Affinage

HIPK2

Homeodomain-interacting protein kinase 2 · UniProt Q9H2X6

Length
1198 aa
Mass
131.0 kDa
Annotated
2026-06-10
100 papers in source corpus 61 papers cited in narrative 61 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HIPK2 is a nuclear DYRK-family serine/threonine kinase that acts as a stress-responsive signaling hub coupling genotoxic and ER stress to apoptotic gene expression, developmental transcriptional control, and cytokinesis (PMID:11120354, PMID:17349959, PMID:22658722). Its catalytic activity depends on cis-autophosphorylation of activation-loop residues Y354 and S357, which is required for substrate binding and for nuclear retention, and a crystal structure of the kinase domain confirms an active conformation with a CMGC-insert region structurally unique among DYRK kinases (PMID:23000554, PMID:23485397, PMID:31341017). HIPK2 localizes to subnuclear HIPK domains and is recruited to PML nuclear bodies through both covalent SUMO-1 modification at Lys25 and a non-covalent SUMO-interacting motif, and this PML/SUMO-dependent compartmentalization is required for HIPK2-mediated p53 Ser46 phosphorylation and apoptosis (PMID:10535925, PMID:12907596, PMID:15958389, PMID:21145359, PMID:21192925). The central pro-apoptotic output is phosphorylation of p53 at Ser46—potentiated by the Axin/Daxx scaffold and by inhibitory phosphorylation of SIRT1 (Ser682) that permits p53 acetylation—driving selective apoptotic and antioxidant target gene expression (PMID:15526030, PMID:17210684, PMID:26113041). HIPK2 stability is the principal switch governing this decision: in unstressed or growth states it is held low by E3 ligases Siah-1, Siah2, MDM2, and SCF(Fbx3), while DNA damage (via ATM/ATR), the stabilizers Zyxin, XAF1, PML, and Pin1, and oncogenic regulators (HIF-1α, Src) tune its abundance to set the apoptotic threshold (PMID:17349959, PMID:18536714, PMID:19043406, PMID:18809579, PMID:21248071, PMID:24145406, PMID:24196445, PMID:25313037). Beyond p53, HIPK2 directly phosphorylates and degrades anti-apoptotic ΔNp63α (T397) and the WIP1 phosphatase, represses Wnt/β-catenin signaling by phosphorylating β-catenin at Ser33/37 for degradation, modulates TGF-β-Smad, JNK, NF-κB (via HDAC3 Ser374), and NRF2 pathways, and controls cytokinetic abscission by phosphorylating histone H2B (S14) and the severing enzyme spastin (S268) at the midbody (PMID:20307497, PMID:21602882, PMID:22658722, PMID:23871434, PMID:31284535, PMID:34244427). Through these activities HIPK2 functions in neuronal survival and development and is a driver of organ fibrosis and pathological cardiac remodeling (PMID:15492043, PMID:17159989, PMID:22406746, PMID:36182775).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1999 High

    Established HIPK2 as a SUMO-modified nuclear-speckle protein, defining its subnuclear localization machinery before any catalytic function was known.

    Evidence Yeast two-hybrid with mUBC9, co-IP, and localization in cells

    PMID:10535925

    Open questions at the time
    • Functional consequence of SUMOylation not resolved
    • No link to kinase activity established at this stage
  2. 2000 Medium

    Placed HIPK2 in the DYRK kinase subfamily and showed a conserved catalytic lysine is essential, defining it as a bona fide kinase.

    Evidence Sequence alignment and kinase-dead catalytic-lysine mutant assay

    PMID:11120354

    Open questions at the time
    • No physiological substrate identified
    • Activation mechanism unknown
  3. 2001 Medium

    Connected HIPK2 to the p53 pathway and cell-cycle control, showing it stabilizes p53 and lowers MDM2 in a kinase-dependent manner.

    Evidence Overexpression, reporter assays, kinase-dead mutant, and flow cytometry; in vitro HMGI(Y) phosphorylation

    PMID:11532197 PMID:11593421

    Open questions at the time
    • Direct p53 phosphosite not yet identified
    • Mechanism of MDM2 reduction unresolved
  4. 2002 High

    Identified HIPK2 as a cofactor of p53-family transcription factors, linking it to nuclear-body-localized apoptotic transcription.

    Evidence Yeast two-hybrid, GST pulldown, co-IP, confocal microscopy, reporter and FACS assays with p73/p53; RanBPM interaction

    PMID:11925430 PMID:12220523

    Open questions at the time
    • RanBPM interaction has no functional follow-up
    • Kinase-substrate relationship with p73 not defined
  5. 2003 High

    Defined PML nuclear bodies and Daxx as the platform for HIPK2 apoptotic signaling, showing PML is required for p53 Ser46 phosphorylation and HIPK2 activates JNK via Daxx in TGF-β apoptosis.

    Evidence Immunofluorescence, PML-knockout fibroblasts, co-IP, in vitro kinase assay, siRNA, JNK/apoptosis assays; TP53INP1 cooperation

    PMID:12565818 PMID:12851404 PMID:12907596 PMID:14678985

    Open questions at the time
    • PML isoform recruitment determinants only partly mapped
    • Direct Daxx phosphosite not defined
  6. 2004 High

    Identified Axin as a scaffold that stimulates HIPK2-mediated p53 Ser46 phosphorylation and established HIPK2 in Wnt-linked transcription factor control (NLK/c-Myb, Brn3a, HMGA1).

    Evidence Co-IP, siRNA, kinase-dead and domain mutants, reporter and apoptosis assays, HIPK2-knockout mice with neuronal phenotypes

    PMID:14990717 PMID:15082531 PMID:15492043 PMID:15526030

    Open questions at the time
    • How Axin relieves the putative autoinhibitory domain unresolved
    • In vivo relevance of c-Myb axis not tested in mammals
  7. 2005 High

    Showed HIPK2 SUMOylation is phosphorylation-dependent and functionally selective, fine-tuning interactions (Groucho, JNK) and identified MDM2 as both substrate and target, and PCAF cooperation for p21 induction.

    Evidence In vitro SUMOylation/desumoylation, kinase-dead mutants, ChIP, reporter assays, SuPr-1 and SENP1 analyses; in vitro MDM2 kinase assay

    PMID:15896780 PMID:15897882 PMID:15958389 PMID:16212962 PMID:16253240

    Open questions at the time
    • MDM2 phosphosite not mapped
    • Reciprocal regulation of SUMO and ubiquitin pathways not integrated
  8. 2006 High

    Demonstrated HIPK2 as a transcriptional kinase activating AML1/p300 acetyltransferase activity and as essential for TGF-β-Smad survival of dopamine neurons, established with genetic knockouts.

    Evidence Co-IP, in vitro kinase assay, HAT assay, Hipk1/2 double-knockout and Hipk2-knockout mice with Smad interaction

    PMID:16917507 PMID:17159989

    Open questions at the time
    • Direct Smad phosphorylation not demonstrated
    • AML1/p300 phosphosites not all mapped
  9. 2007 High

    Established the abundance-based apoptotic switch: MDM2 degrades HIPK2 to enforce growth arrest, while HIPK2 represses Wnt/LEF1 targets via CtBP, with Daxx refining p53 target selection.

    Evidence Degradation-resistant HIPK2 mutant, MDM2 overexpression, siRNA, YH-domain deletion, HIPK2-knockout mice, skin carcinogenesis model

    PMID:17210684 PMID:17349959 PMID:17666529

    Open questions at the time
    • Threshold setting the arrest-versus-apoptosis decision not quantified
    • CtBP recruitment determinants partly mapped
  10. 2008 High

    Defined Siah-1 and Siah2 as the core E3 ligases controlling HIPK2 stability and showed DNA damage (ATM/ATR-Siah-1 Ser19) and hypoxia reciprocally regulate this destruction.

    Evidence Co-IP, ubiquitination assays, siRNA, ATM/ATR inhibition, Siah2-knockout cells, phosphosite mapping; PML/SCF(Fbx3) protection; ZBTB4 substrate identification

    PMID:18536714 PMID:18809579 PMID:19043406 PMID:19448668

    Open questions at the time
    • Integration of multiple competing ligases not resolved
    • ZBTB4 phosphosite not mapped
  11. 2010 High

    Extended HIPK2 substrate range to direct β-catenin Ser33/37 phosphorylation (Wnt repression), ATF1 (antioxidant gene control), and refined SUMO/SIM-based PML targeting.

    Evidence In vitro kinase assays, mutagenesis, siRNA, reporter assays, HIPK2-null MEFs, Xenopus embryo and DCAF7/Han11 scaffold studies

    PMID:20307497 PMID:20940704 PMID:20980392 PMID:21145359

    Open questions at the time
    • Priming-independent β-catenin recognition mechanism not structurally explained
    • Han11 scaffold stoichiometry undefined
  12. 2011 High

    Identified ΔNp63α (T397) as a degradation substrate linking HIPK2 to chemosensitivity, and expanded the stability network (Zyxin, HIF-1α) controlling HIPK2-dependent p53 Ser46 signaling.

    Evidence In vitro kinase assay, site mutagenesis, siRNA, cell survival assays; co-IP and dimerization assays for Zyxin/Siah-1; HIF-1α perturbations

    PMID:21248071 PMID:21248371 PMID:21602882

    Open questions at the time
    • In vivo ΔNp63α axis not tested in mice
    • HIF-1α-HIPK2 degradation lacks ligase identity
  13. 2012 High

    Revealed a non-transcriptional role in cytokinesis through histone H2B Ser14 phosphorylation at the midbody and established HIPK2 as a pathway-integrating driver of organ fibrosis.

    Evidence In vitro kinase assay, HIPK2 knockout/RNAi, phosphomimetic H2B-S14D rescue, live imaging; Hipk2-knockout mice in multiple kidney fibrosis models

    PMID:22406746 PMID:22658722

    Open questions at the time
    • How H2B-S14P drives abscission mechanically unresolved
    • Relative contribution of p53/TGF-β/Wnt arms to fibrosis not dissected
  14. 2013 High

    Defined the activation mechanism (cis-autophosphorylation of Y354/S357 and Thr880/Ser882 creating a Pin1 docking signal) and added WIP1 as a substrate plus scaffold/upstream regulators (Han11, Src, TAK1-Y361).

    Evidence In vitro autophosphorylation and kinase assays, mutagenesis, ubiquitination assays, zebrafish models, knockout mice, MS phosphosite mapping, co-IP

    PMID:20940704 PMID:23000554 PMID:23485397 PMID:23565059 PMID:23871434 PMID:24145406 PMID:24196445

    Open questions at the time
    • How tyrosine autophosphorylation switches to S/T specificity not fully explained
    • Multiple upstream kinase inputs not integrated into one model
  15. 2014 High

    Added XAF1 as a Siah2 antagonist stabilizing HIPK2, and uncovered a kinase-independent role supporting Dvl via PP1c, embedding HIPK2 in both positive and negative Wnt regulation.

    Evidence Co-IP, ubiquitination assays, domain mutants, p53 phosphorylation assays; PP1c/Dvl co-IP, ubiquitination, zebrafish Wnt assays

    PMID:25159144 PMID:25313037

    Open questions at the time
    • Reconciliation of HIPK2 as both β-catenin-degrading and Dvl-stabilizing unresolved
    • XAF1 regulation upstream not defined
  16. 2015 High

    Showed HIPK2 phosphorylates SIRT1 (Ser682) to disrupt the SIRT1-AROS complex and permit p53 acetylation, mechanistically linking HIPK2 to acetylation-dependent apoptotic gene expression.

    Evidence In vitro kinase assay, SIRT1 activity assay, co-IP, ChIP, PML knockdown

    PMID:26113041

    Open questions at the time
    • Selectivity over SIRT1's many substrates not addressed
    • In vivo SIRT1-Ser682 relevance untested
  17. 2016 High

    Identified ER stress as an activating input (Ser359/Thr360 activation-loop phosphorylation) driving IRE1α-ASK1-JNK death, with disease relevance in ALS, and extended fibrosis/diabetic nephropathy roles.

    Evidence Phospho-specific antibodies, HIPK2-knockout mice in SOD1G93A ALS model, kinase assays; siRNA and diabetic mouse model for MeCP2/miR-25; DCAF7-E1A adaptor study

    PMID:27307198 PMID:27321923 PMID:27941951

    Open questions at the time
    • Upstream kinase phosphorylating the activation loop under ER stress unidentified
    • MeCP2 phosphosite not mapped
  18. 2017 Medium

    Established a bidirectional HIPK2-NRF2 regulatory loop, placing HIPK2 within antioxidant/redox transcriptional control.

    Evidence ChIP identifying NRF2 binding site, reporter assays, gain/loss-of-function, HIPK2-knockout mice

    PMID:28692050

    Open questions at the time
    • Whether HIPK2 directly phosphorylates NRF2 not established
    • Physiological trigger of the loop undefined
  19. 2018 High

    Linked HIPK2-JNK-c-Jun signaling to transcriptional repression of NMDA receptor subunit genes, extending its role in neuronal signaling and survival.

    Evidence Hipk2-knockout mice, transcriptomics, JNK assays, synaptic fractionation, electrophysiology

    PMID:29581378

    Open questions at the time
    • Direct transcriptional targets of HIPK2 vs c-Jun not separated
    • Mechanism of subunit-selective repression unclear
  20. 2019 High

    Provided the active-conformation crystal structure and a second cytokinetic substrate (spastin Ser268), and identified STAT3-driven HIPK2 transcription in kidney injury.

    Evidence X-ray crystallography at 2.2 Å with CX-4945; in vitro kinase assay, phosphomimetic/non-phosphorylatable spastin mutants, abscission assays; ChIP for STAT3

    PMID:31131063 PMID:31284535 PMID:31341017

    Open questions at the time
    • Structure of full-length or substrate-bound HIPK2 lacking
    • Coordination of H2B and spastin phosphorylation at midbody not integrated
  21. 2021 High

    Defined HIPK2-HDAC3 (Ser374) suppression of NF-κB inflammation and an ATM-SPOP non-degradative ubiquitination axis driving HP1γ phosphorylation in DNA repair, plus cardiac apoptosis roles.

    Evidence In vitro kinase and HDAC3 activity assays, knockout mice, sepsis models; co-IP, ubiquitination, SPOP mutants, ChIP; HIPK2-knockout/inhibitor MI models

    PMID:34133717 PMID:34244427 PMID:34837851

    Open questions at the time
    • How non-degradative ubiquitination alters HIPK2 catalysis unresolved
    • Tissue-specific selectivity of HDAC3 vs other substrates undefined
  22. 2022 Medium

    Mapped HIPK2 effectors (EGR3/CLEC4D via ERK1/2-CREB; Smad3) in pathological cardiac remodeling, supporting HIPK2 inhibition as a cardioprotective strategy.

    Evidence HIPK2-knockout mice, pharmacological inhibitors, microarray, siRNA rescue, TAC model

    PMID:36182775

    Open questions at the time
    • Whether EGR3/CLEC4D are direct HIPK2 transcriptional outputs unclear
    • Cell-type-specific kinase substrates in heart not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HIPK2 integrates its many competing upstream regulators and broad substrate repertoire into context-specific decisions (survival vs apoptosis, transcriptional vs cytokinetic) remains unresolved.
  • No structure of substrate- or scaffold-bound HIPK2
  • No systematic map of which inputs dominate in each tissue
  • Quantitative model of the stability-based apoptotic threshold lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 3 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5357801 Programmed Cell Death 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-73894 DNA Repair 3 R-HSA-1640170 Cell Cycle 2
Partners
AXIN1DAXXMDM2PIN1PMLSIAH1SIAH2TP53

Evidence

Reading pass · 61 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 HIPK2 is covalently modified by SUMO-1 at nuclear speckles. HIPK2 contains a speckle-retention signal that interacts with the SUMO E2 conjugating enzyme mUBC9, and SUMO-1 modification correlates with HIPK2 localization to nuclear speckles (dots). Yeast two-hybrid, co-immunoprecipitation, cell-based localization Proceedings of the National Academy of Sciences of the United States of America High 10535925
2000 HIPK2 is a member of the DYRK kinase subfamily; a conserved lysine residue in the kinase domain is essential for HIPK2 kinase function. Sequence alignment, kinase-dead mutant functional assay Biochimie Medium 11120354
2001 HIPK2 interacts with HMGI(Y) proteins through its PEST domain and phosphorylates HMGI(Y) in vitro; HIPK2 overexpression induces G2/M cell cycle arrest. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, colony assay, flow cytometry Oncogene Medium 11593421
2001 HIPK2 overexpression stabilizes p53 protein and decreases MDM2 protein levels (post-transcriptionally), thereby increasing p53 transcriptional activity; kinase-dead HIPK2 does not produce these effects. Overexpression, reporter assay, western blot, kinase-dead mutant BMC molecular biology Medium 11532197
2002 HIPK2 interacts with RanBPM in the nucleus; both wild-type and kinase-dead HIPK2 co-localize with RanBPM in defined nuclear structures. Yeast two-hybrid, co-immunoprecipitation, co-localization Biochemical and biophysical research communications Low 12220523
2002 HIPK2 interacts with p73α via the oligomerization domain region (aa 812-907 of HIPK2), co-localizes with p73 and p53 in nuclear bodies, and potentiates p73/p53-induced transcriptional repression and apoptotic response to genotoxic drugs. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, confocal microscopy, reporter assay, FACS The Journal of biological chemistry High 11925430
2003 Endogenous HIPK2 and HIPK3 reside in novel subnuclear HIPK domains distinct from PML-NBs; PML isoform IV (but not III) recruits HIPK2 to PML-NBs; PML is required for HIPK2-mediated p53 Ser46 phosphorylation and antiproliferative function. Immunofluorescence, confocal microscopy, PML-knockout fibroblasts, functional reporter assay Cancer research High 12907596
2003 HIPK2 co-localizes with Daxx in PML nuclear bodies, interacts with Daxx in vitro and in vivo via its kinase domain, phosphorylates Daxx, and activates the JNK pathway (via Daxx-MKK4/MKK7) to potentiate TGF-β-induced apoptosis; RNAi knockdown of HIPK2 inhibits TGF-β-induced JNK activation. Co-immunoprecipitation, in vitro binding, in vitro kinase assay, siRNA knockdown, JNK activation assay, apoptosis assay Cancer research High 14678985
2003 TP53INP1 isoforms physically interact with HIPK2 and p53, co-localize in PML nuclear bodies, and cooperate with HIPK2 to regulate p53 transcriptional activity on p21, mdm2, pig3, and bax promoters. Co-immunoprecipitation, confocal microscopy, reporter assay, overexpression The Journal of biological chemistry Medium 12851404
2003 HIPK2 (PKM) modifies PML nuclear body (ND10) structure through both its kinase domain and a SUMO-1 interaction motif, and alters post-translational modification of PML. Overexpression, immunofluorescence, western blot Experimental cell research Medium 12565818
2004 Axin interacts with HIPK2 and forms a multimeric complex with p53; Axin stimulates HIPK2-mediated phosphorylation of p53 at Ser46, facilitating p53-dependent transcription and apoptosis. The Axin-binding region of HIPK2 acts as a putative autoinhibitory domain. Co-immunoprecipitation, siRNA knockdown, kinase-dead mutant, reporter assay, apoptosis assay The EMBO journal High 15526030
2004 Wnt-1 signal activates a TAK1→HIPK2→NLK pathway that phosphorylates c-Myb at multiple sites through direct NLK-c-Myb interaction facilitated by HIPK2, leading to c-Myb ubiquitination and proteasomal degradation. Co-immunoprecipitation, in vitro kinase assay, overexpression, ubiquitination assay, differentiation assay Genes & development High 15082531
2004 HIPK2 interacts with the POU-domain transcription factor Brn3a, promotes Brn3a DNA binding, but suppresses Brn3a-dependent transcription of brn3a, trkA, and bcl-xL; targeted deletion of HIPK2 increases TrkA and Bcl-xL expression and reduces apoptosis in trigeminal ganglion neurons. Co-immunoprecipitation, reporter assay, HIPK2 knockout mice, immunohistochemistry, neuronal survival assay The Journal of cell biology High 15492043
2004 Herpes simplex virus US11 protein interacts with HIPK2 through the PEST domain of HIPK2, alters HIPK2 subcellular distribution, and protects cells from HIPK2-induced cell growth arrest. Yeast two-hybrid, co-immunoprecipitation, localization, growth assay Journal of virology Medium 14990717
2005 HIPK2 is SUMO-1 modified at Lys25 in vitro and in vivo; this sumoylation is phosphorylation-dependent (kinase-dead HIPK2 is not efficiently sumoylated) and inhibits HIPK2-induced JNK activation and p53-independent antiproliferative function. SUMO protease SuPr-1 co-localizes with HIPK2 in PML nuclear bodies and deconjugates SUMO-1 from HIPK2. In vitro SUMOylation, co-immunoprecipitation, siRNA, reporter assay, kinase-dead mutant The Journal of biological chemistry High 15958389
2005 HIPK2 depletion inhibits PCAF-mediated p53 acetylation and p53 binding to the p21Waf1 promoter following nonapoptotic DNA damage; HIPK2 cooperates with PCAF to selectively induce p53 transcriptional activity toward p21Waf1. siRNA knockdown, chromatin immunoprecipitation, reporter assay, western blot Oncogene Medium 15897882
2005 Phosphorylation-dependent SUMO modification of HIPK2 at Lys25 differentially regulates its interactions: sumoylation disrupts interaction with Groucho corepressor and inhibits HIPK2 regulation of Groucho-mediated transcriptional repression, but does not affect p53-mediated transactivation. In vitro SUMOylation, co-immunoprecipitation, reporter assay, kinase-dead mutant FEBS letters Medium 15896780
2005 HIPK2 interacts with MDM2 in vitro and in vivo, phosphorylates MDM2 in vitro, and promotes MDM2 nuclear export and proteasomal degradation in a p53-independent manner; additionally, HIPK2-dependent p53 Ser46 phosphorylation suppresses MDM2 at the transcriptional level. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, western blot, subcellular fractionation FEBS letters Medium 16212962
2005 SENP1 desumoylates HIPK2 both in vitro and in vivo; desumoylation of HIPK2 by SENP1 leads to dissociation of HIPK2 from nuclear bodies; SENP1 contains a nuclear export sequence regulating its cytoplasmic-nuclear shuttling which in turn controls HIPK2 desumoylation. In vitro desumoylation assay, co-immunoprecipitation, SENP1 mutant analysis, localization FEBS letters Medium 16253240
2006 HIPK2 forms a complex with AML1 and p300, phosphorylates both AML1 and p300 to stimulate their transcriptional and histone acetyltransferase (HAT) activities; p300 phosphorylation is triggered by phosphorylated AML1 as well as by PU.1, c-MYB, c-JUN and c-FOS. In Hipk1/2 double-knockout mouse embryos, phosphorylation of AML1 and p300 is impaired. Co-immunoprecipitation, in vitro kinase assay, HAT activity assay, double-knockout mice The EMBO journal High 16917507
2006 HIPK2 is required for TGFβ-mediated survival of midbrain dopamine neurons; HIPK2 function depends on its interaction with receptor-regulated Smads to activate TGFβ target genes; loss of HIPK2 causes selective dopamine neuron apoptosis during programmed cell death. Hipk2 knockout mice, TGFβ3 survival assay, Smad interaction studies Nature neuroscience High 17159989
2007 MDM2-mediated proteasomal degradation of HIPK2 prevents p53 Ser46 phosphorylation during cytostatic (non-severe) DNA damage; a degradation-resistant HIPK2 mutant converts growth arrest to apoptosis. p53 actively represses HIPK2 via MDM2 to inhibit the apoptotic pathway. Degradation-resistant HIPK2 mutant, MDM2 overexpression, siRNA, p53 Ser46 phosphorylation assay, apoptosis assay Molecular cell High 17349959
2007 Daxx associates with the Axin/HIPK2/p53 complex; Axin-Daxx interaction is enhanced by UV irradiation, and Axin tethers Daxx to p53 to cooperate with HIPK2-mediated Ser46 phosphorylation and selectively activate PUMA expression. Co-immunoprecipitation, siRNA knockdown, reporter assay, colony formation assay, cell death assay Cancer research Medium 17210684
2007 HIPK2 suppresses LEF1/β-catenin-mediated transcriptional activation of cyclin D1 by recruiting the corepressor CtBP through its C-terminal YH domain; deletion of the YH domain abolishes CtBP recruitment and loss of HIPK2 expands the epidermal stem cell compartment. HIPK2 knockout mice, reporter assay, YH-domain deletion mutant, gene expression analysis, skin carcinogenesis model Proceedings of the National Academy of Sciences of the United States of America High 17666529
2007 HIPK2 phosphorylates HMGA1a at Ser-35, Thr-52, and Thr-77 (and HMGA1b at Thr-41 and Thr-66), reducing HMGA1a binding affinity to DNA; the site preference of HIPK2 differs from that of cdc2. In vitro kinase assay, mass spectrometry, electrophoretic mobility shift assay Journal of proteome research Medium 17960875
2008 HIPK2 is an unstable protein that interacts with E3 ubiquitin ligase Siah-1 in unstressed cells; Siah-1 knockdown increases HIPK2 stability, and Siah-1 promotes HIPK2 polyubiquitination and proteasomal degradation. DNA damage disrupts the HIPK2-Siah-1 complex via ATM/ATR-dependent phosphorylation of Siah-1 at Ser19, stabilizing HIPK2. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, ATM/ATR inhibitor, phosphorylation site mutant Nature cell biology High 18536714
2008 Under normoxia, HIPK2 phosphorylates Siah2 at Ser26, Ser28, and Ser68, weakening mutual binding and destabilizing Siah2. Hypoxia increases HIPK2/Siah2 interaction, enabling efficient HIPK2 polyubiquitylation and proteasomal degradation; hypoxia-induced HIPK2 elimination is reduced in Siah2-deficient cells. Co-immunoprecipitation, ubiquitination assay, Siah2-knockout cells, hypoxia treatment, phosphorylation mapping Nature cell biology High 19043406
2008 PML protects HIPK2 and p300 from SCFFbx3-mediated proteasomal degradation; Fbx3 forms SCF(Fbx3) ubiquitin ligase that promotes ubiquitin-proteasome degradation of HIPK2; PML, Fbx3, and HIPK2 synergistically activate p53-induced transcription. The leukemia-associated PML-RARα induces HIPK2 degradation. Purification of PML complex, co-immunoprecipitation, ubiquitination assay, reporter assay Molecular and cellular biology High 18809579
2009 HIPK2 phosphorylates the transcription factor ZBTB4, leading to its proteasomal degradation under normal growth conditions and upon DNA damage; kinase-deficient HIPK2 does not cause ZBTB4 degradation; the two proteins interact in vitro and colocalize in vivo. In vitro binding, co-immunoprecipitation, kinase-dead mutant, siRNA, western blot Oncogene Medium 19448668
2009 Siah1 is an E3 ubiquitin ligase for HIPK2, targeting it for poly-ubiquitination and proteasomal degradation; this degradation is blocked by MLK-3, EBV LMP-1, or DNA-damaging stimuli. Co-immunoprecipitation, ubiquitination assay, DNA damage treatment, western blot Cancer letters Medium 19250734
2010 HIPK2 is a new kinase for ATF1, phosphorylating it at Ser198 (not Ser63); HIPK2 overrides ATF1-mediated repression of ferritin H and other antioxidant genes at the ARE in a kinase-activity-dependent manner; induction of antioxidant genes by genotoxic stress is impaired in HIPK2-null MEFs. In vitro kinase assay, HIPK2-null MEFs, reporter assay, RT-PCR Journal of cell science High 20980392
2010 HIPK2 phosphorylates β-catenin at Ser33 and Ser37, targeting it for proteasomal degradation without requiring a priming kinase; HIPK2 knockdown increases β-catenin nuclear accumulation and Wnt target gene expression; co-injection of HIPK2 mRNA blocks β-catenin-induced axis duplication in Xenopus embryos. In vitro kinase assay, site-directed mutagenesis, siRNA, reporter assay, Xenopus embryo assay Biochemical and biophysical research communications High 20307497
2010 HIPK2 contains a SUMO-interacting motif (SIM) that binds all three major SUMO isoforms non-covalently; SIM mutation prevents localization of HIPK2 to nuclear speckles and PML nuclear bodies, disrupts colocalization with Pc2, and alters HIPK2 functional activity. SIM point mutant analysis, co-immunoprecipitation, immunofluorescence, SUMO binding assay Biochimica et biophysica acta Medium 21145359
2010 SIM-mediated HIPK2 recruitment to PML-IV nuclear bodies is required for HIPK2-mediated p53 Ser46 phosphorylation and induction of apoptosis; HIPK2 specifically co-localizes with PML-I and PML-IV, and HIPK2 SIM mutants fail to activate or phosphorylate p53. Mutational analysis, co-immunoprecipitation, immunofluorescence, colony formation assay, p53 phosphorylation assay Experimental cell research Medium 21192925
2011 HIPK2 phosphorylates ΔNp63α at Thr397, promoting its proteasomal degradation in response to DNA damage; the non-phosphorylatable ΔNp63α-T397A mutant is not degraded and confers chemoresistance. In vitro kinase assay, site-directed mutagenesis, siRNA, western blot, cell survival assay Oncogene High 21602882
2011 Zyxin stabilizes HIPK2 by interfering with Siah-1 dimerization; Zyxin co-localizes with HIPK2 at the cytoskeleton and nucleus, physically interacts with Siah-1, and its depletion accelerates HIPK2 proteasomal degradation and reduces DNA damage-induced p53 Ser46 phosphorylation. Co-immunoprecipitation, siRNA knockdown, western blot, p53 phosphorylation assay, caspase activation assay Cancer research Medium 21248071
2011 HIF-1α upregulation induces proteasomal degradation of HIPK2, thereby antagonizing p53-mediated apoptosis; HIF-1α inhibition by siRNA, dominant-negative HIF-1α, or zinc re-establishes HIPK2 levels and p53-mediated chemosensitivity. siRNA knockdown, dominant-negative HIF-1α, zinc supplementation, western blot, apoptosis assay Aging Medium 21248371
2012 HIPK2 binds and phosphorylates histone H2B at S14 (H2B-S14P); HIPK2 and H2B co-localize at the midbody during cytokinesis; HIPK2 depletion causes loss of H2B-S14P at the midbody, cytokinesis failure, and tetra/polyploidization. Phosphomimetic H2B-S14D rescues cytokinesis in HIPK2-null cells. Co-immunoprecipitation, in vitro kinase assay, HIPK2 knockout/RNAi, phosphomimetic mutant rescue, live-cell imaging Molecular cell High 22658722
2012 HIPK2 is a key regulator of kidney fibrosis; it activates p53, TGF-β-Smad3, and Wnt-Notch pathways in renal tubular epithelial cells to drive apoptosis and EMT; HIPK2 knockout attenuates kidney fibrosis in multiple murine models; HIV-induced oxidative stress increases HIPK2 by inhibiting Siah1-mediated proteasomal degradation. Hipk2-knockout mice, siRNA knockdown, pathway activation assays, mouse fibrosis models Nature medicine High 22406746
2012 HIPK2 is heavily autophosphorylated; cis-autophosphorylation at Y354 and S357 in the activation loop is essential for kinase activity, substrate binding, and interaction with Pin1; HIPK2 activation-loop phosphorylation is required for its biological activity as regulator of gene expression and cell proliferation. In vitro kinase assay, phosphosite mutants, cis-autophosphorylation assay, reporter assay, cell proliferation assay Journal of molecular cell biology High 23000554
2013 HIPK2 autophosphorylates at Thr880/Ser882 upon DNA damage; this autophosphorylation creates a binding signal for the phospho-specific isomerase Pin1, which stabilizes HIPK2 by inhibiting its polyubiquitination and modulating Siah-1-HIPK2 interaction; Pin1 is required for DNA damage-induced HIPK2 stabilization, p53 Ser46 phosphorylation, and apoptosis in zebrafish. Autophosphorylation assay, co-immunoprecipitation, ubiquitination assay, zebrafish in vivo model, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 24145406
2013 Autophosphorylation of HIPK2 at activation-loop Y354 is an autocatalytic event essential for S/T-kinase activity; prevention of Y354 phosphorylation by mutagenesis or purvalanol A reduces HIPK2 kinase activity, induces aberrant tyrosine-kinase activity in cis, and causes cytoplasmic relocalization of HIPK2. Site-directed mutagenesis, kinase inhibitor, in vitro kinase assay, subcellular localization Biochimica et biophysica acta High 23485397
2013 HIPK2 identifies WIP1 phosphatase as a substrate, phosphorylating and targeting it for proteasomal degradation in unstressed cells; upon ionizing radiation, ATM-dependent AMPKα2-mediated HIPK2 phosphorylation dissociates WIP1 from HIPK2, allowing WIP1 stabilization and termination of ATM signaling. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, hipk2-knockout mice, γ-H2AX assay, cell cycle checkpoint analysis Molecular cell High 23871434
2013 Han11/DCAF7/WDR68 is a scaffold protein that directly binds HIPK2 and MEKK1, coupling these kinases together; Han11 controls the threshold, amplitude, and kinetics of HIPK2- and MEKK1-driven signaling; loss of Han11 lowers the threshold of HIPK2-triggered transcriptional responses. In vitro binding, co-immunoprecipitation, siRNA knockdown in C. elegans and human cells, reporter assay The EMBO journal High 20940704
2013 Src kinase phosphorylates HIPK2 at nine tyrosine residues (including Tyr354 in the kinase domain), increases HIPK2 half-life by interfering with Siah-1-mediated degradation, and redistributes HIPK2 from the nucleus to the cytoplasm, thereby decreasing drug-induced p53 Ser46 phosphorylation and apoptosis. Mass spectrometry, phosphorylation-specific antibody, co-immunoprecipitation, half-life assay, subcellular fractionation, apoptosis assay Cell cycle (Georgetown, Tex.) Medium 24196445
2013 HIPK1 and HIPK2 are transcriptional corepressors that regulate TGF-β-dependent angiogenesis; TGF-β-TAK1 signaling activates HIPK2 by phosphorylating conserved Y-361 within the kinase domain; point mutation Y361A abolishes HIPK2 corepressor activity; the effect of HIPK2 is mediated through interaction with transcription factor MEF2C. Hipk1/2 knockout mice, siRNA knockdown in endothelial cells, reporter assay, Y361 mutant, co-immunoprecipitation PLoS biology High 23565059
2014 XAF1 blocks Siah2 interaction with and ubiquitination of HIPK2, thereby stabilizing HIPK2 and stimulating HIPK2-mediated Ser46 phosphorylation of p53; XAF1 physically interacts with Siah2 through its zinc finger domains 5 and 6. Co-immunoprecipitation, ubiquitination assay, siRNA, p53 phosphorylation assay, ZF domain mutants Proceedings of the National Academy of Sciences of the United States of America Medium 25313037
2014 Hipk2 and PP1c cooperate to maintain Dvl protein levels; Hipk2 facilitates PP1c-mediated dephosphorylation of Dvl via its C-terminal domain, blocking Itch-mediated ubiquitination and degradation of phosphorylated Dvl; inhibition of Hipk2 or PP1c reduces Dvl levels and suppresses Wnt/β-catenin and Wnt/PCP signaling in cells and zebrafish. Co-immunoprecipitation, ubiquitination assay, siRNA, zebrafish embryo assay, Wnt reporter assay Cell reports High 25159144
2015 HIPK2 phosphorylates SIRT1 at Ser682 upon lethal DNA damage; this phosphorylation inhibits SIRT1 deacetylase activity by disrupting the SIRT1-AROS activator complex, promoting p53 acetylation and apoptotic target gene expression; SIRT1-HIPK2 co-localize at PML nuclear bodies, and PML depletion abrogates SIRT1 Ser682 phosphorylation. Co-immunoprecipitation, in vitro kinase assay, SIRT1 activity assay, siRNA, ChIP, PML-knockdown Cell death and differentiation High 26113041
2016 ER stress (induced by tunicamycin or SOD1G93A) activates HIPK2 by phosphorylating Ser359/Thr360 in its activation loop; activated HIPK2 promotes ER-stress-induced cell death via the IRE1α-ASK1-JNK pathway; loss of HIPK2 delays disease onset and reduces motor neuron death in SOD1G93A ALS mice. Phospho-specific antibody, HIPK2-knockout mice, kinase assay, in vivo ALS model, cell death assay Neuron High 27321923
2016 HIPK2 phosphorylates MeCP2, and the resulting p-MeCP2 suppresses processing of miR-25, leading to elevated NOX4 in diabetic nephropathy; SIAH1 decreases in diabetic glomeruli, correlating with increased HIPK2 protein stability. siRNA knockdown, western blot, qRT-PCR, streptozotocin diabetic mouse model Scientific reports Medium 27941951
2016 DCAF7/WDR68 serves as an adaptor for HIPK2 binding to the adenovirus E1A oncoprotein; DCAF7 is required for HIPK2-mediated hyperphosphorylation of E1A; DCAF7 binds HIPK2 via a conserved 12-amino acid motif; the closely related HIPK1 does not bind DCAF7. Immunoprecipitation, pulldown, DCAF7 motif mutant, overexpression phosphorylation assay Scientific reports Medium 27307198
2017 HIPK2 is a direct transcriptional target of NRF2; a functional NRF2 binding site was identified in the HIPK2 gene locus; HIPK2 is also required for robust NRF2 responsiveness in cells and in vivo, establishing a bidirectional HIPK2-NRF2 regulatory loop. ChIP, reporter assay, gain-of-function, loss-of-function (HIPK2 KO mice), NRF2 target gene assay Oncogene Medium 28692050
2018 HIPK2-JNK-c-Jun signaling suppresses transcription of Grin2a and Grin2c (encoding GluN2A and GluN2C NMDA receptor subunits); loss of HIPK2 decreases JNK-c-Jun signaling, derepresses GluN2A/GluN2C expression, and increases GluN2A/GluN2B ratio in synapse and mitochondria, activating the ERK-CREB prosurvival pathway. Hipk2-knockout mice, transcriptomic analysis, JNK activity assay, synaptic fractionation, electrophysiology The Journal of neuroscience High 29581378
2019 Crystal structure of the HIPK2 kinase domain bound to CX-4945 at 2.2 Å reveals an active conformation stabilized by activation-loop phosphorylation; the CMGC-insert region and the αC-β4 loop insert adopt conformations unique among DYRK-family kinases; CX-4945 engages the active site in a hybrid CK2α/Pim1-like binding mode. X-ray crystallography at 2.2 Å The Journal of biological chemistry High 31341017
2019 HIPK2 binds and phosphorylates the microtubule-severing enzyme spastin at Ser268; midbody-localized spastin phosphorylation at S268 is HIPK2-dependent; non-phosphorylatable spastin-S268A fails to localize at the midbody and cannot rescue abscission defects in HIPK2-depleted cells; phosphomimetic spastin-S268D restores midbody localization and successful abscission. Co-immunoprecipitation, in vitro kinase assay, phosphomimetic/non-phosphorylatable mutants, immunofluorescence, cytokinesis assay Cells High 31284535
2019 EGFR/STAT3 signaling drives HIPK2 expression in kidney tubular epithelial cells; ChIP analysis shows STAT3 directly binds the promoter region of HIPK2; HIPK2 silencing attenuates vancomycin-induced AKI-to-CKD progression. ChIP analysis, EGFR mutant mice, gefitinib treatment, HIPK2 siRNA, western blot Theranostics Medium 31131063
2021 HIPK2 binds and phosphorylates HDAC3 at Ser374, inhibiting its deacetylase activity, thus preventing deacetylation of NF-κB p65 at Lys218 and suppressing NF-κB-driven inflammatory gene expression in macrophages. Co-immunoprecipitation, in vitro kinase assay, HDAC3 activity assay, site-directed mutagenesis, HIPK2 knockout mice, CLP and LPS models Proceedings of the National Academy of Sciences of the United States of America High 34244427
2021 Upon DNA damage, ATM phosphorylates SPOP at Ser119, potentiating SPOP binding to HIPK2 and triggering non-degradative ubiquitination of HIPK2; this modification increases HIPK2-mediated phosphorylation of HP1γ, promoting HP1γ dissociation from H3K9me3 to initiate DNA damage repair; cancer-associated SPOP mutations abrogate this axis. Co-immunoprecipitation, ubiquitination assay, in vitro kinase assay, phospho-specific antibodies, SPOP mutants, ChIP Nucleic acids research High 34133717
2021 HIPK2 suppression attenuates cardiomyocyte apoptosis after myocardial infarction via decreasing p53 phosphorylation; miR-222 targets HIPK2 to mediate exercise-induced cardioprotection; protective effect of HIPK2 suppression is reversed by p53 activators. HIPK2-knockout mice, HIPK2 inhibitor, lentiviral knockdown, p53 activator rescue, OGD/R assay in hESC-CMs EBioMedicine Medium 34837851
2022 HIPK2 inhibition protects against pathological cardiac remodeling by reducing EGR3 and CLEC4D expression via ERK1/2-CREB inhibition in cardiomyocytes, and by suppressing Smad3 phosphorylation in cardiac fibroblasts. HIPK2 knockout mice, pharmacological inhibitors, microarray, siRNA rescue (EGR3/CLEC4D/Smad3), TAC model EBioMedicine Medium 36182775

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Circular RNA HIPK2 regulates astrocyte activation via cooperation of autophagy and ER stress by targeting MIR124-2HG. Autophagy 224 28786753
2008 Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nature cell biology 167 18536714
2007 MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis. Molecular cell 154 17349959
2004 Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK. Genes & development 146 15082531
1999 Covalent modification of the homeodomain-interacting protein kinase 2 (HIPK2) by the ubiquitin-like protein SUMO-1. Proceedings of the National Academy of Sciences of the United States of America 142 10535925
2004 Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation. The EMBO journal 140 15526030
2003 TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity. The Journal of biological chemistry 134 12851404
2012 A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nature medicine 129 22406746
2003 HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells. Cancer research 126 14678985
2007 HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 118 17666529
2010 Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells. Oncogene 117 20514025
2003 PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-mediated p53 phosphorylation and cell cycle arrest but is dispensable for the formation of HIPK domains. Cancer research 117 12907596
2008 An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nature cell biology 115 19043406
2007 HIPK2: a versatile switchboard regulating the transcription machinery and cell death. Cell cycle (Georgetown, Tex.) 114 17245128
2006 Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation. The EMBO journal 114 16917507
2006 Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons. Nature neuroscience 113 17159989
2007 HIPK2: a multitalented partner for transcription factors in DNA damage response and development. Biochemistry and cell biology = Biochimie et biologie cellulaire 109 17713576
2009 Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 93 19794125
2006 Overlapping roles for homeodomain-interacting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals. Molecular and cellular biology 93 16537918
2007 Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death. Cancer research 85 17210684
2004 Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival. The Journal of cell biology 85 15492043
2009 Apoptosis and autophagy: Regulation of apoptosis by DNA damage signalling - roles of p53, p73 and HIPK2. The FEBS journal 81 19788416
2001 High mobility group I (Y) proteins bind HIPK2, a serine-threonine kinase protein which inhibits cell growth. Oncogene 79 11593421
2009 HIPK2 modulates p53 activity towards pro-apoptotic transcription. Molecular cancer 78 19828042
2019 EGFR drives the progression of AKI to CKD through HIPK2 overexpression. Theranostics 76 31131063
2012 Updates on HIPK2: a resourceful oncosuppressor for clearing cancer. Journal of experimental & clinical cancer research : CR 76 22889244
2012 HIPK2: A tumour suppressor that controls DNA damage-induced cell fate and cytokinesis. BioEssays : news and reviews in molecular, cellular and developmental biology 74 23169233
2016 Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis. Neuron 73 27321923
2008 PML activates transcription by protecting HIPK2 and p300 from SCFFbx3-mediated degradation. Molecular and cellular biology 73 18809579
2002 Identification and characterization of HIPK2 interacting with p73 and modulating functions of the p53 family in vivo. The Journal of biological chemistry 73 11925430
2017 Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses. Oncogene 72 28692050
2008 How cells switch HIPK2 on and off. Cell death and differentiation 63 18974774
2021 HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis. Proceedings of the National Academy of Sciences of the United States of America 61 34244427
2015 HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism. Cell death and differentiation 61 26113041
2014 XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313. Proceedings of the National Academy of Sciences of the United States of America 61 25313037
2005 HIPK2 contributes to PCAF-mediated p53 acetylation and selective transactivation of p21Waf1 after nonapoptotic DNA damage. Oncogene 61 15897882
2012 HIPK2 kinase activity depends on cis-autophosphorylation of its activation loop. Journal of molecular cell biology 58 23000554
2004 HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function. Oncogene 58 15122315
2013 WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation. Molecular cell 57 23871434
2008 Restoring wtp53 activity in HIPK2 depleted MCF7 cells by modulating metallothionein and zinc. Experimental cell research 55 18996371
2011 The loss of the p53 activator HIPK2 is responsible for galectin-3 overexpression in well differentiated thyroid carcinomas. PloS one 54 21698151
2011 Cutaneous HPV23 E6 prevents p53 phosphorylation through interaction with HIPK2. PloS one 54 22110707
2021 Exosomal miR-1260b derived from non-small cell lung cancer promotes tumor metastasis through the inhibition of HIPK2. Cell death & disease 52 34321461
2014 Verbascoside promotes apoptosis by regulating HIPK2-p53 signaling in human colorectal cancer. BMC cancer 52 25282590
2020 Silencing of circular RNA HIPK2 in neural stem cells enhances functional recovery following ischaemic stroke. EBioMedicine 51 32062357
2012 HIPK2 controls cytokinesis and prevents tetraploidization by phosphorylating histone H2B at the midbody. Molecular cell 51 22658722
2010 The WD40-repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions. The EMBO journal 51 20940704
2016 The adaptor protein DCAF7 mediates the interaction of the adenovirus E1A oncoprotein with the protein kinases DYRK1A and HIPK2. Scientific reports 50 27307198
2013 Transcriptional corepressors HIPK1 and HIPK2 control angiogenesis via TGF-β-TAK1-dependent mechanism. PLoS biology 49 23565059
2011 HIF-1α antagonizes p53-mediated apoptosis by triggering HIPK2 degradation. Aging 47 21248371
2010 Unfolded p53 in the pathogenesis of Alzheimer's disease: is HIPK2 the link? Aging 47 20876941
2021 Exercise downregulates HIPK2 and HIPK2 inhibition protects against myocardial infarction. EBioMedicine 45 34837851
2013 HIPK2 catalytic activity and subcellular localization are regulated by activation-loop Y354 autophosphorylation. Biochimica et biophysica acta 45 23485397
2013 Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proceedings of the National Academy of Sciences of the United States of America 45 24145406
2010 HIPK2-a therapeutical target to be (re)activated for tumor suppression: role in p53 activation and HIF-1α inhibition. Cell cycle (Georgetown, Tex.) 45 20234185
2016 Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy. Scientific reports 44 27941951
2011 Zyxin is a critical regulator of the apoptotic HIPK2-p53 signaling axis. Cancer research 44 21248071
2005 Regulation of homeodomain-interacting protein kinase 2 (HIPK2) effector function through dynamic small ubiquitin-related modifier-1 (SUMO-1) modification. The Journal of biological chemistry 44 15958389
2011 HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage. Oncogene 43 21602882
2017 Homeodomain-interacting protein kinase 2 (HIPK2): a promising target for anti-cancer therapies. Oncotarget 42 28107201
2013 Posttranslational modifications regulate HIPK2, a driver of proliferative diseases. Journal of molecular medicine (Berlin, Germany) 41 23616089
2019 The SIAH1-HIPK2-p53ser46 Damage Response Pathway is Involved in Temozolomide-Induced Glioblastoma Cell Death. Molecular cancer research : MCR 40 30796178
2010 Role of the SUMO-interacting motif in HIPK2 targeting to the PML nuclear bodies and regulation of p53. Experimental cell research 40 21192925
2005 Desumoylation of homeodomain-interacting protein kinase 2 (HIPK2) through the cytoplasmic-nuclear shuttling of the SUMO-specific protease SENP1. FEBS letters 40 16253240
2000 Human homeodomain-interacting protein kinase-2 (HIPK2) is a member of the DYRK family of protein kinases and maps to chromosome 7q32-q34. Biochimie 40 11120354
2003 The homeodomain-interacting kinase PKM (HIPK-2) modifies ND10 through both its kinase domain and a SUMO-1 interaction motif and alters the posttranslational modification of PML. Experimental cell research 39 12565818
2022 Inhibition of HIPK2 protects stress-induced pathological cardiac remodeling. EBioMedicine 38 36182775
2018 Update on the Regulation of HIPK1, HIPK2 and HIPK3 Protein Kinases by microRNAs. MicroRNA (Shariqah, United Arab Emirates) 37 29793420
2018 Overexpression of homeodomain-interacting protein kinase 2 (HIPK2) attenuates sepsis-mediated liver injury by restoring autophagy. Cell death & disease 36 30154452
2010 Homeodomain-interacting protein kinase 2 (HIPK2) targets beta-catenin for phosphorylation and proteasomal degradation. Biochemical and biophysical research communications 36 20307497
2010 Transcriptional regulation of ferritin and antioxidant genes by HIPK2 under genotoxic stress. Journal of cell science 35 20980392
2010 Control of nuclear HIPK2 localization and function by a SUMO interaction motif. Biochimica et biophysica acta 35 21145359
2023 Extracellular Vesicle-Conjugated Functional Matrix Hydrogels Prevent Senescence by Exosomal miR-3594-5p-Targeted HIPK2/p53 Pathway for Disc Regeneration. Small (Weinheim an der Bergstrasse, Germany) 34 37165721
2014 Role of HIPK2 in kidney fibrosis. Kidney international supplements 34 26312158
2013 Src kinase modulates the apoptotic p53 pathway by altering HIPK2 localization. Cell cycle (Georgetown, Tex.) 34 24196445
2021 MiR-221-3p targets HIPK2 to promote diabetic wound healing. Microvascular research 33 34973299
2009 The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. Oncogene 33 19448668
2002 HIPK2 associates with RanBPM. Biochemical and biophysical research communications 33 12220523
2014 Identification of Hipk2 as an essential regulator of white fat development. Proceedings of the National Academy of Sciences of the United States of America 31 24785298
2009 HIPK2 is involved in cell proliferation and its suppression promotes growth arrest independently of DNA damage. Cell proliferation 31 19438900
2005 Differential interactions of the homeodomain-interacting protein kinase 2 (HIPK2) by phosphorylation-dependent sumoylation. FEBS letters 31 15896780
2001 HIPK2 overexpression leads to stabilization of p53 protein and increased p53 transcriptional activity by decreasing Mdm2 protein levels. BMC molecular biology 31 11532197
2021 Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP-HIPK2 axis. Nucleic acids research 30 34133717
2020 HIPK2 suppresses tumor growth and progression of hepatocellular carcinoma through promoting the degradation of HIF-1α. Oncogene 30 32034309
2012 HIPK2 downregulates vimentin and inhibits breast cancer cell invasion. Cancer biology & therapy 30 22236966
2014 HIPK2 modification code for cell death and survival. Molecular & cellular oncology 29 27308327
2020 Circ-HIPK2 Accelerates Cell Apoptosis and Autophagy in Myocardial Oxidative Injury by Sponging miR-485-5p and Targeting ATG101. Journal of cardiovascular pharmacology 28 33027196
2009 Stabilization of HIPK2 by escape from proteasomal degradation mediated by the E3 ubiquitin ligase Siah1. Cancer letters 28 19250734
2022 HIPK2 in cancer biology and therapy: Recent findings and future perspectives. Cellular signalling 27 36241057
2020 SPEN induces miR-4652-3p to target HIPK2 in nasopharyngeal carcinoma. Cell death & disease 27 32641685
2019 HIPK2 role in the tumor-host interaction: Impact on fibroblasts transdifferentiation CAF-like. IUBMB life 26 31414572
2015 HIPK2 deficiency causes chromosomal instability by cytokinesis failure and increases tumorigenicity. Oncotarget 26 25868975
2005 HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations. FEBS letters 26 16212962
2007 Homeodomain-interacting protein kinase-2 (HIPK2) phosphorylates HMGA1a at Ser-35, Thr-52, and Thr-77 and modulates its DNA binding affinity. Journal of proteome research 25 17960875
2014 Synthesis and properties of a selective inhibitor of homeodomain-interacting protein kinase 2 (HIPK2). PloS one 24 24586573
2004 US11 of herpes simplex virus type 1 interacts with HIPK2 and antagonizes HIPK2-induced cell growth arrest. Journal of virology 24 14990717
2019 HIPK2 Phosphorylates the Microtubule-Severing Enzyme Spastin at S268 for Abscission. Cells 23 31284535
2019 The crystal structure of the protein kinase HIPK2 reveals a unique architecture of its CMGC-insert region. The Journal of biological chemistry 23 31341017
2018 HIPK2-Mediated Transcriptional Control of NMDA Receptor Subunit Expression Regulates Neuronal Survival and Cell Death. The Journal of neuroscience : the official journal of the Society for Neuroscience 23 29581378
2014 Hipk2 and PP1c cooperate to maintain Dvl protein levels required for Wnt signal transduction. Cell reports 23 25159144

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