VRK1 (Vaccinia-related kinase 1)

2007-04-01   Pedro 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.

Identity

HGNC
LOCATION
14q32.2
LOCUSID
ALIAS
PCH1,PCH1A
FUSION GENES

DNA/RNA

Atlas Image
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).

Proteins

Note

Enzyme Number (IUBMB): "EC 2.7.11.1".
Atlas Image
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

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 gene
Disregulation of TLX3 and NKX2-5 homeobox genes, but not of VRK1.
Fusion 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 name
Head and neck squamous cell carcinoma.
Oncogenesis
Overexpression of VRK1 protein that positively correlates with hdm2, cdk2, cdk4 and survivin.
Entity name
Neuroblastomas
Cytogenetics
Loss of heterozygosis (31 %) in marker (D14S987) in 14q32.2 which is located 5 with respect to the VRK1 gene.
Entity name
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 name
Nasopharyngeal carcinoma
Cytogenetics
Loss of heterozygosis in marker (D14S51) in 14q32.2 which is located 0.15Mb 3 to the VRK1 gene.
Entity name
Cytogenetics
Loss of heterozygosis in marker (D14S65) in 14q32.2 which is located 0.15Mb 3 to the VRK1 gene.

Breakpoints

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

Article Bibliography

Pubmed IDLast YearTitleAuthors
103475561999Loss of heterozygosity of 14q32 in colorectal carcinoma.Bando T et al
118838972002Kinetic properties of p53 phosphorylation by the human vaccinia-related kinase 1.Barcia R et al
147475642004Members 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 et al
173448462007Patterns of somatic mutation in human cancer genomes.Greenman C et al
108392942000Detailed deletion mapping of chromosome band 14q32 in human neuroblastoma defines a 1.1-Mb region of common allelic loss.Hoshi M et al
109515722000The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein.Lopez-Borges S et al
126610092003Activation 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 et al
97546441998Loss of heterozygosity on chromosome 14 in nasopharyngeal carcinoma.Mutirangura A et al
145003642003The 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 et al
173080842007Activation 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 et al
93446561997Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase.Nezu J et al
164953362006The vaccinia-related kinases phosphorylate the N' terminus of BAF, regulating its interaction with DNA and its retention in the nucleus.Nichols RJ et al
165471552006VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma.Santos CR et al
113423192000Consistent loss of heterozygosity at 14Q32 in lymphoid blast crisis of chronic myeloid leukemia.Sercan HO et al
153780022004c-Jun phosphorylation by the human vaccinia-related kinase 1 (VRK1) and its cooperation with the N-terminal kinase of c-Jun (JNK).Sevilla A et al
100837421999Isolation and mapping of a polymorphic CA repeat sequence at the human VRK1 locus.Sugimoto J et al
167828682006p53 downregulates its activating vaccinia-related kinase 1, forming a new autoregulatory loop.Valbuena A et al
127823112003Expression of the VRK (vaccinia-related kinase) gene family of p53 regulators in murine hematopoietic development.Vega FM et al
155428442004p53 Stabilization and accumulation induced by human vaccinia-related kinase 1.Vega FM et al
129231952003Identification of target genes of the p16INK4A-pRB-E2F pathway.Vernell R et al

Other Information

Locus ID:

NCBI: 7443
MIM: 602168
HGNC: 12718
Ensembl: ENSG00000100749

Variants:

dbSNP: 7443
ClinVar: 7443
TCGA: ENSG00000100749
COSMIC: VRK1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000100749ENST00000216639Q99986
ENSG00000100749ENST00000553683H0YJF7
ENSG00000100749ENST00000557222H0YJ50
ENSG00000100749ENST00000557352H0YJJ9

Expression (GTEx)

0
10
20
30
40
50
60
70

Pathways

PathwaySourceExternal ID
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
M PhaseREACTOMER-HSA-68886
Mitotic ProphaseREACTOMER-HSA-68875
Nuclear Envelope BreakdownREACTOMER-HSA-2980766
Clearance of Nuclear Envelope Membranes from ChromatinREACTOMER-HSA-2993913
Mitotic Metaphase and AnaphaseREACTOMER-HSA-2555396
Mitotic AnaphaseREACTOMER-HSA-68882
Nuclear Envelope ReassemblyREACTOMER-HSA-2995410
Initiation of Nuclear Envelope ReformationREACTOMER-HSA-2995383

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
383676822024Loss of VRK1 alters the nuclear phosphoproteome in the DNA damage response to doxorubicin.2
385365532024VRK1 promotes DNA-induced type I interferon production.0
387320932024VRK1 Regulates Sensitivity to Oxidative Stress by Altering Histone Epigenetic Modifications and the Nuclear Phosphoproteome in Tumor Cells.0
388061312024ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons.0
383676822024Loss of VRK1 alters the nuclear phosphoproteome in the DNA damage response to doxorubicin.2
385365532024VRK1 promotes DNA-induced type I interferon production.0
387320932024VRK1 Regulates Sensitivity to Oxidative Stress by Altering Histone Epigenetic Modifications and the Nuclear Phosphoproteome in Tumor Cells.0
388061312024ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons.0
367350432023Circvrk1 downregulation attenuates brain microvascular endothelial cell damage induced by oxygen-glucose deprivation through modulating the miR-150-5p/MLLT1 axis.0
370754942023Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway.1
372576652023VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases.2
375472972023Downregulation of VRK1 Inhibits Progression of Lung Squamous Cell Carcinoma through DNA Damage.1
367350432023Circvrk1 downregulation attenuates brain microvascular endothelial cell damage induced by oxygen-glucose deprivation through modulating the miR-150-5p/MLLT1 axis.0
370754942023Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway.1
372576652023VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases.2

Citation

Pedro A. Lazo ; Francisco M. Vega ; Ana Sevilla ; Alberto Valbuena ; Marta Sanz-Garcia ; Inmaculada Lopez-Sanchez ; Sandra Blanco

VRK1 (Vaccinia-related kinase 1)

Atlas Genet Cytogenet Oncol Haematol. 2007-04-01

Online version: http://atlasgeneticsoncology.org/gene/43556/favicon/css/js/template.js