Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

VRK2

  • Diana M. Monsalve
  • Sandra Blanco
  • Isabel F. Fernández
  • Marta Vázquez-Cedeira
  • Pedro A. Lazo
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_562

Synonyms

Historical Background

Mammalian VRK (vaccinia-related kinases) were originally identified as two human EST, VRK1 and VRK2, expressed in proliferating cell lines and regenerating liver. These EST have homology to the catalytic region of the B1R kinase of vaccinia virus (Nezu et al. 1997) that is expressed early in viral infection and is required for viral DNA replication. These VRK proteins were classified as a new group of Ser-Thr kinases in the human kinome diverging very early from the same branch that led to casein kinase I (CK1) (Manning et al. 2002). This family has only one ortholog gene in invertebrates, such as C. elegans and Drosophila melanogaster, and is not present in yeast (Klerkx et al. 2009).

VRK2 Gene and Expression

The human VRK2gene is located in chromosome 2p16.1 and generates two messages by alternative splicing. Their translation generates two protein isoforms, VRK2A (also known as...

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

References

  1. Blanco S, Klimcakova L, Vega FM, Lazo PA. The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines. Febs J. 2006;273:2487–504.  https://doi.org/10.1111/j.1742-4658.2006.05256.x.CrossRefPubMedGoogle Scholar
  2. Blanco S, Santos C, Lazo PA. Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1. Mol Cell Biol. 2007;27:7273–83.  https://doi.org/10.1128/MCB.00025-07.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Blanco S, Sanz-Garcia M, Santos CR, Lazo PA. Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein. PLoS One. 2008;3:e1660.  https://doi.org/10.1371/journal.pone.0001660.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Boyle KA, Traktman P. Members of a novel family of mammalian protein kinases complement the DNA-negative phenotype of a vaccinia virus ts mutant defective in the B1 kinase. J Virol. 2004;78:1992–2005.  https://doi.org/10.1128/JVI.78.4.1992-2005.2004CrossRefPubMedPubMedCentralGoogle Scholar
  5. Epilepsies. ILAECoC. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol. 2014;13:893–903.  https://doi.org/10.1016/S1474-4422(14)70171-1.
  6. Fedorov O, Marsden B, Pogacic V, Rellos P, Muller S, Bullock AN, et al. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007;104:20523–8.  https://doi.org/10.1073/pnas.0708800104.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Fernandez IF, Blanco S, Lozano J, Lazo PA. VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer. Mol Cell Biol. 2010;30:4687–97.  https://doi.org/10.1128/MCB.01581-09.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Gorjanacz M, Klerkx EP, Galy V, Santarella R, Lopez-Iglesias C, Askjaer P, et al. Caenorhabditis elegans BAF-1 and its kinase VRK-1 participate directly in post-mitotic nuclear envelope assembly. EMBO J. 2008;26:132–43.  https://doi.org/10.1038/sj.emboj.7601470.CrossRefGoogle Scholar
  9. Hennig EE, Mikula M, Rubel T, Dadlez M, Ostrowski J. Comparative kinome analysis to identify putative colon tumor biomarkers. J Mol Med. 2012;90:447–56.  https://doi.org/10.1007/s00109-011-0831-6.CrossRefPubMedGoogle Scholar
  10. Irish Schizophrenia Genomics Consortium, the Wellcome Trust Case Control Consortium. Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biol Psychiatry. 2012;  https://doi.org/10.1016/j.biopsych.2012.05.035.CrossRefGoogle Scholar
  11. Kerner B, Rao AR, Christensen B, Dandekar S, Yourshaw M, Nelson SF. Rare genomic variants link bipolar disorder with anxiety disorders to creb-regulated intracellular signaling pathways. Front Psychol. 2013;4:154.  https://doi.org/10.3389/fpsyt.2013.00154.CrossRefGoogle Scholar
  12. Kim S, Lee D, Lee J, Song H, Kim HJ, Kim KT. VRK2 controls the stability of the eukaryotic chaperonin TRiC/CCT by inhibiting the deubiquitinating enzyme USP25. Mol Cell Biol. 2015;  https://doi.org/10.1128/MCB.01325-14.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Kim S, Park DY, Lee D, Kim W, Jeong YH, Lee J, et al. Vaccinia-related kinase 2 mediates accumulation of polyglutamine aggregates via negative regulation of the chaperonin TRiC. Mol Cell Biol. 2014;34:643–52.  https://doi.org/10.1128/MCB.00756-13.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Klerkx EP, Lazo PA, Askjaer P. Emerging biological functions of the vaccinia-related kinase (VRK) family. Histol Histopathol. 2009;24:749–59.  https://doi.org/10.14670/HH-24.749CrossRefPubMedGoogle Scholar
  15. Komurov K, Padron D, Cheng T, Roth M, Rosenblatt KP, White MA. Comprehensive mapping of the human kinome to epidermal growth factor receptor signaling. J Biol Chem. 2010;285:21134–42.  https://doi.org/10.1074/jbc.M110.137828.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Li LY, Liu MY, Shih HM, Tsai CH, Chen JY. Human cellular protein VRK2 interacts specifically with Epstein-Barr virus BHRF1, a homologue of Bcl-2, and enhances cell survival. J Gen Virol. 2006;87:2869–78.  https://doi.org/10.1099/vir.0.81953-0CrossRefPubMedGoogle Scholar
  17. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912–34.  https://doi.org/10.1126/science.1075762.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Monsalve DM, Merced T, Fernandez IF, Blanco S, Vazquez-Cedeira M, Lazo PA. Human VRK2 modulates apoptosis by interaction with Bcl-xL and regulation of BAX gene expression. Cell Death Dis. 2013;4:e513.  https://doi.org/10.1038/cddis.2013.40.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Nezu J, Oku A, Jones MH, Shimane M. Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase. Genomics. 1997;45:327–31.  https://doi.org/10.1006/geno.1997.4938CrossRefPubMedGoogle Scholar
  20. Nichols RJ, Traktman P. Characterization of three paralogous members of the mammalian vaccinia related kinase family. J Biol Chem. 2004;279:7934–46.  https://doi.org/10.1074/jbc.M310813200CrossRefPubMedGoogle Scholar
  21. Nichols RJ, Wiebe MS, Traktman P. The vaccinia-related kinases phosphorylate the N′ terminus of BAF, regulating its interaction with DNA and its retention in the nucleus. Mol Biol Cell. 2006;17:2451–64.  https://doi.org/10.1091/mbc.E05-12-1179.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Rodriguez-Hernandez I, Vazquez-Cedeira M, Santos-Briz A, Garcia JL, Fernandez IF, Gomez-Moreta JA, et al. VRK2 identifies a subgroup of primary high-grade astrocytomas with a better prognosis. BMC Clin Pathol. 2013;13:23.  https://doi.org/10.1186/1472-6890-13-23.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Sanz-Garcia M, Lopez-Sanchez I, Lazo PA. Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities. Mol Cell Proteomics. 2008;7:2199–214.  https://doi.org/10.1074/mcp.M700586-MCP200.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Sanz-Garcia M, Vazquez-Cedeira M, Kellerman E, Renbaum P, Levy-Lahad E, Lazo PA. Substrate profiling of human vaccinia-related kinases identifies coilin, a Cajal body nuclear protein, as a phosphorylation target with neurological implications. J Proteome. 2011;75:548–60.  https://doi.org/10.1016/j.jprot.2011.08.019.CrossRefGoogle Scholar
  25. Scheeff ED, Eswaran J, Bunkoczi G, Knapp S, Manning G. Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site. Structure. 2009;17:128–38.  https://doi.org/10.1016/j.str.2008.10.018.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Suzuki Y, Ogawa K, Koyanagi Y. Functional disruption of the moloney murine leukemia virus preintegration complex by vaccinia-related kinases. J Biol Chem. 2010;285:24032–43.  https://doi.org/10.1074/jbc.M110.116640.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Tesli M, Wirgenes KV, Hughes T, Bettella F, Athanasiu L, Hoseth ES, et al. VRK2 gene expression in schizophrenia, bipolar disorder and healthy controls. Br J Psychiatry. 2016;  https://doi.org/10.1192/bjp.bp.115.161950.CrossRefPubMedGoogle Scholar
  28. Vazquez-Cedeira M, Barcia-Sanjurjo I, Sanz-Garcia M, Barcia R, Lazo PA. Differential inhibitor sensitivity between human kinases VRK1 and VRK2. PLoS One. 2011;6:e23235.  https://doi.org/10.1371/journal.pone.0023235.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Vazquez-Cedeira M, Lazo PA. Human VRK2 (vaccinia-related kinase 2) modulates tumor cell invasion by hyperactivation of NFAT1 and expression of cyclooxygenase-2. J Biol Chem. 2012;287:42739–50.  https://doi.org/10.1074/jbc.M112.404285.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Vega FM, Gonzalo P, Gaspar ML, Lazo PA. Expression of the VRK (vaccinia-related kinase) gene family of p53 regulators in murine hematopoietic development. FEBS Lett. 2003;544:176–80.  https://doi.org/10.1016/S0014-5793(03)00501-5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del CáncerConsejo Superior de Investigaciones Científicas (CSIC)-Universidad de SalamancaSalamancaSpain
  2. 2.Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de SalamancaSalamancaSpain
  3. 3.Instituto de Investigación Biomédica de Salamanca (IBSAL)Hospital Universitario de SalamancaSalamancaSpain