Background

Extracellular signal-regulated kinase 3 (Erk3) and Erk4 are atypical members of the mitogen-activated protein (MAP) kinase family of serine/threonine kinases. The Erk3 and Erk4 genes were originally identified in 1991 and 1992, by homology cloning with probes derived from the MAP kinase Erk1 (Boulton et al. 1991; Gonzalez et al. 1992). In human, Erk3 is encoded by the MAPK6 gene located on chromosome 15q21.2. The MAPK4 gene present on chromosome 18q21.1 encodes Erk4. The high sequence identity of Erk3 and Erk4 proteins and the similar organization of their genes indicate that the two proteins are true paralogs. It is noteworthy that MAPK6 and MAPK4 are the only  MAP kinase genes that are restricted to the vertebrate lineage.

Structure of Erk3 and Erk4

Erk3 and Erk4 are related protein kinases of 100 and 70 kDa, respectively, that define a distinct subfamily of  MAP kinases (Coulombe and Meloche 2007). They are characterized...

This is a preview of subscription content, log in to check access.

References

  1. Aberg E, Perander M, Johansen B, Julien C, Meloche S, Keyse SM, Seternes OM. Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4. J Biol Chem. 2006;281:35499–510.PubMedCrossRefGoogle Scholar
  2. Anhe GF, Torrao AS, Nogueira TC, Caperuto LC, Amaral ME, Medina MC, Azevedo-Martins AK, Carpinelli AR, Carvalho CR, Curi R, Boschero AC, Bordin S. ERK3 associates with MAP2 and is involved in glucose-induced insulin secretion. Mol Cell Endocrinol. 2006;251:33–41.PubMedCrossRefGoogle Scholar
  3. Boulton TG, Nye SH, Robbins DJ, Ip NY, Radziejewska E, Morgenbesser SD, DePinho RA, Panayotatos N, Cobb MH, Yancopoulos GD. 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.PubMedCrossRefGoogle Scholar
  4. Cheng M, Boulton TG, Cobb MH. ERK3 is a constitutively nuclear protein kinase. J Biol Chem. 1996;271:8951–8.PubMedCrossRefGoogle Scholar
  5. Coulombe P, Meloche S. Atypical mitogen-activated protein kinases: structure, regulation and functions. Biochim Biophys Acta. 2007;1773:1376–87.PubMedCrossRefGoogle Scholar
  6. Coulombe P, Rodier G, Pelletier S, Pellerin J, Meloche S. Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation. Mol Cell Biol. 2003;23:4542–58.PubMedCrossRefGoogle Scholar
  7. Deleris P, Rousseau J, Coulombe P, Rodier G, Tanguay PL, Meloche S. Activation loop phosphorylation of the atypical MAP kinases ERK3 and ERK4 is required for binding, activation and cytoplasmic relocalization of MK5. J Cell Physiol. 2008;217:778–88.PubMedCrossRefGoogle Scholar
  8. Gonzalez FA, Raden DL, Rigby MR, Davis RJ. Heterogenous expression of four MAP kinase isoforms in human tissues. FEBS Lett. 1992;304:170–8.PubMedCrossRefGoogle Scholar
  9. Hansen CA, Bartek J, Jensen S. A functional link between the human cell cycle-regulatory phosphatase Cdc14A and the atypical mitogen-activated kinase Erk3. Cell Cycle. 2008;7:325–34.PubMedCrossRefGoogle Scholar
  10. Julien C, Coulombe P, Meloche S. Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression. J Biol Chem. 2003;278:42615–24.PubMedCrossRefGoogle Scholar
  11. Kant S, Schumacher S, Singh MK, Kispert A, Kotlyarov A, Gaestel M. Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5. J Biol Chem. 2006;281:35511–19.PubMedCrossRefGoogle Scholar
  12. Klinger S, Turgeon B, Levesque K, Wood GA, Aagaard-Tillery KM, Meloche S. Loss of Erk3 function in mice leads to intrauterine growth restriction, pulmonary immaturity, and neonatal lethality. Proc Natl Acad Sci USA. 2009;106:16710–15.PubMedCrossRefGoogle Scholar
  13. Perander M, Aberg E, Johansen B, Dreyer B, Guldvik IJ, Outzen H, Keyse SM, Seternes OM. The Ser(186) phospho-acceptor site within ERK4 is essential for its ability to interact with and activate PRAK/MK5. Biochem J. 2008;411:613–22.PubMedCrossRefGoogle Scholar
  14. Rousseau J, Klinger S, Rachalski A, Turgeon B, Deleris P, Vigneault E, Poirier-Heon JF, Davoli MA, Mechawar N, El Mestikawy S, Cermakian N, Meloche S. Targeted inactivation of Mapk4 in mice reveals specific non-redundant unctions of Erk3/Erk4 subfamily mitogen-activated protein kinases. Mol Cell Biol. 2010;30:5752–63.PubMedCrossRefGoogle Scholar
  15. Schumacher S, Laass K, Kant S, Shi Y, Visel A, Gruber AD, Kotlyarov A, Gaestel M. Scaffolding by ERK3 regulates MK5 in development. EMBO J. 2004;23:4770–9.PubMedCrossRefGoogle Scholar
  16. Seternes OM, Mikalsen T, Johansen B, Michaelsen E, Armstrong CG, Morrice NA, Turgeon B, Meloche S, Moens U, Keyse SM. Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. EMBO J. 2004;23:4780–91.PubMedCrossRefGoogle Scholar
  17. Sun M, Wei Y, Yao L, Xie J, Chen X, Wang H, Jiang J, Gu J. Identification of extracellular signal-regulated kinase 3 as a new interaction partner of cyclin D3. Biochem Biophys Res Commun. 2006;340:209–14.PubMedCrossRefGoogle Scholar
  18. Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, Xie C, Chen J, Deng Q, Yamout M, Dong MQ, Frangou CG, Yates 3rd JR, Wright PE, Han J. PRAK is essential for ras-induced senescence and tumor suppression. Cell. 2007;128:295–308.PubMedCrossRefGoogle Scholar
  19. Tanguay PL, Rodier G, Meloche S. C-terminal domain phosphorylation of ERK3 controlled by Cdk1 and Cdc14 regulates its stability in mitosis. Biochem J. 2010;428:103–11.PubMedCrossRefGoogle Scholar
  20. Turgeon B, Saba-El-Leil MK, Meloche S. Cloning and characterization of mouse extracellular-signal-regulated protein kinase 3 as a unique gene product of 100 kDa. Biochem J. 2000;346(Pt 1):169–75.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Institut de Recherche en Immunologie et CancérologieUniversité de MontréalMontrealCanada
  2. 2.Department of PharmacologyInstitut de Recherche en Immunologie et Cancérologie, Université de MontréalMontrealCanada
  3. 3.Program of Molecular BiologyInstitut de Recherche en Immunologie et Cancérologie, Université de MontréalMontrealCanada