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VRK1 (Vaccinia-related kinase 1)

Written2007-04Pedro A. Lazo, Francisco M. Vega, Ana Sevilla, Alberto Valbuena, Marta Sanz-Garcia, Inmaculada Lopez-Sanchez, Sandra Blanco
Instituto de Biologia Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, Salamanca, Spain.

(Note : for Links provided by Atlas : click)

Identity

HGNC (Hugo) VRK1
LocusID (NCBI) 7443
Atlas_Id 43556
Location 14q32.2  [Link to chromosome band 14q32]
Location_base_pair Starts at 97263684 and ends at 97347951 bp from pter ( according to hg19-Feb_2009)  [Mapping VRK1.png]
Local_order Centromere-----PAPOLA--VRK1--BCL11B------Telomere.
Fusion genes
(updated 2016)
VRK1 (14q32.2) / ALOX5AP (13q12.3)VRK1 (14q32.2) / SAMD4A (14q22.2)ZFHX4 (8q21.11) / VRK1 (14q32.2)

DNA/RNA

 
  VRK1 gene structure based on data available in the Ensembl release 43. Upstream non-coding exons (green). Coding exons (yellow), 3' unstranslated sequence (red). The size of the exons in nucleotides is indicated below each exon. Exon number is indicated within the exon.
Description 13 exons in 84.22 kilobases. Transcription initiated from cetromere to telomere direction.
Transcription Initiation codon located in exon 2. Normal message is 1702 nucleotides. Some alternatively spliced RNA messages have been detected; but they are likely to represent splicing intermediates since there is no protein has been detected expressed from these alternative messages in humans.
Pseudogene None.
There are two closely related genes VRK2 and VRK3.
SNP: 289 single nucleotide polymorphisms identified in human VRK1.
ALLELE VARIANTS: CA Polymorphisms. Near the PAPOLA (Polyadenyl polymerase) with respect to VRK1 there is a polymorphic dinucleotide (CA) sequence that has high heterozygosity (0.81). Might be a useful marker in the genetic study of disorders localized at the 14q32 region, such as autosomal recessive congenital microphthalmia (CMIC).

Protein

Note Enzyme Number (IUBMB): "EC 2.7.11.1".
 
  ABRS: ATP-binding region signature
SRPKAS: Ser/Thr protein kinases active-site signature
ELTS:Endosomal-lysosomal targeting sequence
NLS: Nuclear localization signal
Description Protein of 396 aminoacids. 46 kDa. Serine-threonine kinase domain (residues 26-300). Nuclear localization signal (in C-terminal region) Protein autophosphorylated in several residues.
Expression VRK1 is widely expressed in proliferating cells, normal and tumoral. It is not present in quiescent or differentiated cells that do not divide in human biopsies.
Localisation Subcellular localisation varies depending on cell type and growth conditions. Most commonly VRK1 is expressed and detected in the nucleus, excluding the nucleolus. However, in some cells it is in the cytosol, particularly associated with endoplasmic reticulum and Golgi.
Occasionally it is observed in the nucleolus, but outside the nucleus .The regulation of the subcellular localization is unknown.
Function Serine-threonine kinase activity.
Phosphorylates p53 in Threonine-18 preventing its interaction with Hdm2 and activates p53-dependent transcription. Phosphorylates c-Jun and ATF2 transcription factors. VRK1 also phosphorylates BAF1 required for nuclear envelope assembly.
In human cell lines siRNA specific for VRK1 results in defective cell proliferation. The level of VRK1 protein is regulated proteolytically by a p53-dependent-transcription mechanism. This mechanism results in the induction of a targeting of VRK1 to enter the endosomal-lysosomal pathway.
Homology The kinase domain is highly homologous to that in other ser-thr kinases. The C-terminal region has no homology to any known protein or domain. This C-terminal region of VRK1 is different form that in human VRK2, or in the VRK-1 homolog of distant species such as Drosophila, C. elegans or Dario Rerio. This C-terminal divergence suggest the possibility of different protein interactions and thus of differential regulation.

Mutations

Note All mutations reported in study by Greenman el al. 2007.
Germinal Normal:
Mutation in nucleotide 45 in the cDNA coding region ; A to G that is silent (A15A).
Mutation in nucleotide 705 in the cDNA coding region ; C to T that is silent (G235G).
Somatic Colorectal carcinoma:
Heterozygous mutation in nucleotide 42 in the cDNA coding region; T to C (silent S14S).

Implicated in

Note
Entity T-cell acute lymphoblastic leukemia
Cytogenetics Translocation t(5;14)(q35;q32).
BCR (Breakpoint cluster region), detected as a DNAseI hypersensitive site between VRK1 and BCL11B in T-cell acute lymphoblastic leukemia with t(5,14)(q35;q32).
Hybrid/Mutated Gene Disregulation of TLX3 and NKX2-5 homeobox genes, but not of VRK1.
Abnormal Protein None.
Oncogenesis In this translocation the breakpoint occurs in a DNAseI hypersensitive site located between VRK1 and BCL11B genes; but the structure, or expression, of VRK1 does not appear to be affected. In this translocation there is a dysregulation of TLX3 and NKX2-5 homeobox genes (both on chromosome 5).
  
Entity Head and neck squamous cell carcinoma.
Oncogenesis Overexpression of VRK1 protein that positively correlates with hdm2, cdk2, cdk4 and survivin.
  
Entity Neuroblastomas
Cytogenetics Loss of heterozygosis (31 %) in marker (D14S987) in 14q32.2 which is located 5' with respect to the VRK1 gene.
  
Entity Colorectal carcinoma
Cytogenetics Loss of heterozygosis (40-60 %) depending on markers (D14S65; D14S250; D14S5267) in 14q32.2 which is located 3' to the VRK1 gene at less than 0.3 Mb. D14S65 is 0.15 Mb 3' with respect to VRK1.
  
Entity Nasopharyngeal carcinoma
Cytogenetics Loss of heterozygosis in marker (D14S51) in 14q32.2 which is located 0.15Mb 3' to the VRK1 gene.
  
Entity Chronic myelogenous leukemia (Blastic crisis)
Cytogenetics Loss of heterozygosis in marker (D14S65) in 14q32.2 which is located 0.15Mb 3' to the VRK1 gene.
  

Breakpoints

 
  Localization of loss of heterozygosis (LOH) and translocation breakpoints reported in 14q32.2. The breakpoint cluster region has multiple DNAseI hypersensitive sites.

Bibliography

Loss of heterozygosity of 14q32 in colorectal carcinoma.
Bando T, Kato Y, Ihara Y, Yamagishi F, Tsukada K, Isobe M
Cancer genetics and cytogenetics. 1999 ; 111 (2) : 161-165.
PMID 10347556
 
Kinetic properties of p53 phosphorylation by the human vaccinia-related kinase 1.
Barcia R, López-Borges S, Vega FM, Lazo PA
Archives of biochemistry and biophysics. 2002 ; 399 (1) : 1-5.
PMID 11883897
 
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.
Boyle KA, Traktman P
Journal of virology. 2004 ; 78 (4) : 1992-2005.
PMID 14747564
 
Patterns of somatic mutation in human cancer genomes.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR
Nature. 2007 ; 446 (7132) : 153-158.
PMID 17344846
 
Detailed deletion mapping of chromosome band 14q32 in human neuroblastoma defines a 1.1-Mb region of common allelic loss.
Hoshi M, Otagiri N, Shiwaku HO, Asakawa S, Shimizu N, Kaneko Y, Ohi R, Hayashi Y, Horii A
British journal of cancer. 2000 ; 82 (11) : 1801-1807.
PMID 10839294
 
Vaccinia-related kinase-1.
Lazo PA, Vega FM, Sevilla A
Afcs Nature Molecule Page. 2005.
 
The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein.
Lopez-Borges S, Lazo PA
Oncogene. 2000 ; 19 (32) : 3656-3664.
PMID 10951572
 
Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2).
MacLeod RA, Nagel S, Kaufmann M, Janssen JW, Drexler HG
Genes, chromosomes & cancer. 2003 ; 37 (1) : 84-91.
PMID 12661009
 
Loss of heterozygosity on chromosome 14 in nasopharyngeal carcinoma.
Mutirangura A, Pornthanakasem W, Sriuranpong V, Supiyaphun P, Voravud N
International journal of cancer. Journal international du cancer. 1998 ; 78 (2) : 153-156.
PMID 9754644
 
The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2).
Nagel S, Kaufmann M, Drexler HG, MacLeod RA
Cancer research. 2003 ; 63 (17) : 5329-5334.
PMID 14500364
 
Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3'-BCL11B enhancers and coregulation by PU.1 and HMGA1.
Nagel S, Scherr M, Kel A, Hornischer K, Crawford GE, Kaufmann M, Meyer C, Drexler HG, MacLeod RA
Cancer research. 2007 ; 67 (4) : 1461-1471.
PMID 17308084
 
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 ; 45 (2) : 327-331.
PMID 9344656
 
The vaccinia-related kinases phosphorylate the N' terminus of BAF, regulating its interaction with DNA and its retention in the nucleus.
Nichols RJ, Wiebe MS, Traktman P
Molecular biology of the cell. 2006 ; 17 (5) : 2451-2464.
PMID 16495336
 
VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma.
Santos CR, Rodríguez-Pinilla M, Vega FM, Rodríguez-Peralto JL, Blanco S, Sevilla A, Valbuena A, Hern´ndez T, van Wijnen AJ, Li F, de Alava E, S´nchez-Céspedes M, Lazo PA
Molecular cancer research : MCR. 2006 ; 4 (3) : 177-185.
PMID 16547155
 
Consistent loss of heterozygosity at 14Q32 in lymphoid blast crisis of chronic myeloid leukemia.
Sercan HO, Sercan ZY, Kizildag S, Undar B, Soydan S, Sakizli M
Leukemia & lymphoma. 2000 ; 39 (3-4) : 385-390.
PMID 11342319
 
c-Jun phosphorylation by the human vaccinia-related kinase 1 (VRK1) and its cooperation with the N-terminal kinase of c-Jun (JNK).
Sevilla A, Santos CR, Barcia R, Vega FM, Lazo PA
Oncogene. 2004 ; 23 (55) : 8950-8958.
PMID 15378002
 
Isolation and mapping of a polymorphic CA repeat sequence at the human VRK1 locus.
Sugimoto J, Yamauchi T, Hatakeyama T, Isobe M
Journal of human genetics. 1999 ; 44 (2) : 133-134.
PMID 10083742
 
p53 downregulates its activating vaccinia-related kinase 1, forming a new autoregulatory loop.
Valbuena A, Vega FM, Blanco S, Lazo PA
Molecular and cellular biology. 2006 ; 26 (13) : 4782-4793.
PMID 16782868
 
Expression of the VRK (vaccinia-related kinase) gene family of p53 regulators in murine hematopoietic development.
Vega FM, Gonzalo P, Gaspar ML, Lazo PA
FEBS letters. 2003 ; 544 (1-3) : 176-180.
PMID 12782311
 
p53 Stabilization and accumulation induced by human vaccinia-related kinase 1.
Vega FM, Sevilla A, Lazo PA
Molecular and cellular biology. 2004 ; 24 (23) : 10366-10380.
PMID 15542844
 
Identification of target genes of the p16INK4A-pRB-E2F pathway.
Vernell R, Helin K, Müller H
The Journal of biological chemistry. 2003 ; 278 (46) : 46124-46137.
PMID 12923195
 

Citation

This paper should be referenced as such :
Lazo, Pedro A
VRK1 (Vaccinia-related kinase 1)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4):285-288.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/VRK1ID43556ch14q32.html


External links

Nomenclature
HGNC (Hugo)VRK1   12718
Cards
AtlasVRK1ID43556ch14q32
Entrez_Gene (NCBI)VRK1  7443  vaccinia related kinase 1
AliasesPCH1; PCH1A
GeneCards (Weizmann)VRK1
Ensembl hg19 (Hinxton)ENSG00000100749 [Gene_View]  chr14:97263684-97347951 [Contig_View]  VRK1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000100749 [Gene_View]  chr14:97263684-97347951 [Contig_View]  VRK1 [Vega]
ICGC DataPortalENSG00000100749
TCGA cBioPortalVRK1
AceView (NCBI)VRK1
Genatlas (Paris)VRK1
WikiGenes7443
SOURCE (Princeton)VRK1
Genetics Home Reference (NIH)VRK1
Genomic and cartography
GoldenPath hg19 (UCSC)VRK1  -     chr14:97263684-97347951 +  14q32.2   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)VRK1  -     14q32.2   [Description]    (hg38-Dec_2013)
EnsemblVRK1 - 14q32.2 [CytoView hg19]  VRK1 - 14q32.2 [CytoView hg38]
Mapping of homologs : NCBIVRK1 [Mapview hg19]  VRK1 [Mapview hg38]
OMIM602168   607596   
Gene and transcription
Genbank (Entrez)AB000449 AK290110 BC005970 BC103761 BC112075
RefSeq transcript (Entrez)NM_003384
RefSeq genomic (Entrez)NC_000014 NC_018925 NG_016293 NT_026437 NW_004929393
Consensus coding sequences : CCDS (NCBI)VRK1
Cluster EST : UnigeneHs.422662 [ NCBI ]
CGAP (NCI)Hs.422662
Alternative Splicing GalleryENSG00000100749
Gene ExpressionVRK1 [ NCBI-GEO ]   VRK1 [ EBI - ARRAY_EXPRESS ]   VRK1 [ SEEK ]   VRK1 [ MEM ]
Gene Expression Viewer (FireBrowse)VRK1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7443
GTEX Portal (Tissue expression)VRK1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ99986   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ99986  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ99986
Splice isoforms : SwissVarQ99986
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 ]   
PhosPhoSitePlusQ99986
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_kinase_AS   
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
Conserved Domain (NCBI)VRK1
DMDM Disease mutations7443
Blocks (Seattle)VRK1
PDB (SRS)2KTY    2KUL    2LAV    2RSV    3OP5   
PDB (PDBSum)2KTY    2KUL    2LAV    2RSV    3OP5   
PDB (IMB)2KTY    2KUL    2LAV    2RSV    3OP5   
PDB (RSDB)2KTY    2KUL    2LAV    2RSV    3OP5   
Structural Biology KnowledgeBase2KTY    2KUL    2LAV    2RSV    3OP5   
SCOP (Structural Classification of Proteins)2KTY    2KUL    2LAV    2RSV    3OP5   
CATH (Classification of proteins structures)2KTY    2KUL    2LAV    2RSV    3OP5   
SuperfamilyQ99986
Human Protein AtlasENSG00000100749
Peptide AtlasQ99986
HPRD03701
IPIIPI00019640   IPI01025546   IPI01025615   IPI01025249   
Protein Interaction databases
DIP (DOE-UCLA)Q99986
IntAct (EBI)Q99986
FunCoupENSG00000100749
BioGRIDVRK1
STRING (EMBL)VRK1
ZODIACVRK1
Ontologies - Pathways
QuickGOQ99986
Ontology : AmiGOprotein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  nucleoplasm  nucleolus  cytoplasm  Golgi stack  spindle  cytosol  protein phosphorylation  mitotic nuclear division  mitotic nuclear envelope disassembly  mitotic nuclear envelope reassembly  regulation of cell shape  protein kinase binding  nucleosomal histone binding  histone kinase activity (H3-S10 specific)  histone H3-S10 phosphorylation  protein autophosphorylation  cell division  histone kinase activity (H3-T3 specific)  histone H3-T3 phosphorylation  Golgi disassembly  
Ontology : EGO-EBIprotein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  nucleoplasm  nucleolus  cytoplasm  Golgi stack  spindle  cytosol  protein phosphorylation  mitotic nuclear division  mitotic nuclear envelope disassembly  mitotic nuclear envelope reassembly  regulation of cell shape  protein kinase binding  nucleosomal histone binding  histone kinase activity (H3-S10 specific)  histone H3-S10 phosphorylation  protein autophosphorylation  cell division  histone kinase activity (H3-T3 specific)  histone H3-T3 phosphorylation  Golgi disassembly  
REACTOMEQ99986 [protein]
REACTOME PathwaysR-HSA-2993913 Clearance of Nuclear Envelope Membranes from Chromatin [pathway]
REACTOME PathwaysR-HSA-2995383 Initiation of Nuclear Envelope Reformation [pathway]
NDEx NetworkVRK1
Atlas of Cancer Signalling NetworkVRK1
Wikipedia pathwaysVRK1
Orthology - Evolution
OrthoDB7443
GeneTree (enSembl)ENSG00000100749
Phylogenetic Trees/Animal Genes : TreeFamVRK1
HOVERGENQ99986
HOGENOMQ99986
Homologs : HomoloGeneVRK1
Homology/Alignments : Family Browser (UCSC)VRK1
Gene fusions - Rearrangements
Fusion : MitelmanVRK1/SAMD4A [14q32.2/14q22.2]  
Fusion : MitelmanZFHX4/VRK1 [8q21.11/14q32.2]  [t(8;14)(q21;q32)]  
Fusion: TCGAVRK1 14q32.2 SAMD4A 14q22.2 HNSC
Fusion: TCGAZFHX4 8q21.11 VRK1 14q32.2 LUSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerVRK1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)VRK1
dbVarVRK1
ClinVarVRK1
1000_GenomesVRK1 
Exome Variant ServerVRK1
ExAC (Exome Aggregation Consortium)VRK1 (select the gene name)
Genetic variants : HAPMAP7443
Genomic Variants (DGV)VRK1 [DGVbeta]
DECIPHER (Syndromes)14:97263684-97347951  ENSG00000100749
CONAN: Copy Number AnalysisVRK1 
Mutations
ICGC Data PortalVRK1 
TCGA Data PortalVRK1 
Broad Tumor PortalVRK1
OASIS PortalVRK1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICVRK1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDVRK1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
BioMutasearch VRK1
DgiDB (Drug Gene Interaction Database)VRK1
DoCM (Curated mutations)VRK1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)VRK1 (select a term)
intoGenVRK1
NCG5 (London)VRK1
Cancer3DVRK1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602168    607596   
Orphanet3132    23174   
MedgenVRK1
Genetic Testing Registry VRK1
NextProtQ99986 [Medical]
TSGene7443
GENETestsVRK1
Huge Navigator VRK1 [HugePedia]
snp3D : Map Gene to Disease7443
BioCentury BCIQVRK1
ClinGenVRK1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD7443
Chemical/Pharm GKB GenePA37330
Clinical trialVRK1
Miscellaneous
canSAR (ICR)VRK1 (select the gene name)
Probes
Litterature
PubMed55 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineVRK1
EVEXVRK1
GoPubMedVRK1
iHOPVRK1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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