Affinage

VRK1

Serine/threonine-protein kinase VRK1 · UniProt Q99986

Length
396 aa
Mass
45.5 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VRK1 is a nuclear serine/threonine chromatin kinase that integrates mitotic chromatin remodeling, DNA damage signaling, transcription factor activation, and nuclear envelope dynamics through phosphorylation of diverse substrates. VRK1 phosphorylates histone H2AX (S139) and the acetyltransferase Tip60/KAT5 (T158) to initiate a sequential DNA damage response upstream of ATM, 53BP1, and NBS1 foci formation, independently of ATM (PMID:22621922, PMID:33076429, PMID:25923214, PMID:26869104); it phosphorylates BAF/BANF1 to regulate its chromatin dissociation during mitosis, and loss of this activity causes nuclear envelope defects, with VRK2 providing a partially redundant function exploitable as a synthetic lethality (PMID:17170708, PMID:24430874, PMID:36069976). VRK1 additionally phosphorylates transcription factors p53 (T18), CREB (S133), c-Jun, and ATF2 to drive cell cycle entry via cyclin D1 expression, engages nucleosomes through its arginine-rich C-terminal tail binding the acidic patch—a mechanism disrupted by distal spinal muscular atrophy–causing mutations—and its activity is negatively regulated by RanGDP, macroH2A1.2, and SIRT2 (PMID:10951572, PMID:18713830, PMID:35390161, PMID:18617507, PMID:22194607, PMID:36902348).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 Medium

    The initial identification of VRK1 as a novel kinase related to vaccinia B1R established a previously unknown mammalian kinase family predicted to share substrate phosphorylation functions with poxvirus kinases.

    Evidence cDNA cloning and sequence analysis from a human cDNA library

    PMID:9344656

    Open questions at the time
    • No kinase activity demonstrated; prediction based solely on sequence homology
    • No substrates identified
    • No cellular function assigned
  2. 2000 High

    Demonstrating that VRK1 phosphorylates p53 at Thr-18 and possesses strong autophosphorylation activity established it as an active nuclear kinase with a defined substrate and residue specificity relevant to p53 regulation.

    Evidence In vitro kinase assay with recombinant proteins, GFP-fusion localization, mutagenesis

    PMID:10951572

    Open questions at the time
    • In vivo p53-T18 phosphorylation by VRK1 not yet shown
    • Biological consequence of p53-T18 phosphorylation by VRK1 not determined
  3. 2004 High

    Discovery that VRK1 phosphorylates and activates transcription factors ATF2 (T73/S62) and c-Jun (S63/S73) expanded VRK1's role from a single-substrate kinase to a broad transcriptional activator operating on AP-1 family members.

    Evidence In vitro kinase assays, co-immunoprecipitation, kinase-dead mutant controls, luciferase reporters

    PMID:15105425 PMID:15378002

    Open questions at the time
    • Physiological contexts where VRK1 rather than JNK phosphorylates c-Jun/ATF2 not delineated
    • No in vivo target gene profiling
  4. 2006 High

    Using the C. elegans ortholog, genetic evidence established VRK1 as essential for BAF phosphorylation and nuclear envelope assembly, revealing a conserved role in post-mitotic nuclear reformation.

    Evidence RNAi and temperature-sensitive mutant analysis in C. elegans embryos with live imaging

    PMID:17170708

    Open questions at the time
    • Mammalian BAF phosphorylation by VRK1 not yet demonstrated at this point
    • Redundancy with VRK2 not addressed
  5. 2008 High

    Multiple discoveries in 2008 placed VRK1 at the nexus of mitogenic signaling and mitotic regulation: VRK1 phosphorylates CREB-S133 to drive cyclin D1 expression for G1/S transit; Ran-GTP/GDP toggle regulates VRK1 kinase activity including histone H3 phosphorylation; Plk3 phosphorylates VRK1 at S342 to drive Golgi fragmentation; and VRK1 is itself an early-response gene required for cell cycle re-entry.

    Evidence In vitro kinase assays, ChIP, siRNA with cell cycle analysis, reciprocal co-IP with Ran and Plk3, Golgi fragmentation assays, serum stimulation time courses

    PMID:18286197 PMID:18617507 PMID:18713830 PMID:19103756

    Open questions at the time
    • How VRK1 integrates Ran and Plk3 signals during mitosis not resolved
    • Direct link between VRK1-mediated CREB phosphorylation and proliferative advantage in vivo not established
  6. 2009 High

    Demonstrating infertility and progressive spermatogonial loss in hypomorphic Vrk1 mice established VRK1 as essential for mammalian germ cell proliferation in vivo.

    Evidence Gene-trap mouse model with histological analysis of testes

    PMID:19696012

    Open questions at the time
    • Which VRK1 substrates mediate spermatogonial proliferation unknown
    • Female fertility not addressed at this point
  7. 2011 High

    Structural and regulatory insights converged: the NMR solution structure showed the C-terminal tail is critical for catalysis; macroH2A1.2 was identified as an interphase-specific VRK1 inhibitor; VRK1 was shown to be required for meiotic chromosome segregation in oocytes; and VRK1 degradation after DNA damage was shown to proceed through DRAM-dependent autophagy.

    Evidence NMR structure determination, NMR-mapped interaction with macroH2A1.2, gene-trap mouse oocyte analysis, siRNA/chemical inhibitor pathway dissection

    PMID:21277975 PMID:21386980 PMID:21543316 PMID:22194607

    Open questions at the time
    • How macroH2A1.2 release at mitosis is coordinated with VRK1 activation not shown
    • DRAM-dependent degradation pathway not validated in vivo
  8. 2012 High

    VRK1 was established as an upstream initiator of the DNA damage response: it phosphorylates 53BP1 and H2AX for DDR foci formation independently of ATM, and phosphorylates hnRNP A1 to regulate telomere maintenance.

    Evidence In vitro kinase assays, siRNA with rescue in ATM+/+ and ATM−/− cells, immunofluorescence foci quantification, telomere analysis in Vrk1-deficient mice

    PMID:22621922 PMID:22740652

    Open questions at the time
    • Direct 53BP1 phosphorylation site by VRK1 not mapped
    • Whether VRK1 phosphorylation of hnRNP A1 is the primary cause of telomere shortening in vivo not proven
  9. 2014 High

    Mammalian cell studies confirmed VRK1's role in BAF dynamics: VRK1 depletion traps BAF on chromosomes during mitosis, causing nuclear envelope defects and mitotic errors, validating the C. elegans findings in human cells.

    Evidence siRNA depletion, FRAP of GFP-BAF, live-cell imaging in MCF10a and MDA-MB-231 cells

    PMID:24430874

    Open questions at the time
    • Specific BAF phosphorylation sites targeted by VRK1 in mammalian cells not identified
    • Contribution of VRK2 redundancy not dissected
  10. 2015 High

    VRK1 was shown to phosphorylate coilin-S184 to maintain Cajal body integrity, expanding its nuclear roles beyond chromatin to subnuclear organelle homeostasis; separately, VRK1 was found to have both catalytic and non-catalytic roles in neuronal migration via APP regulation.

    Evidence siRNA with kinase-dead rescue, proteasome/export inhibitors for coilin; in utero electroporation with WT/kinase-dead rescue and APP epistasis for neuronal migration

    PMID:25609612 PMID:26068304

    Open questions at the time
    • How VRK1 regulates APP expression mechanistically is unknown
    • Whether coilin phosphorylation is required for CB function beyond structural assembly not tested
  11. 2016 High

    VRK1 was shown to phosphorylate NBS1 at S343 independently of ATM, protecting NBS1 from RNF8-mediated proteasomal degradation, thereby enabling DDR foci formation—further cementing VRK1 as an ATM-independent early DDR kinase.

    Evidence In vitro kinase assay, co-IP of preassembled VRK1-NBS1 complex, siRNA in ATM−/− cells, proteasome inhibitor rescue

    PMID:26869104

    Open questions at the time
    • Whether VRK1-NBS1 complex exists on chromatin at damage sites not shown
    • How VRK1 activation by DSBs is triggered mechanistically remains unclear
  12. 2018 High

    Discovery that VRK1 and Aurora B form a mutually inhibitory complex linked VRK1's histone H3-T3 kinase activity to the chromosomal passenger complex pathway through survivin regulation.

    Evidence Co-immunoprecipitation after nocodazole release, reciprocal in vitro kinase inhibition assays, siRNA with rescue

    PMID:29340707

    Open questions at the time
    • Temporal regulation of VRK1-AURKB cross-inhibition during mitotic progression not resolved
    • Direct structural basis of mutual inhibition unknown
  13. 2020 High

    VRK1 was placed upstream of Tip60/KAT5-mediated ATM acetylation in the DDR, and independently, the conserved VRK-1→AMPK phosphorylation axis was shown to regulate longevity and energy sensing.

    Evidence In vitro kinase assay and kinase-dead rescue for Tip60-T158 and H4K16ac; genetic epistasis in C. elegans longevity mutants with validation of AMPK phosphorylation in human cells

    PMID:32937443 PMID:33076429

    Open questions at the time
    • Specific AMPK residue phosphorylated by VRK1 not mapped in human cells
    • How VRK1 senses metabolic state to activate AMPK is unknown
  14. 2022 High

    A cryo-EM structure revealed VRK1 engages nucleosomes via its arginine-rich C-terminal tail binding the acidic patch for H3T3 phosphorylation, and distal SMA-causing mutations disrupt this interaction; concurrently, VRK1-VRK2 synthetic lethality was demonstrated via BAF phosphorylation dependency; however, an independent study challenged VRK1's role as the mitotic H3T3 kinase, attributing this activity to Haspin.

    Evidence Cryo-EM of VRK1-nucleosome complex, disease mutant biochemistry; VRK1/VRK2 synthetic lethality in xenografts; KiPIK screening, CRISPR, and in vitro assays disputing mitotic H3T3ph role

    PMID:35390161 PMID:35778595 PMID:36069976

    Open questions at the time
    • Whether VRK1 phosphorylates H3T3 in specific non-mitotic contexts (e.g., DDR) is unresolved
    • The contradiction regarding mitotic H3T3 kinase identity (VRK1 vs. Haspin) is not settled
    • Structural basis of disease mutations beyond acidic patch disruption not fully explored
  15. 2023 Medium

    VRK1 was shown to regulate the H3K9 acetylation-to-methylation switch by interacting with histone-modifying enzyme families, and its kinase activity is inhibited by SIRT2, revealing an additional layer of chromatin-level VRK1 regulation.

    Evidence siRNA and VRK-IN-1 inhibitor treatment with histone mark profiling; in vitro interaction and kinase assays for SIRT2-VRK1

    PMID:36902348 PMID:37179361

    Open questions at the time
    • Whether VRK1 directly phosphorylates the chromatin-modifying enzymes it interacts with is not determined
    • SIRT2 inhibition of VRK1 demonstrated in vitro but in vivo physiological relevance not established
    • Mechanism by which VRK1 coordinates multiple histone enzyme complexes is unclear
  16. 2024 Medium

    VRK1 was linked to innate immune signaling by promoting type I interferon production through the cGAS-STING pathway, extending its functional reach beyond chromatin and cell cycle regulation.

    Evidence siRNA knockdown and VRK-IN-1 inhibition in primary BMDMs with dual-luciferase reporter and RT-PCR

    PMID:38536553

    Open questions at the time
    • Direct VRK1 substrate in the STING pathway not identified
    • Single-lab finding not independently replicated
    • Whether this role requires VRK1 chromatin kinase activity or a cytoplasmic pool is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the definitive identity of the mitotic H3T3 kinase (VRK1 vs. Haspin); the molecular trigger that activates VRK1 at DNA damage sites; a comprehensive atlas of VRK1 phosphorylation sites on its many substrates in vivo; and the mechanistic basis of VRK1's non-catalytic roles in processes such as neuronal migration.
  • No consensus on mitotic H3T3 kinase identity
  • VRK1 activation mechanism by DSBs unknown
  • Non-catalytic scaffolding functions poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 14 GO:0016740 transferase activity 6 GO:0042393 histone binding 3 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 5 GO:0005694 chromosome 4 GO:0005654 nucleoplasm 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-73894 DNA Repair 5 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
AURKBBANF1KAT5NBS1PLK3RANSIRT2TP53
Complex memberships
VRK1-AURKB complexVRK1-NBS1 complexVRK1-p53 complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 VRK1 was identified as a novel putative serine/threonine kinase with 40% amino acid identity to the vaccinia virus B1R kinase, predicted to have similar enzymatic functions. cDNA cloning, sequence analysis, Northern blot Genomics Medium 9344656
2000 VRK1 phosphorylates p53 at threonine-18 within the mdm-2 binding site, has strong autophosphorylating activity, and phosphorylates acidic (phosvitin, casein) and basic (histone H2B, MBP) proteins; the C-terminal domain (residues 268-396) contains a nuclear localization signal targeting VRK1 to the nucleus. In vitro kinase assay, GFP fusion protein localization, mutagenesis Oncogene High 10951572
2004 VRK1 colocalizes with and forms a stable complex with ATF2 in the nucleus, phosphorylating ATF2 on Thr-73 and Ser-62, stabilizing the ATF2 protein and activating ATF2-dependent transcription including the collagenase gene promoter; kinase-dead VRK1 (K179E) abolishes these effects. In vitro kinase assay, co-immunoprecipitation, mutagenesis, luciferase reporter assay The Journal of biological chemistry High 15105425
2004 VRK1 phosphorylates c-Jun at Ser63 and Ser73, the same residues targeted by JNK, stabilizing c-Jun and activating c-Jun-dependent transcription; VRK1 interacts with c-Jun but not with JNK, and cooperates additively with JNK at suboptimal doses. In vitro kinase assay, co-immunoprecipitation, luciferase reporter assay, endogenous phosphorylation detection Oncogene High 15378002
2006 VRK-1 (C. elegans ortholog) phosphorylates BAF (BAF-1) to regulate its association with chromatin and nuclear membrane proteins; VRK-1 localizes to the nuclear envelope and chromatin in a cell-cycle-dependent manner, and its depletion causes impaired nuclear envelope formation and BAF delocalization. RNAi, temperature-sensitive mutant analysis, immunofluorescence, live imaging in C. elegans embryos The EMBO journal High 17170708
2007 VRK1 protein exists in distinct intracellular subpopulations: predominantly nuclear, but also cytosolic (tissue-dependent) and in a Golgi apparatus-associated vesicular subpopulation; a single amino acid substitution at T355 (mimicking phosphorylation) near the NLS differentially affects antibody reactivity, indicating regulated subcellular localization. Immunohistochemistry, immunofluorescence, immunoprecipitation with phosphomimetic mutants Archives of biochemistry and biophysics Medium 17617371
2008 VRK1 phosphorylates CREB at Ser133, facilitating recruitment of phospho-CREB to the CRE element in the CCND1 (cyclin D1) promoter; kinase-dead VRK1 or VRK1 knockdown fails to activate CREB and subsequently cyclin D1 expression, reducing S-phase entry. In vitro kinase assay, siRNA knockdown, ChIP, luciferase reporter, kinase-dead mutant Journal of cell science High 18713830
2008 Plk3 interacts with VRK1 forming a stable complex (reciprocal immunoprecipitations and pull-down), colocalizes with VRK1 at the Golgi apparatus, and phosphorylates VRK1 at Ser342 in its C-terminal region; VRK1 is a downstream effector of Plk3 in the MEK1-Plk3-VRK1 pathway controlling Golgi fragmentation during mitosis. Reciprocal co-immunoprecipitation, pull-down, siRNA knockdown, kinase-dead mutant, Ser342 substitution mutant, Golgi fragmentation assay Molecular and cellular biology High 19103756
2008 Ran GTPase interacts with VRK1, forming a stable complex (validated by pulldown and reciprocal immunoprecipitation); inactive RanGDP inhibits VRK1 kinase activity (autophosphorylation and histone H3 phosphorylation at Thr-3 and Ser-10), while constitutively active RanGTP relieves this inhibition; VRK1 does not phosphorylate Ran. Mass spectrometry identification, reciprocal co-immunoprecipitation, pull-down, in vitro kinase assay with GDP/GTP-bound Ran forms Molecular & cellular proteomics High 18617507
2008 VRK1 is an early-response gene: its expression is induced by serum in starved cells paralleling MYC, FOS, and CCND1, and its siRNA-mediated depletion results in G1 cell cycle block with loss of phospho-Rb and cyclin D1. Serum stimulation, siRNA knockdown, flow cytometry, Western blot, luciferase reporter (VRK1 promoter) PloS one High 18286197
2008 p300/CBP protect VRK1 from p53-induced downregulation via the p300 C/H3 domain binding to the p53 transactivation domain; PCAF cannot reverse this protective effect; VRK1 downregulation requires p53-dependent transcription and is also regulated by the autophagic pathway via DRAM. Co-transfection, deletion mutagenesis of p300 C/H3 domain, protein interaction assay PloS one Medium 18612383
2009 Mouse VRK1 is essential for spermatogonial proliferation and gametogenesis; hypomorphic VRK1 mice (GT3/GT3, ~15% WT VRK1 levels) are infertile due to progressive loss of spermatogonia and absence of mitotic/meiotic cells in adult testis; VRK1 is expressed in Sertoli cells and spermatogonia. Gene-trap mouse model, histology, in situ expression analysis Biology of reproduction High 19696012
2010 In C. elegans, VRK-1 is required for normal germ cell proliferation and acts in part by regulating CEP-1 (p53) activity; loss of cep-1 significantly rescues the proliferation defects of vrk-1 mutants, placing VRK-1 upstream of CEP-1/p53 to prevent inappropriate cell cycle arrest. Genetic epistasis (vrk-1 mutant × cep-1 mutant double mutant rescue), RNAi, gene expression profiling Developmental biology High 20599896
2011 VRK1 kinase activity is inhibited by macroH2A1.2 during interphase; macroH2A1.2 directly interacts with VRK1 (interaction characterized by NMR spectroscopy) and suppresses VRK1-mediated histone H3 phosphorylation mainly during interphase; macroH2A1.2 levels are markedly reduced in mitosis. NMR spectroscopy, in vitro interaction assay, kinase assay, cell cycle synchronization The Journal of biological chemistry High 22194607
2011 NMR solution structure of human VRK1 (residues 1-361) revealed that the C-terminal tail orients toward the catalytic site and forms interactions critical for structural stability and catalysis; deletion of the C-terminal tail dramatically reduces VRK1 autocatalytic activity; ATP/analogs interact with hinge region, catalytic loop, DYG motif and C-terminal tail residues. NMR solution structure determination, deletion mutagenesis, NMR titration with ATP The Journal of biological chemistry High 21543316
2011 VRK1 is required for normal meiotic progression during mammalian oogenesis; reduced VRK1 activity in mice causes lagging chromosomes at the metaphase plate and failure of oocytes to be fertilized; this meiotic role is p53-independent. Gene-trap mouse model, oocyte meiosis analysis, chromosomal analysis Mechanisms of development High 21277975
2011 VRK1 downregulation by p53 in response to DNA damage (UV, IR, etoposide, doxorubicin) requires DRAM expression (a p53-induced gene in the endosomal-lysosomal compartment), followed by VRK1 lysosomal degradation via the autophagic pathway (requiring Beclin1); this process requires VRK1 nuclear export (blocked by leptomycin B). siRNA knockdown of DRAM, DRAM overexpression, LC3/p62 detection, proteasome vs lysosome inhibitor treatment, nuclear export inhibition PloS one High 21386980
2012 VRK1 is activated by DNA double-strand breaks from ionizing radiation (IR) and specifically phosphorylates 53BP1; VRK1 knockdown causes defective 53BP1 foci formation in response to IR (independent of p53 and ATM) and prevents activating phosphorylation of ATM, CHK2, and DNA-PK. siRNA knockdown, IR treatment, immunofluorescence for foci formation, Western blot for kinase activation, kinase assay, siRNA-resistant rescue The Journal of biological chemistry High 22621922
2012 VRK1 phosphorylates hnRNP A1, potentiating its binding to telomeric ssDNA and telomerase RNA in vitro and enhancing telomerase activity; VRK1 deficiency in mouse male germ cells causes telomere shortening with abnormal telomere arrangement and activation of DNA-damage signaling. In vitro kinase assay, in vitro DNA/RNA binding assay, telomerase activity assay, mouse genetic model with telomere analysis Nucleic acids research High 22740652
2014 VRK1 depletion in mammalian cells (MCF10a and MDA-MB-231) causes aberrant nuclear envelope architecture; GFP-BAF FRAP shows increased immobile BAF fraction at the NE; in VRK1-depleted cells, BAF does not disperse but remains chromosome-bound from mitosis onset; VRK1 depletion also increases anaphase bridges and multipolar spindles. siRNA depletion, live-cell imaging of GFP-BAF, FRAP, fluorescence microscopy Molecular biology of the cell High 24430874
2014 VRK1 forms a stable basal complex with p53 (through the p53 DNA-binding domain); UV-induced DNA damage activates VRK1 and leads to p53 Thr-18 phosphorylation before p53 accumulates; common DNA-contact p53 mutants (R273H, R248H, R280K) do not disrupt the complex. Co-immunoprecipitation, UV treatment, phospho-specific Western blot, p53 mutant panel FEBS letters Medium 24492002
2015 VRK1 is a nucleosomal chromatin kinase that directly and stably interacts with histones H2AX and H3; VRK1 depletion causes loss of histones H3 and H4 acetylation; in response to ionizing radiation, VRK1 phosphorylates H2AX at Ser139 (γH2AX), and this phosphorylation and γH2AX foci formation are prevented by VRK1 depletion and rescued by kinase-active but not kinase-dead VRK1. In vitro kinase assay, siRNA knockdown with kinase-active/dead rescue, immunofluorescence for foci, histone acetylation measurement Epigenetics High 25923214
2015 VRK1 interacts with and phosphorylates coilin at Ser184, regulating Cajal body (CB) assembly and stability in a cell-cycle-dependent manner; loss of coilin phosphorylation by VRK1 knockdown causes CB disintegration and coilin ubiquitination (partly mediated by Mdm2) and proteasomal degradation in the cytosol; nuclear export of coilin is required for its proteasomal degradation. siRNA knockdown, kinase-dead mutant rescue, immunoprecipitation, proteasome inhibitor treatment, nuclear export inhibition Scientific reports High 26068304
2015 VRK1 is required for neuronal migration and neuronal stem cell proliferation in mice; VRK1 kinase-dead mutant rescues migration impairment but not proliferation, indicating a partly noncatalytic role in migration; VRK1 deficiency downregulates amyloid-β precursor protein (APP), and APP overexpression rescues the migration phenotype caused by Vrk1 knockdown. In utero electroporation shRNA knockdown in mice, wild-type and kinase-dead VRK1 rescue, APP overexpression rescue, neuronal migration assay The Journal of neuroscience High 25609612
2016 VRK1 phosphorylates NBS1 at Ser343 in response to DNA damage (doxorubicin or IR) independently of ATM; VRK1 forms a preassembled complex with NBS1 in non-damaged cells; VRK1 knockdown causes loss of NBS1 foci and NBS1 stability, which is prevented by proteasome inhibitor MG132 or RNF8 knockdown. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown in ATM-/- cells, proteasome inhibitor treatment, immunofluorescence Biochimica et biophysica acta High 26869104
2017 VRK1 directly phosphorylates PXR at Ser350 in low glucose conditions; PO3-PXR scaffolds protein phosphatase PP2Cα, which dephosphorylates SGK2 at Thr193, dissociating SGK2 from the PCK1 gene promoter to activate gluconeogenesis; CDK2 inhibits VRK1 autophosphorylation activity in high glucose conditions. In vitro kinase assay, co-immunoprecipitation, kinase inhibitor (CDK2), reporter assay, fasting mouse liver validation Cellular signalling Medium 28911860
2018 VRK1 and AURKB form a stable protein complex (detected after nocodazole release) in which each kinase inhibits the other's kinase activity and specific phosphorylation of histone H3 (Thr3 by VRK1, Ser10 by AURKB); VRK1 depletion downregulates BIRC5 (survivin) expression and the H3-Thr3ph-survivin complex required for AURKB recruitment to centromeres. Co-immunoprecipitation, reciprocal kinase inhibition assay, siRNA depletion with kinase-active/dead rescue, immunofluorescence Cellular and molecular life sciences High 29340707
2020 VRK1 directly phosphorylates Tip60/KAT5, and VRK1 depletion causes loss of H4K16 acetylation in response to DNA damage; Tip60 phosphorylation by VRK1 is required for activating acetylation of ATM and subsequent ATM autophosphorylation, both lost by VRK1 depletion independently of ATM. In vitro kinase assay, co-immunoprecipitation, siRNA with kinase-active/dead rescue in ATM+/+ and ATM-/- cells, H4K16ac measurement Cancers High 33076429
2020 VRK-1 (C. elegans) directly phosphorylates and activates AMPK; VRK-1 overexpression in soma increases C. elegans lifespan and inhibition decreases it; VRK-1 is required for longevity conferred by mitochondrial respiration mutations (which require AMPK); direct phosphorylation of AMPK by VRK-1 was also demonstrated in cultured human cells. In vitro kinase assay (VRK-1 on AMPK), genetic epistasis (vrk-1 required for AMPK-dependent longevity), lifespan assays, human cell validation Science advances High 32937443
2021 VRK1 vaccinia virus B12 pseudokinase interaction: B12 copurifies with VRK1 in the nucleus, interferes with VRK1's ability to phosphoinactivate BAF, and thus restricts vaccinia virus DNA replication; VRK1 overexpression is sufficient to overcome B12-repressive activity; VRK1 knockdown prevents rescue of B1-deleted virus. Immunoprecipitation, VRK1 knockdown and overexpression, viral replication assay, BAF phosphorylation assay Journal of virology High 33177193
2022 VRK1 interacts with both linker DNA and the nucleosome acidic patch (via an arginine-rich C-terminal tail) to phosphorylate histone H3T3; cryo-EM structure shows the mechanism of chromatin engagement; VRK1 mutations causative in distal spinal muscular atrophy (e.g., R358X, R321C region) interfere with nucleosome acidic patch binding and cause VRK1 mislocalization during mitosis. Cryo-electron microscopy, biochemical acidic patch binding assay, cellular localization assay, pathogenic mutant analysis Nucleic acids research High 35390161
2022 VRK1 knockdown in VRK2-null/methylated cells reduces BAF phosphorylation during mitosis, causing nuclear lobulation, blebbing, micronucleation, G2-M arrest and DNA damage; this synthetic lethality is dependent on VRK1 kinase activity and is rescued by ectopic VRK2 expression. siRNA knockdown, VRK2 rescue overexpression, BAF phosphorylation assay, nuclear morphology analysis, xenograft models Cancer research High 36069976
2022 VRK1 chromatin kinase regulates Tip60/KAT5 acetyltransferase activity by sequential phosphorylations: VRK1 phosphorylates Tip60 at T158 (early, transient), protecting it from ubiquitin-mediated degradation and promoting chromatin recruitment; DNA-PK subsequently phosphorylates Tip60 at S199, and both phosphorylations together are required for full Tip60 trans-acetylase activity toward H4 and ATM. In vitro kinase assay, phosphomimetic/phosphonull mutants, siRNA depletion, chromatin fractionation, kinase inhibitors (DNA-PK inhibitors) Biochimica et biophysica acta. Gene regulatory mechanisms High 36280132
2022 Haspin, not VRK1 or VRK2, is required for H3T3 phosphorylation during mitosis; despite earlier reports implicating VRK1 in H3T3ph, in vitro kinase assays, KiPIK screening, RNAi, and CRISPR/Cas9 approaches failed to substantiate a direct role for VRK1/VRK2 in phosphorylation of H3T3 or H3S10 during mitosis. In vitro kinase assay, KiPIK screening, RNAi, CRISPR/Cas9, mitotic H3 phosphorylation analysis Scientific reports Medium 35778595
2023 VRK1 depletion/inhibition (with VRK-IN-1) causes a switch in H3K9 post-translational modifications: loss of H3K9 acetylation and facilitation of H3K9 methylation; VRK1 stably interacts with KAT, HDAC, KMT, and KDM family members, acting as a master regulator of chromatin epigenetic patterns. siRNA depletion, VRK1-specific inhibitor (VRK-IN-1), inhibitors of acetylases/deacetylases/methyltransferases/demethylases, immunoprecipitation for interactions Epigenetics & chromatin Medium 37179361
2023 VRK1 kinase activity is inhibited by direct interaction of its N-terminal kinase domain with SIRT2; the VRK1-SIRT2 complex formation causes loss of H4K16ac similarly to VRK1 depletion or VRK-IN-1 inhibitor; SIRT2 deacetylates H4K16, opposing Tip60-mediated acetylation that is activated by VRK1. In vitro interaction, pull-down, in vitro kinase assay, immunoprecipitation, immunofluorescence, SIRT2 inhibitors International journal of molecular sciences Medium 36902348
2024 VRK1 promotes type I interferon production through the cGAS-STING pathway; VRK1 knockdown attenuates type I IFN and ISG induction by dsDNA stimuli (HTDNA, Poly(dA:dT)); VRK-IN-1 inhibitor phenocopies this, and VRK1 acts at the STING level. siRNA knockdown, pharmacological inhibition (VRK-IN-1), dual-luciferase reporter, RT-PCR, primary BMDMs Molecular biology reports Medium 38536553
2025 VRK1 interacts with CHD1L and phosphorylates CHD1L at serine 122; this phosphorylation upregulates SNAI1 expression, promoting epithelial-mesenchymal transition (EMT) and HCC progression. Immunoprecipitation combined with mass spectrometry, phosphorylation site identification, RNA-seq, in vitro and in vivo functional assays Cell death & disease Medium 40234378
2025 VRK1 promotes YBX1 protein stability by inhibiting its ubiquitination and degradation, and phosphorylates YBX1 to promote its nuclear translocation, thereby regulating glioma stem cell stemness and proliferation via the YBX1/SOX2 pathway; VRK1 expression is upregulated by histone lactylation (H3K18la) at its promoter. Ubiquitination assay, phosphorylation assay, nuclear translocation analysis, patient-derived GSC functional assays, nanoliposome in vivo model Advanced science Medium 40990975

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Caenorhabditis elegans BAF-1 and its kinase VRK-1 participate directly in post-mitotic nuclear envelope assembly. The EMBO journal 181 17170708
2009 Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. American journal of human genetics 128 19646678
1997 Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase. Genomics 122 9344656
2000 The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein. Oncogene 115 10951572
2004 Human vaccinia-related kinase 1 (VRK1) activates the ATF2 transcriptional activity by novel phosphorylation on Thr-73 and Ser-62 and cooperates with JNK. The Journal of biological chemistry 102 15105425
2004 c-Jun phosphorylation by the human vaccinia-related kinase 1 (VRK1) and its cooperation with the N-terminal kinase of c-Jun (JNK). Oncogene 92 15378002
2008 Human VRK1 is an early response gene and its loss causes a block in cell cycle progression. PloS one 90 18286197
2008 VRK1 phosphorylates CREB and mediates CCND1 expression. Journal of cell science 84 18713830
2014 Depletion of the protein kinase VRK1 disrupts nuclear envelope morphology and leads to BAF retention on mitotic chromosomes. Molecular biology of the cell 77 24430874
2006 VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma. Molecular cancer research : MCR 74 16547155
2011 Roles of VRK1 as a new player in the control of biological processes required for cell division. Cellular signalling 71 21514377
2013 Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly. JAMA neurology 60 24126608
2017 Circular RNA profile indicates circular RNA VRK1 is negatively related with breast cancer stem cells. Oncotarget 58 29221160
2015 VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage. Epigenetics 55 25923214
2008 Plk3 interacts with and specifically phosphorylates VRK1 in Ser342, a downstream target in a pathway that induces Golgi fragmentation. Molecular and cellular biology 52 19103756
2012 Vaccinia-related kinase 1 (VRK1) is an upstream nucleosomal kinase required for the assembly of 53BP1 foci in response to ionizing radiation-induced DNA damage. The Journal of biological chemistry 50 22621922
2011 Downregulation of VRK1 by p53 in response to DNA damage is mediated by the autophagic pathway. PloS one 50 21386980
2019 Ginsenoside Rg3 regulates DNA damage in non-small cell lung cancer cells by activating VRK1/P53BP1 pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 48 31629252
2021 The human VRK1 chromatin kinase in cancer biology. Cancer letters 45 33516791
2009 Mice deficient in the serine/threonine protein kinase VRK1 are infertile due to a progressive loss of spermatogonia. Biology of reproduction 44 19696012
2007 Identification of a dominant epitope in human vaccinia-related kinase 1 (VRK1) and detection of different intracellular subpopulations. Archives of biochemistry and biophysics 43 17617371
2018 Implication of the VRK1 chromatin kinase in the signaling responses to DNA damage: a therapeutic target? Cellular and molecular life sciences : CMLS 42 29679095
2018 VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis. Cellular and molecular life sciences : CMLS 39 29340707
2008 Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities. Molecular & cellular proteomics : MCP 39 18617507
2014 VRK1 interacts with p53 forming a basal complex that is activated by UV-induced DNA damage. FEBS letters 38 24492002
2014 Vaccinia-related kinase 1 (VRK1) confers resistance to DNA-damaging agents in human breast cancer by affecting DNA damage response. Oncotarget 38 24731990
2007 Alteration of the VRK1-p53 autoregulatory loop in human lung carcinomas. Lung cancer (Amsterdam, Netherlands) 38 17689819
2011 Differential inhibitor sensitivity between human kinases VRK1 and VRK2. PloS one 37 21829721
2011 Macro histone H2A1.2 (macroH2A1) protein suppresses mitotic kinase VRK1 during interphase. The Journal of biological chemistry 36 22194607
2011 NMR solution structure of human vaccinia-related kinase 1 (VRK1) reveals the C-terminal tail essential for its structural stability and autocatalytic activity. The Journal of biological chemistry 35 21543316
2013 Molecular genetic analysis of VRK1 in mammary epithelial cells: depletion slows proliferation in vitro and tumor growth and metastasis in vivo. Oncogenesis 34 23732708
2012 HnRNP A1 phosphorylated by VRK1 stimulates telomerase and its binding to telomeric DNA sequence. Nucleic acids research 34 22740652
2015 The spinal muscular atrophy with pontocerebellar hypoplasia gene VRK1 regulates neuronal migration through an amyloid-β precursor protein-dependent mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 25609612
2015 VRK1 regulates Cajal body dynamics and protects coilin from proteasomal degradation in cell cycle. Scientific reports 32 26068304
2022 VRK1 Is a Synthetic-Lethal Target in VRK2-Deficient Glioblastoma. Cancer research 31 36069976
2019 Olaparib and ionizing radiation trigger a cooperative DNA-damage repair response that is impaired by depletion of the VRK1 chromatin kinase. Journal of experimental & clinical cancer research : CR 31 31101118
2016 Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia. Neurology 31 27281532
2016 VRK1 phosphorylates and protects NBS1 from ubiquitination and proteasomal degradation in response to DNA damage. Biochimica et biophysica acta 30 26869104
2015 Expanding Phenotype of VRK1 Mutations in Motor Neuron Disease. Journal of clinical neuromuscular disease 29 26583493
2011 The kinase VRK1 is required for normal meiotic progression in mammalian oogenesis. Mechanisms of development 29 21277975
2021 HNRNP A1 Promotes Lung Cancer Cell Proliferation by Modulating VRK1 Translation. International journal of molecular sciences 28 34071140
2017 Expression of VRK1 and the downstream gene BANF1 in esophageal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 28 28298069
2020 VRK-1 extends life span by activation of AMPK via phosphorylation. Science advances 26 32937443
2020 VRK1 Phosphorylates Tip60/KAT5 and Is Required for H4K16 Acetylation in Response to DNA Damage. Cancers 26 33076429
2021 Circular RNA VRK1 facilitates pre-eclampsia progression via sponging miR-221-3P to regulate PTEN/Akt. Journal of cellular and molecular medicine 25 33738906
2019 VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes. Scientific reports 25 31527692
2017 VRK1 promotes cisplatin resistance by up-regulating c-MYC via c-Jun activation and serves as a therapeutic target in esophageal squamous cell carcinoma. Oncotarget 25 29029460
2017 Glucose elicits serine/threonine kinase VRK1 to phosphorylate nuclear pregnane X receptor as a novel hepatic gluconeogenic signal. Cellular signalling 24 28911860
2018 Overexpression of the VRK1 kinase, which is associated with breast cancer, induces a mesenchymal to epithelial transition in mammary epithelial cells. PloS one 23 30180179
2010 Genome-wide analysis of germ cell proliferation in C.elegans identifies VRK-1 as a key regulator of CEP-1/p53. Developmental biology 23 20599896
2008 The C/H3 domain of p300 is required to protect VRK1 and VRK2 from their downregulation induced by p53. PloS one 23 18612383
2019 A novel mutation in VRK1 associated with distal spinal muscular atrophy. Journal of human genetics 22 30617279
2019 Loss of Cajal bodies in motor neurons from patients with novel mutations in VRK1. Human molecular genetics 22 31090908
2022 Multivalent DNA and nucleosome acidic patch interactions specify VRK1 mitotic localization and activity. Nucleic acids research 21 35390161
2022 VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system. JCI insight 21 36040810
2015 High VRK1 expression contributes to cell proliferation and survival in hepatocellular carcinoma. Pathology, research and practice 20 26706601
2018 A novel VRK1 mutation associated with recessive distal hereditary motor neuropathy. Annals of clinical and translational neurology 18 30847374
2020 Identification of VRK1 as a New Neuroblastoma Tumor Progression Marker Regulating Cell Proliferation. Cancers 17 33233777
2019 Motor neuron diseases caused by a novel VRK1 variant - A genotype/phenotype study. Annals of clinical and translational neurology 17 31560180
2021 VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells. Frontiers in cell and developmental biology 16 34195200
2020 Downregulation of VRK1 reduces the expression of BANF1 and suppresses the proliferative and migratory activity of esophageal cancer cells. Oncology letters 15 32724356
2009 Protein kinase VRK-1 regulates cell invasion and EGL-17/FGF signaling in Caenorhabditis elegans. Developmental biology 15 19679119
2019 Novel VRK1 Mutations in a Patient with Childhood-onset Motor Neuron Disease. Internal medicine (Tokyo, Japan) 14 31178479
2020 VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy. Annals of clinical and translational neurology 13 32365420
2018 Vrk1 partial Knockdown in Mice Results in Reduced Brain Weight and Mild Motor Dysfunction, and Indicates Neuronal VRK1 Target Pathways. Scientific reports 13 30050127
2023 The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase. Epigenetics & chromatin 12 37179361
2022 Ankle2 deficiency-associated microcephaly and spermatogenesis defects in zebrafish are alleviated by heterozygous deletion of vrk1. Biochemical and biophysical research communications 12 35940133
2020 Identification of a homozygous VRK1 mutation in two patients with adult-onset distal hereditary motor neuropathy. Muscle & nerve 12 31837156
2017 Comparative Interactomes of VRK1 and VRK3 with Their Distinct Roles in the Cell Cycle of Liver Cancer. Molecules and cells 12 28927264
2016 Oncogenic Sox2 regulates and cooperates with VRK1 in cell cycle progression and differentiation. Scientific reports 12 27334688
2023 VRK1 Kinase Activity Modulating Histone H4K16 Acetylation Inhibited by SIRT2 and VRK-IN-1. International journal of molecular sciences 11 36902348
2023 VRK1 variants at the cross road of Cajal body neuropathogenic mechanisms in distal neuropathies and motor neuron diseases. Neurobiology of disease 10 37257665
2022 Dissecting the roles of Haspin and VRK1 in histone H3 phosphorylation during mitosis. Scientific reports 10 35778595
2022 The VRK1 chromatin kinase regulates the acetyltransferase activity of Tip60/KAT5 by sequential phosphorylations in response to DNA damage. Biochimica et biophysica acta. Gene regulatory mechanisms 10 36280132
2021 Adult-Onset Spinal Muscular Atrophy due to Mutations in the VRK1 Gene. Neurology. Genetics 10 34169149
2020 VRK1 variants in two Portuguese unrelated patients with childhood-onset motor neuron disease. Amyotrophic lateral sclerosis & frontotemporal degeneration 10 32242460
2022 Distal spinal muscular atrophy featured by predominant calf muscle involvement in VRK1 associated disease - Case series and review. Neuromuscular disorders : NMD 8 35641352
2021 Dysfunctional Homozygous VRK1-D263G Variant Impairs the Assembly of Cajal Bodies and DNA Damage Response in Hereditary Spastic Paraplegia. Neurology. Genetics 8 34504951
2025 Histone Lactylation-Driven Upregulation of VRK1 Expression Promotes Stemness and Proliferation of Glioma Stem Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 7 40990975
2021 The Vaccinia Virus B12 Pseudokinase Represses Viral Replication via Interaction with the Cellular Kinase VRK1 and Activation of the Antiviral Effector BAF. Journal of virology 7 33177193
2021 VRK1 promotes proliferation, migration, and invasion of gastric carcinoma cells by activating β-catenin. Neoplasma 7 34374295
2016 Expression of vaccinia-related kinase 1 (VRK1) accelerates cell proliferation but overcomes cell adhesion mediated drug resistance (CAM-DR) in multiple myeloma. Hematology (Amsterdam, Netherlands) 6 27319807
2023 Behavioral and neurological effects of Vrk1 deficiency in zebrafish. Biochemical and biophysical research communications 5 37429068
2023 Downregulation of VRK1 Inhibits Progression of Lung Squamous Cell Carcinoma through DNA Damage. Canadian respiratory journal 5 37547297
2024 Loss of VRK1 alters the nuclear phosphoproteome in the DNA damage response to doxorubicin. Chemico-biological interactions 4 38367682
2024 VRK1 promotes DNA-induced type I interferon production. Molecular biology reports 4 38536553
2024 ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons. Neurobiology of disease 4 38806131
2022 Inhibition of VRK1 suppresses proliferation and migration of vascular smooth muscle cells and intima hyperplasia after injury via mTORC1/β-catenin axis. BMB reports 4 35410639
2024 VRK1 Regulates Sensitivity to Oxidative Stress by Altering Histone Epigenetic Modifications and the Nuclear Phosphoproteome in Tumor Cells. International journal of molecular sciences 3 38732093
2019 Ras-PI3K pathway promotes osteosarcoma progression via regulating VRK1-mediated H2A phosphorylation at threonine 120. Artificial cells, nanomedicine, and biotechnology 3 31810390
2025 VRK1/BANF1/GLI1 Axis Regulates Tumor Development and Progression of Colorectal Cancer. International journal of biological sciences 2 40384864
2024 Pathogenic effects of Leu200Pro and Arg387His VRK1 protein variants on phosphorylation targets and H4K16 acetylation in distal hereditary motor neuropathy. Journal of molecular medicine (Berlin, Germany) 2 38554151
2024 Nuclear functions regulated by the VRK1 kinase. Nucleus (Austin, Tex.) 2 38753965
2022 Dysregulation of Cellular VRK1, BAF, and Innate Immune Signaling by the Vaccinia Virus B12 Pseudokinase. Journal of virology 2 35543552
2025 Lentinan suppresses the progression of neuroblastoma by inhibiting FOS-mediated transcription activation of VRK1 to stabilize p53 protein. Cell death discovery 1 40089488
2025 VRK1 promotes epithelial-mesenchymal transition in hepatocellular carcinoma mediated by SNAI1 via phosphorylating CHD1L. Cell death & disease 1 40234378
2024 Inactivation of VRK1 sensitizes ovarian cancer to PARP inhibition through regulating DNA-PK stability. Experimental cell research 1 38614421
2024 CMT2 and distal hereditary motor neuropathy associated with VRK1 variants: Case series. Neuromuscular disorders : NMD 1 39693713
2023 Circ VRK1/microRNA-17/PTEN axis modulates the angiogenesis of human brain microvascular endothelial cells to affect injury induced by oxygen-glucose deprivation/reperfusion. BMC neuroscience 1 36707796
2025 VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix. Cancer science 0 41111449