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VRK2 (vaccinia related kinase 2)

Written2012-05Marta Vázquez-Cedeira, Sandra Blanco, Isabel F Fernández, Diana M Monsalve, Pedro A Lazo
Instituto de Biologia Molecular y Celular del Cancer, CSIC-Universidad de Salamanca,, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain

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HGNC (Hugo) VRK2
HGNC Previous namevaccinia related kinase 2
LocusID (NCBI) 7444
Atlas_Id 42799
Location 2p16.1  [Link to chromosome band 2p16]
Location_base_pair Starts at 58046642 and ends at 58159920 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping VRK2.png]
Local_order Telomere -- LOC100131953 - VRK2 - FANCL - EIF3FP3 -- Centromere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
VRK2 (2p16.1)::AGO3 (1p34.3)VRK2 (2p16.1)::CHSY1 (15q26.3)VRK2 (2p16.1)::CREM (10p11.21)
VRK2 (2p16.1)::FANCL (2p16.1)VRK2 (2p16.1)::FUS (16p11.2)
Note Member of the kinase branch in the human kinome (Manning et al., 2002) that separated into the Vaccinia-related kinase subfamily and the Casein kinase 1 serine/threonine protein kinase family (Nezu et al., 1997; Nichols and Traktman, 2004).


Note The subcellular localization of protein codified from this gene is dependent on two alternatively spliced variants (Blanco et al., 2006). Other alternative splicing messages have been detected but no proteins have been identified expressed from these alternative messages in humans.
  VRK2 gene structure based in data available in Ensembl release 66. Two alternatively spliced variants coding two isoforms, VRK2A and VRK2B. Non-coding regions of exons are indicated in orange and coding regions in yellow. Exon lenght is indicated in scale (and number of base pairs are indicated below). Exon number is indicated within the exon. Introns are not in scale and intron lenght is indicated below each intron.
Description According to Entrez-Gene, VRK2 gene maps to NC_000002.11 in the region between 58273777 and 58387055 on the plus strand and spans across 113.180 kilobases.
Transcription Initiation codon located in exon 2. Normal message is 1888 nucleotides and has 13 exons (isoform VRK2A). An alternatively spliced variant have been detected with a message of 2036 nucleotides and 14 exons (isoform VRK2B).
Pseudogene None. There are two closely related genes: VRK1 and VRK3 (Nichols and Traktman, 2004).


Note Enzyme number (IUBMB): EC
  Isoforms of human VRK2 protein. They share identical sequence until aminoacid 394.
Description VRK2 protein has two isoforms: VRK2A isoform is a 508 amino acid 58.141 KDa protein and VRK2B isoform, a 397 amino acid 45.030 KDa protein (Blanco et al., 2006). Both isoforms present a serine-threonine kinase domain (residues 29-266) with an ATP-binding site (residues 36-61) and three active kinase motifs (residues 164-168, 184-188 and 218-220). Protein autophosphorylated in several residues (Nichols and Traktman, 2004).
Expression VRK2A is widely expressed in normal and tumoral cells and all human cell lines tested expressed this isoform. VRK2B is expressed only in some cell lines (Blanco et al., 2006; Fernandez et al., 2010). VRK2A expression positively correlated with estrogen and progesterone receptors and inversely with ErbB2 in breast carcinomas (Fernandez et al., 2010).
Localisation VRK2A contains a hydrophobic domain in the C-terminal region that anchors this protein to reticulum endoplasmic and mitochondria membranes. VRK2B lacks this region and it is a soluble protein localized in cytosol and nucleus (Blanco et al., 2006).
Function Serine-threonine kinase activity (Nichols and Traktman, 2004).
VRK2 modulates signals mediated by mitogen-activated protein kinases (MAPK). Both isoforms interacts with JIP1 protein inhibiting the phosphorylation state of JNK and the AP-1 transcriptional responses mediated by IL-1 and hypoxia signals (Blanco et al., 2007; Blanco et al., 2008). Also, VRK2A interacts with the anchorage protein KSR1 and Mek1 inhibiting Raf-Ras-Mek1-Erk1/2 signaling mediated by EGF (Fernandez et al., 2010).
VRK2A interacts with BHFR1 protein from Epstein-Barr virus (a homologue of human anti-apoptotic Bcl-2 protein) enhancing viral survival after infection (Li et al., 2006).
VRK2A and VRK2B phosphorylate p53 in T18 in vitro, but only VRK2B stabilizes and activates p53 in vivo (Blanco et al., 2006).
VRK2 activity is inhibited by the small GTPase RAN protein (Sanz-Garcia et al., 2008).
Homology The kinase domain of VRK2 presents several differences to most of protein kinases. DFG and APE motifs, that limited activation loop, are substituted by DYG and SID motifs respectively. VRK2 protein structure, as well as other VRK proteins, presents an additional helix (αC4) in the N-lobule that anchors αC helix to the C-lobule (Scheeff et al., 2009).


Note Mutation reported in Catalogue of Somatic Mutations in Cancer from Sanger Institute.
Somatic Ovarian carcinoma: heterozygous mutation in nucleotide 32 in the cDNA coding region; T to A (missense substitution, L11H).

Implicated in

Entity Breast cancer
Note Immunohistochemistry: There is a high expression of VRK2 protein in breast carcinomas positive for estrogen and/or progesterone receptors (Fernandez et al., 2010). Breast carcinomas expressing ERBB2 have low levels of VRK2 protein (Fernandez et al., 2010).
Oncogenesis VRK2 is a negative modulator of MAPK pathway in response to EGF through interaction with the KSR1 scaffold protein. VRK2 inhibits activation of ERK in response to EGF, ERBB2, RASG12V and B-RAFV600E, without affecting the AKT pathway (Fernandez et al., 2010).
Entity Adrenocortical carcinoma
Cytogenetics Loss of heterozygosity/allelic imbalance in a minimal region flanked by D2S391 and D2S288 markers in 2p16, was observed associated with carcinomas but not with benign tumors (Kjellman et al., 1999).
Entity Infertility
Disease Vrk2 -/- and pog -/- mice are infertile due to no development of follicles in females and lack of spermatogenesis in males (Lu and Bishop, 2003).
Entity Cortical dysplasia
Disease VRK2 gene was suggested as a gene responsible to cortical dysplasia presented in several patients with a microdelection in the p15-16.1 region of chromosome 2 (Chabchoub et al., 2008). However, another study reported that VRK2 gene is not included in this critical region (Felix et al., 2010).
Entity Schizophrenia
Disease A novel variant, rs2312147[C], showing association with an increased risk of schizophrenia is located over 50 kb upstream of VRK2 gene in 2p15.1 region (Steinberg et al., 2011).


The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines.
Blanco S, Klimcakova L, Vega FM, Lazo PA.
FEBS J. 2006 Jun;273(11):2487-504.
PMID 16704422
Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein.
Blanco S, Sanz-Garcia M, Santos CR, Lazo PA.
PLoS One. 2008 Feb 20;3(2):e1660.
PMID 18286207
The facial dysmorphy in the newly recognised microdeletion 2p15-p16.1 refined to a 570 kb region in 2p15.
Chabchoub E, Vermeesch JR, de Ravel T, de Cock P, Fryns JP.
J Med Genet. 2008 Mar;45(3):189-92.
PMID 18310269
Further characterization of microdeletion syndrome involving 2p15-p16.1.
Felix TM, Petrin AL, Sanseverino MT, Murray JC.
Am J Med Genet A. 2010 Oct;152A(10):2604-8.
PMID 20799320
VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer.
Fernandez IF, Blanco S, Lozano J, Lazo PA.
Mol Cell Biol. 2010 Oct;30(19):4687-97. Epub 2010 Aug 2.
PMID 20679487
Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16.
Kjellman M, Roshani L, Teh BT, Kallioniemi OP, Hoog A, Gray S, Farnebo LO, Holst M, Backdahl M, Larsson C.
J Clin Endocrinol Metab. 1999 Feb;84(2):730-5.
PMID 10022445
Human cellular protein VRK2 interacts specifically with Epstein-Barr virus BHRF1, a homologue of Bcl-2, and enhances cell survival.
Li LY, Liu MY, Shih HM, Tsai CH, Chen JY.
J Gen Virol. 2006 Oct;87(Pt 10):2869-78.
PMID 16963744
Late onset of spermatogenesis and gain of fertility in POG-deficient mice indicate that POG is not necessary for the proliferation of spermatogonia.
Lu B, Bishop CE.
Biol Reprod. 2003 Jul;69(1):161-8. Epub 2003 Feb 5.
PMID 12606378
The protein kinase complement of the human genome.
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S.
Science. 2002 Dec 6;298(5600):1912-34.
PMID 12471243
Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase.
Nezu J, Oku A, Jones MH, Shimane M.
Genomics. 1997 Oct 15;45(2):327-31.
PMID 9344656
Characterization of three paralogous members of the Mammalian vaccinia related kinase family.
Nichols RJ, Traktman P.
J Biol Chem. 2004 Feb 27;279(9):7934-46. Epub 2003 Nov 25.
PMID 14645249
Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities.
Sanz-Garcia M, Lopez-Sanchez I, Lazo PA.
Mol Cell Proteomics. 2008 Nov;7(11):2199-214. Epub 2008 Jul 9.
PMID 18617507
Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site.
Scheeff ED, Eswaran J, Bunkoczi G, Knapp S, Manning G.
Structure. 2009 Jan 14;17(1):128-38.
PMID 19141289
Common variants at VRK2 and TCF4 conferring risk of schizophrenia.
Steinberg S, de Jong S; Irish Schizophrenia Genomics Consortium, Andreassen OA, Werge T, Borglum AD, Mors O, Mortensen PB, Gustafsson O, Costas J, Pietilainen OP, Demontis D, Papiol S, Huttenlocher J, Mattheisen M, Breuer R, Vassos E, Giegling I, Fraser G, Walker N, Tuulio-Henriksson A, Suvisaari J, Lonnqvist J, Paunio T, Agartz I, Melle I, Djurovic S, Strengman E; GROUP, Jurgens G, Glenthoj B, Terenius L, Hougaard DM, Orntoft T, Wiuf C, Didriksen M, Hollegaard MV, Nordentoft M, van Winkel R, Kenis G, Abramova L, Kaleda V, Arrojo M, Sanjuan J, Arango C, Sperling S, Rossner M, Ribolsi M, Magni V, Siracusano A, Christiansen C, Kiemeney LA, Veldink J, van den Berg L, Ingason A, Muglia P, Murray R, Nothen MM, Sigurdsson E, Petursson H, Thorsteinsdottir U, Kong A, Rubino IA, De Hert M, Rethelyi JM, Bitter I, Jonsson EG, Golimbet V, Carracedo A, Ehrenreich H, Craddock N, Owen MJ, O'Donovan MC; Wellcome Trust Case Control Consortium 2, Ruggeri M, Tosato S, Peltonen L, Ophoff RA, Collier DA, St Clair D, Rietschel M, Cichon S, Stefansson H, Rujescu D, Stefansson K.
Hum Mol Genet. 2011 Oct 15;20(20):4076-81. Epub 2011 Jul 26.
PMID 21791550


This paper should be referenced as such :
Vazquez-Cedeira, M ; Blanco, S ; Fernandez, IF ; Monsalve, DM ; Lazo, PA
VRK2 (vaccinia related kinase 2)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(11):841-843.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)VRK2   12719
Entrez_Gene (NCBI)VRK2    VRK serine/threonine kinase 2
GeneCards (Weizmann)VRK2
Ensembl hg19 (Hinxton)ENSG00000028116 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000028116 [Gene_View]  ENSG00000028116 [Sequence]  chr2:58046642-58159920 [Contig_View]  VRK2 [Vega]
ICGC DataPortalENSG00000028116
TCGA cBioPortalVRK2
AceView (NCBI)VRK2
Genatlas (Paris)VRK2
SOURCE (Princeton)VRK2
Genetics Home Reference (NIH)VRK2
Genomic and cartography
GoldenPath hg38 (UCSC)VRK2  -     chr2:58046642-58159920 +  2p16.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)VRK2  -     2p16.1   [Description]    (hg19-Feb_2009)
GoldenPathVRK2 - 2p16.1 [CytoView hg19]  VRK2 - 2p16.1 [CytoView hg38]
Genome Data Viewer NCBIVRK2 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB000450 AJ512204 AK058199 AK223540 AK292727
RefSeq transcript (Entrez)NM_001130480 NM_001130481 NM_001130482 NM_001130483 NM_001288836 NM_001288837 NM_001288838 NM_001288839 NM_006296
Consensus coding sequences : CCDS (NCBI)VRK2
Gene ExpressionVRK2 [ NCBI-GEO ]   VRK2 [ EBI - ARRAY_EXPRESS ]   VRK2 [ SEEK ]   VRK2 [ MEM ]
Gene Expression Viewer (FireBrowse)VRK2 [ Firebrowse - Broad ]
GenevisibleExpression of VRK2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7444
GTEX Portal (Tissue expression)VRK2
Human Protein AtlasENSG00000028116-VRK2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)VRK2
Human Protein Atlas [tissue]ENSG00000028116-VRK2 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed77 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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