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VRK2 (vaccinia related kinase 2)

Identity

HGNC (Hugo) VRK2
LocusID (NCBI) 7444
Location 2p16.1
Location_base_pair Starts at 58273777 and ends at 58387055 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Telomere -- LOC100131953 - VRK2 - FANCL - EIF3FP3 -- Centromere.
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).

DNA/RNA

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).

Protein

Note Enzyme number (IUBMB): EC 2.7.11.1.
 
  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).

Mutations

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).
  

External links

Nomenclature
HGNC (Hugo)VRK2   12719
Cards
AtlasVRK2ID42799ch2p16
Entrez_Gene (NCBI)VRK2  7444  vaccinia related kinase 2
GeneCards (Weizmann)VRK2
Ensembl (Hinxton)ENSG00000028116 [Gene_View]  chr2:58273777-58387055 [Contig_View]  VRK2 [Vega]
ICGC DataPortalENSG00000028116
cBioPortalVRK2
AceView (NCBI)VRK2
Genatlas (Paris)VRK2
WikiGenes7444
SOURCE (Princeton)NM_001130480 NM_001130481 NM_001130482 NM_001130483 NM_001288836 NM_001288837 NM_001288838 NM_001288839 NM_006296
Genomic and cartography
GoldenPath (UCSC)VRK2  -  2p16.1   chr2:58273777-58387055 +  2p16.1   [Description]    (hg19-Feb_2009)
EnsemblVRK2 - 2p16.1 [CytoView]
Mapping of homologs : NCBIVRK2 [Mapview]
OMIM602169   
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
RefSeq genomic (Entrez)AC_000134 NC_000002 NC_018913 NG_029717 NT_022184 NW_001838769 NW_004929300
Consensus coding sequences : CCDS (NCBI)VRK2
Cluster EST : UnigeneHs.744058 [ NCBI ]
CGAP (NCI)Hs.744058
Alternative Splicing : Fast-db (Paris)GSHG0016480
Alternative Splicing GalleryENSG00000028116
Gene ExpressionVRK2 [ NCBI-GEO ]     VRK2 [ SEEK ]   VRK2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ86Y07 (Uniprot)
NextProtQ86Y07  [Medical]
With graphics : InterProQ86Y07
Splice isoforms : SwissVarQ86Y07 (Swissvar)
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom [organisation]   Prot_kinase_dom [organisation]   Ser/Thr_kinase_AS [organisation]  
Related proteins : CluSTrQ86Y07
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
DMDM Disease mutations7444
Blocks (Seattle)Q86Y07
PDB (SRS)2V62   
PDB (PDBSum)2V62   
PDB (IMB)2V62   
PDB (RSDB)2V62   
Human Protein AtlasENSG00000028116 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ86Y07
HPRD03702
IPIIPI00329275   IPI00375427   IPI00375428   IPI00375429   IPI00893010   IPI00375430   IPI00892903   IPI00893024   
Protein Interaction databases
DIP (DOE-UCLA)Q86Y07
IntAct (EBI)Q86Y07
FunCoupENSG00000028116
BioGRIDVRK2
InParanoidQ86Y07
Interologous Interaction database Q86Y07
IntegromeDBVRK2
STRING (EMBL)VRK2
Ontologies - Pathways
Ontology : AmiGOprotein serine/threonine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  endoplasmic reticulum  endoplasmic reticulum membrane  protein phosphorylation  integral component of membrane  viral process  mitochondrial membrane  cellular response to oxidative stress  regulation of MAPK cascade  protein autophosphorylation  regulation of interleukin-1-mediated signaling pathway  
Ontology : EGO-EBIprotein serine/threonine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  endoplasmic reticulum  endoplasmic reticulum membrane  protein phosphorylation  integral component of membrane  viral process  mitochondrial membrane  cellular response to oxidative stress  regulation of MAPK cascade  protein autophosphorylation  regulation of interleukin-1-mediated signaling pathway  
Protein Interaction DatabaseVRK2
Wikipedia pathwaysVRK2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)VRK2
snp3D : Map Gene to Disease7444
SNP (GeneSNP Utah)VRK2
SNP : HGBaseVRK2
Genetic variants : HAPMAPVRK2
Exome VariantVRK2
1000_GenomesVRK2 
ICGC programENSG00000028116 
Somatic Mutations in Cancer : COSMICVRK2 
CONAN: Copy Number AnalysisVRK2 
Mutations and Diseases : HGMDVRK2
Mutations and Diseases : intOGenVRK2
Genomic VariantsVRK2  VRK2 [DGVbeta]
dbVarVRK2
ClinVarVRK2
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM602169   
MedgenVRK2
GENETestsVRK2
Disease Genetic AssociationVRK2
Huge Navigator VRK2 [HugePedia]  VRK2 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneVRK2
Homology/Alignments : Family Browser (UCSC)VRK2
Phylogenetic Trees/Animal Genes : TreeFamVRK2
Chemical/Protein Interactions : CTD7444
Chemical/Pharm GKB GenePA37331
Clinical trialVRK2
Cancer Resource (Charite)ENSG00000028116
Other databases
Probes
Litterature
PubMed35 Pubmed reference(s) in Entrez
CoreMineVRK2
iHOPVRK2
OncoSearchVRK2

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 
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
 
Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1.
Blanco S, Santos C, Lazo PA.
Mol Cell Biol. 2007 Oct;27(20):7273-83. Epub 2007 Aug 20.
PMID 17709393
 
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
 
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
 
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
 
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
 
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Contributor(s)

Written05-2012Marta 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, and Instituto de Investigacion Biomedica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain

Citation

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 online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/VRK2ID42799ch2p16.html

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indexed on : Tue Aug 26 15:26:17 CEST 2014

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