Affinage

DYRK1A

Dual specificity tyrosine-phosphorylation-regulated kinase 1A · UniProt Q13627

Length
763 aa
Mass
85.6 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DYRK1A is a dual-specificity protein kinase that serves as a pleiotropic regulator of neuronal development, cell cycle progression, apoptosis, immunity, and angiogenesis, with its gene dosage critically constrained in brain development (PMID:12192061, PMID:9932450). It achieves activity through tyrosine autophosphorylation in its activation loop and thereafter phosphorylates exogenous substrates exclusively on serine/threonine residues (PMID:9932450). A recurring biochemical theme is its action as a priming kinase that creates GSK3 phosphorylation sites, demonstrated for eIF2Bepsilon, tau, and RCAN1 (PMID:11311121, PMID:21965663). Through direct substrate phosphorylation DYRK1A controls transcriptional programs (CREB, Gli1, the DREAM-complex subunit LIN52, FOXO1, STAT3) and couples to cell-cycle and survival machinery: it phosphorylates LIN52 at Ser28 to enable DREAM complex assembly and entry into quiescence/senescence (PMID:21498570), phosphorylates caspase-9 at Thr125 and SIRT1 at Thr522 to favor cell survival (PMID:19081073, PMID:20167603), and represses D-cyclins by phosphorylating Cyclin D2 (Thr280) to drive its degradation and suppress Rb/E2F signaling (PMID:27056896). In the immune compartment it sustains B-lineage malignancy via FOXO1/STAT3 phosphorylation and activates noncanonical NF-kappaB by phosphorylating TRAF3 at Ser29 to block NIK degradation (PMID:33393494, PMID:34255829). DYRK1A activity and localization are tuned by multiple inputs: 14-3-3 binding enhances activity, PPM1B dephosphorylates the autophosphorylation site Ser258 to inhibit it, TRAF2-mediated K63 ubiquitination relocalizes it to vesicles, and TROAP enforces cytoplasmic retention (PMID:15369779, PMID:33380426, PMID:34117217, PMID:33500384). In addition to its catalytic roles, DYRK1A exerts kinase-independent functions, stabilizing tau mRNA and promoting chromatin accessibility at the ACE2/DPP4 loci to enable coronavirus entry (PMID:23948904, PMID:37310920), and it modulates enhancer activity through phosphorylation of the acetyltransferases p300/CBP (PMID:30137413). Several findings tie DYRK1A to neurological disease: it primes tau phosphorylation relevant to Alzheimer pathology and undergoes proteolytic processing in AD hippocampus that retunes its substrate specificity toward STAT3alpha (PMID:11311121, PMID:30885273, PMID:33380426).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 Medium

    Established the basic cell biology of the protein — where it acts and that it oligomerizes — placing it on the Down syndrome critical region of chromosome 21.

    Evidence Subcellular fractionation, two-hybrid self-interaction, and interspecific backcross mapping of murine Dyrk

    PMID:9070862

    Open questions at the time
    • No catalytic activity or substrate defined
    • Functional consequence of self-association unknown
  2. 1999 High

    Defined the defining catalytic mechanism — resolving how a kinase with tyrosine autophosphorylation acts only as a Ser/Thr kinase on substrates.

    Evidence In vitro kinase assays with autophosphorylation analysis and substrate specificity profiling

    PMID:9932450

    Open questions at the time
    • Cotranslational nature of autophosphorylation not addressed here
    • No physiological substrates identified at this stage
  3. 2001 High

    Identified DYRK1A as a GSK3-priming kinase and a direct activator of CRE-dependent transcription, linking it to both tau biology and neuronal differentiation.

    Evidence In vitro kinase assays on eIF2Bepsilon/tau with cross-kinase comparison; Co-IP, reporter assays, and dominant-negative blockade in hippocampal progenitor cells

    PMID:11311121 PMID:11518709

    Open questions at the time
    • CREB phosphorylation site and selectivity defined by single lab
    • Relative in vivo contribution of priming vs direct phosphorylation unresolved
  4. 2002 High

    Genetic loss-of-function and a transcriptional readout together established a nonredundant, dosage-sensitive role in brain growth and Gli1-dependent transcription.

    Evidence Dyrk1A knockout mouse with histology and cell counting; reporter and nuclear localization assays in C3H10T1/2 cells

    PMID:12138125 PMID:12192061

    Open questions at the time
    • Molecular substrates driving the brain phenotype not identified
    • Mechanism of Gli1 nuclear retention not biochemically resolved
  5. 2004 Medium

    Showed DYRK1A activity is regulated post-translationally by a protein interaction, revealing 14-3-3 as a positive modulator independent of phosphorylation status.

    Evidence Yeast two-hybrid, in vitro binding/kinase assays, and inhibitory-peptide cell assay

    PMID:15369779

    Open questions at the time
    • Structural basis of activation unknown
    • Physiological contexts where 14-3-3 regulation operates not defined
  6. 2005 Medium

    Extended DYRK1A into apoptotic control of neuronal differentiation by identifying HIP-1 as a substrate whose phosphorylation suppresses cell death.

    Evidence Co-IP, in vitro kinase assay, cell-death and neurite outgrowth assays in H19-7 cells

    PMID:15906374

    Open questions at the time
    • Phosphosite on HIP-1 not mapped
    • Single-lab cellular evidence
  7. 2008 High

    Connected DYRK1A directly to apoptotic machinery in vivo by identifying caspase-9 Thr125 phosphorylation as dosage-sensitive protection of developing retina.

    Evidence In vitro kinase assay with site identification plus knockout/overexpression mice and electroretinography

    PMID:19081073

    Open questions at the time
    • Generality beyond retina untested
    • Interplay with other caspase-9 regulators not addressed
  8. 2009 High

    Provided a selective chemical-genetic tool (harmine) enabling pharmacological dissection of DYRK1A in cells and neurons.

    Evidence Quantitative in vitro kinase assays across DYRK family, cell-based substrate assays, and hippocampal neuron neuritogenesis

    PMID:19796173

    Open questions at the time
    • Off-target activity of harmine on other kinases
    • Does not distinguish kinase-dependent from kinase-independent functions
  9. 2010 High

    Defined a survival axis whereby DYRK1A phosphorylates SIRT1 (Thr522) to enhance its deacetylase turnover and p53 deacetylation, protecting cells from DNA-damage death.

    Evidence In vitro kinase assays, phosphosite mutants, deacetylase activity assays, siRNA knockdown, apoptosis assays

    PMID:20167603

    Open questions at the time
    • In vivo relevance of SIRT1 axis not tested
    • Single-study mechanism
  10. 2011 High

    Established DYRK1A as a cell-cycle controller and broadened its priming-kinase and apoptotic roles by identifying LIN52 (DREAM assembly), RCAN1, and ASK1 as substrates.

    Evidence MS phosphosite mapping plus in vitro kinase assays with mutagenesis; DREAM Co-IP and quiescence/senescence assays; calcineurin and NFAT assays; JNK pathway assays

    PMID:21498570 PMID:21965663 PMID:22110360

    Open questions at the time
    • How DYRK1A access to nuclear vs cytoplasmic substrates is controlled
    • ASK1 finding rests on single-lab cellular evidence
  11. 2013 Medium

    Revealed a kinase-independent function — stabilization of tau mRNA favoring exon-10 isoforms — distinguishing DYRK1A's catalytic from non-catalytic contributions to tau pathology.

    Evidence Kinase-dead mutant, mRNA stability assays in HEK-293FT, and analysis of Ts65Dn mouse brain

    PMID:23948904

    Open questions at the time
    • RNA-binding mechanism unknown
    • Whether DYRK1A binds tau mRNA directly not shown
  12. 2016 High

    Showed DYRK1A restrains the cell cycle by phosphorylating Cyclin D2 (Thr280) for degradation and suppressing Rb/E2F, explaining impaired cardiomyocyte proliferation.

    Evidence Cardiac-specific overexpression mice, Co-IP, in vitro kinase assay, proteasome rescue, E2F target analysis

    PMID:27056896

    Open questions at the time
    • Endogenous-dosage relevance vs overexpression unclear
    • Specificity among D-cyclins partially resolved
  13. 2018 High

    Expanded DYRK1A into chromatin/enhancer regulation and angiogenesis via p300/CBP phosphorylation and VEGFR2-dependent NFAT signaling.

    Evidence Proteomics, reciprocal Co-IP, ChIP-seq and H3K27ac ChIP-seq with knockdown; endothelial Ca2+ imaging, NFAT reporters, and heterozygous-mouse retinal vascularization

    PMID:29742440 PMID:30137413

    Open questions at the time
    • Direct p300/CBP phosphosites and functional consequences not fully mapped
    • Mechanism of VEGFR2 maintenance not at molecular resolution
  14. 2018 Medium

    Linked DYRK1A to oncogenic receptor signaling in solid tumors by stabilizing c-MET through SPRY2 and prolonging ERK activation.

    Evidence Knockdown in PDAC cell lines and mouse models with protein stability and ERK signaling analysis

    PMID:30343272

    Open questions at the time
    • Direct phosphorylation events in the SPRY2/c-MET axis not defined here
    • Single-lab
  15. 2019 Medium

    Demonstrated that disease-associated proteolytic processing of DYRK1A retunes substrate specificity, accumulating in AD astrocytes with enhanced STAT3alpha affinity.

    Evidence Western blot/IHC of human AD hippocampus, in vitro proteolysis, substrate affinity comparison, APP/PS1 mouse analysis

    PMID:30885273

    Open questions at the time
    • Protease responsible not identified
    • Functional output of STAT3alpha rewiring in vivo unclear
  16. 2021 High

    A burst of studies defined DYRK1A's immune/oncogenic substrates (FOXO1/STAT3, TRAF3-Ser29) and a regulatory network (PPM1B dephosphorylation of Ser258, TRAF2 K63-ubiquitination/vesicle targeting, TROAP cytoplasmic retention, CDK5-SOX2 axis).

    Evidence Genetic/pharmacological leukemia models; Co-IP and in vitro kinase/phosphatase/ubiquitination assays; subcellular fractionation; GSC self-renewal and HCC tumor assays

    PMID:33380426 PMID:33393494 PMID:33500384 PMID:33924599 PMID:34117217 PMID:34255829

    Open questions at the time
    • Integration of competing localization/regulatory inputs not modeled
    • Several axes (TRAF2 vesicle, TROAP, CDK5) rest on single-lab evidence
  17. 2023 High

    Defined new kinase-independent and circuit-level roles — chromatin-accessibility-driven ACE2/DPP4 transcription enabling coronavirus entry, and an ABLIM3 synaptic substrate controlling feedforward inhibition and social behavior.

    Evidence Genome-wide CRISPR screen with kinase-dead rescue and ATAC-seq; genetic epistasis, chemogenetics, electrophysiology, and behavior in Dyrk1a+/- mice

    PMID:37310920 PMID:37797581

    Open questions at the time
    • How DYRK1A promotes chromatin accessibility mechanistically unresolved
    • ABLIM3 phosphosite and direct kinase action not fully detailed
  18. 2023 Low

    Implicated DYRK1A in Parkinson's-relevant alpha-synuclein Ser129 phosphorylation, though only via in vivo knockdown correlation.

    Evidence AAV-shRNA knockdown in a PD model with Western blot for P-alpha-synuclein and apoptosis markers

    PMID:37469393

    Open questions at the time
    • Direct in vitro phosphorylation of alpha-synuclein not demonstrated
    • Single study; correlation not causation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DYRK1A's many competing regulatory inputs (14-3-3, PPM1B, TRAF2 ubiquitination, TROAP, proteolysis) are integrated to direct it to specific substrates and subcellular compartments in a given cell remains unresolved.
  • No unified model of localization/substrate selection
  • Kinase-dependent vs kinase-independent contributions not systematically partitioned across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0140110 transcription regulator activity 4 GO:0016740 transferase activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-4839726 Chromatin organization 2
Partners
EP300LIN52PPM1BRCAN1SIRT1TRAF2TRAF3TROAP
Complex memberships
DREAM complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 DYRK1A (and DYRK2) phosphorylates eIF2Bepsilon at Ser539 in vitro, priming it for subsequent GSK3 phosphorylation at Ser535; DYRK1A also phosphorylates tau at Thr212 in vitro, priming tau for GSK3 phosphorylation at Ser208, establishing DYRK1A as a GSK3-priming kinase. In vitro kinase assays with recombinant proteins; comparison across multiple proline-directed kinases; in vivo phosphorylation state analysis The Biochemical journal High 11311121
2001 DYRK1A directly phosphorylates CREB during neuronal differentiation of hippocampal progenitor cells, leading to stimulation of CRE-mediated gene transcription; DYRK1A activity is induced by bFGF and specifically binds active CREB. In vitro kinase assay; co-immunoprecipitation; reporter gene assay; dominant-negative blockade of DYRK1A in H19-7 cells The Journal of biological chemistry Medium 11518709
2002 DYRK1A (Dyrk1) enhances Gli1-dependent transcriptional activity in the nucleus by retaining Gli1 in the nucleus and increasing its transcriptional activity independently of nuclear export; DYRK1A acts synergistically with Sonic hedgehog signaling but is not regulated by Shh. Reporter gene assays; nuclear localization assays; co-expression studies in C3H10T1/2 cells; kinase activity assay The Journal of biological chemistry Medium 12138125
2002 Dyrk1A haploinsufficiency in mice causes decreased brain size, increased neuronal densities in specific regions, reduced neuron numbers in superior colliculus, and neonatal lethality of nulls at midgestation, establishing a nonredundant vital role in brain growth. Gene targeting (knockout mouse); cell counting; histological analysis; neurobehavioral testing Molecular and cellular biology High 12192061
2004 14-3-3 protein interacts with the N-terminus of DYRK1A independently of DYRK1A phosphorylation status, and this binding increases DYRK1A kinase activity in a dose-dependent manner in vitro; a peptide inhibiting 14-3-3 binding decreased DYRK1A activity in COS7 cells. Yeast two-hybrid screen; in vitro binding assay; in vitro kinase assay; co-immunoprecipitation; cell-based kinase assay with inhibitory peptide Biochemical and biophysical research communications Medium 15369779
2005 DYRK1A selectively binds and phosphorylates HIP-1 (huntingtin-interacting protein 1) during neuronal differentiation; DYRK1A-mediated phosphorylation of HIP-1 blocks HIP-1-mediated cell death and enhances neurite outgrowth; upon apoptotic stimulation (etoposide), HIP-1 dissociates from DYRK1A and binds caspase-3, promoting its activation. Co-immunoprecipitation; in vitro kinase assay; cell death assays; neurite outgrowth measurement in H19-7 cells Journal of neuroscience research Medium 15906374
2008 DYRK1A phosphorylates caspase-9 on threonine residue 125, and this phosphorylation event is required to protect retina cells from apoptotic cell death during development; changes in Dyrk1a gene dosage strongly alter inner retina layer cellularity without affecting proliferation or specification of progenitors. In vitro kinase assay; gene dosage manipulation (knockout/overexpression mice); retinal cell counting; functional electroretinography Developmental cell High 19081073
2009 Harmine is a potent and selective inhibitor of DYRK1A (IC50 ~33 nM for substrate phosphorylation in vitro), inhibiting DYRK1A more potently than DYRK1B, DYRK2, or DYRK4; harmine inhibits DYRK1A substrate phosphorylation in cultured cells (IC50 ~48 nM) and interferes with neuritogenesis in hippocampal neurons. In vitro kinase assay; in vitro bacterial translation system; cell-based substrate phosphorylation assay; hippocampal neuron culture with neurite analysis The FEBS journal High 19796173
2010 DYRK1A directly phosphorylates SIRT1 at Thr522, activating its deacetylase activity by promoting product release and increasing enzymatic turnover; activated SIRT1 deacetylates p53, promoting cell survival; knockdown of DYRK1A leads to hypophosphorylation of SIRT1 and sensitizes cells to DNA damage-induced death. In vitro kinase assay; phosphomimetic/dephosphorylation mimetic mutants; deacetylase activity assays; siRNA knockdown; apoptosis assays The Journal of biological chemistry High 20167603
2011 DYRK1A specifically phosphorylates LIN52 on serine residue 28, and this phosphorylation is required for DREAM complex assembly (containing p130, E2F4, DP1, and MuvB core proteins); inhibiting DYRK1A activity or mutating LIN52 S28 disrupts DREAM assembly and impairs entry into quiescence and Ras-induced senescence. Mass spectrometric phosphopeptide identification; in vitro kinase assay with point mutants; co-immunoprecipitation of DREAM components; quiescence and senescence assays Genes & development High 21498570
2011 DYRK1A directly interacts with and phosphorylates RCAN1 at Ser112 and Thr192; phosphorylation at Ser112 primes RCAN1 for GSK3β phosphorylation at Ser108; phosphorylation at Thr192 enhances RCAN1 inhibition of calcineurin phosphatase activity, reduces NFAT transcriptional activity, extends RCAN1 half-life, and enhances tau phosphorylation. Co-immunoprecipitation; in vitro kinase assay; calcineurin phosphatase activity assay; NFAT reporter assay; protein half-life measurement; immunohistochemistry in transgenic mice The Journal of biological chemistry High 21965663
2011 DYRK1A positively regulates the ASK1-JNK signaling pathway during apoptotic cell death; DYRK1A directly interacts with and phosphorylates ASK1, promoting ASK1-mediated JNK1 activation. Co-immunoprecipitation; in vitro kinase assay; JNK activity assay; apoptosis induction in neuronal cells Experimental neurobiology Medium 22110360
2013 DYRK1A enhances tau mRNA stability (not transcription) to increase tau expression in a dose-dependent, kinase-activity-independent manner, preferentially increasing exon 10-containing isoforms. RT-PCR and Western blot for tau mRNA/protein; co-expression in HEK-293FT cells; kinase-dead mutant; mRNA stability assay; analysis of Ts65Dn mouse brains Journal of Alzheimer's disease : JAD Medium 23948904
2016 DYRK1A interacts with all members of the D-cyclin family and represses their protein levels; specifically, forced DYRK1A expression increases phosphorylation of Cyclin D2 (Ccnd2) at Thr280, promoting its proteasomal degradation; this results in hypo-phosphorylated Rb1, suppressed Rb/E2F signaling, and impaired cardiomyocyte cell cycle progression. Transgenic cardiac-specific overexpression mouse; co-immunoprecipitation; in vitro kinase assay; Western blot for cyclin levels; proteasome inhibitor rescue; E2F target gene expression analysis Cardiovascular research High 27056896
2018 DYRK1A interacts with histone acetyltransferases p300 and CBP; overexpression of DYRK1A causes hyperphosphorylation of p300 and CBP; DYRK1A co-localizes genome-wide with p300 and CBP at enhancers and near transcription start sites; DYRK1A knockdown reduces H3K27 acetylation at enhancers, indicating DYRK1A modulates p300/CBP activity at enhancers. Proteomics/mass spectrometry; co-immunoprecipitation; ChIP-sequencing; shRNA knockdown and overexpression; H3K27ac ChIP-seq Nucleic acids research High 30137413
2018 DYRK1A positively regulates VEGF-dependent NFAT transcriptional responses in endothelial cells by maintaining VEGFR2 accumulation; DYRK1A silencing reduces intracellular Ca2+ influx in response to VEGF, dampening PLCγ1 activation and NFAT signaling; Dyrk1a heterozygous mice show defects in developmental retinal vascularization. siRNA silencing in primary endothelial cells; Ca2+ imaging; NFAT reporter assay; VEGFR2 accumulation assay; PLCγ1 phosphorylation; retinal vascularization in heterozygous mice Cell reports High 29742440
2019 DYRK1A undergoes proteolytic processing in Alzheimer's disease patient hippocampus; truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3α; proteolysis modifies DYRK1A kinase substrate specificity without abolishing kinase activity. Western blot of human AD and control hippocampus; immunohistochemistry; in vitro proteolysis assay; substrate affinity comparison; APP/PS1 mouse model analysis Acta neuropathologica communications Medium 30885273
2021 DYRK1A phosphorylates FOXO1 and STAT3 to support B-ALL development; genetic and pharmacological inhibition of DYRK1A decreases leukemic cell expansion; loss of DYRK1A-mediated FOXO1/STAT3 signaling disrupts DNA damage and ROS regulation, leading to preferential cell death in leukemic B cells. Genetic knockdown and pharmacological inhibition; in vitro and in vivo leukemia models; substrate phosphorylation assays; ROS and DNA damage assays The Journal of clinical investigation High 33393494
2021 DYRK1A phosphorylates TRAF3 at serine-29 to interfere with TRAF3-mediated NIK (NF-κB-inducing kinase) degradation, thereby facilitating BAFF-induced NIK accumulation and noncanonical NF-κB activation in B cells. Co-immunoprecipitation; in vitro kinase assay; genetic knockdown/knockout; noncanonical NF-κB pathway activation assays; mouse model of lupus and B-ALL Blood High 34255829
2021 PPM1B (a PP2C family Ser/Thr phosphatase) dephosphorylates DYRK1A at Ser258, inhibiting DYRK1A activity; DYRK1A autophosphorylates Ser258; PPM1B-mediated dephosphorylation reduces DYRK1A-dependent tau phosphorylation at Thr212 and inhibits toxic tau oligomerization. LC-MS/MS identification of DYRK1A-binding proteins; in vitro kinase/phosphatase assays; co-immunoprecipitation; tau phosphorylation and aggregation assays in HEK293 cells The Journal of biological chemistry High 33380426
2021 TRAF2 (E3 ligase) binds the PVQE motif of DYRK1A (between PEST and histidine repeat domain) and mediates K63-linked ubiquitination of DYRK1A, causing its translocation to vesicle membranes; vesicle-localized DYRK1A phosphorylates Sprouty 2, inhibiting EGFR degradation. Co-immunoprecipitation; ubiquitination assays (K63-linkage specific); subcellular fractionation; vesicle localization studies; EGFR degradation assays; DYRK1A knockdown Cell death & disease Medium 34117217
2021 DYRK1A promotes DYRK1A-CDK5-SOX2 axis in glioblastoma: DYRK1A deactivates CDK5 to decrease SOX2 expression and promote GSC differentiation commitment; DYRK1A inhibition insulates GSCs from differentiation signals by maintaining CDK5/SOX2 activity. siRNA knockdown; pharmacological inhibition; CDK5 activity assays; SOX2 expression analysis; glioblastoma stem cell self-renewal assays International journal of molecular sciences Medium 33924599
2021 TROAP directly binds DYRK1A/B and causes cytoplasmic retention of DYRK1A/B, promoting cell cycle progression via activation of Akt/GSK-3β signaling in hepatocellular carcinoma cells. Co-immunoprecipitation; subcellular fractionation/localization assays; shRNA knockdown; Akt/GSK-3β pathway activation assays; in vitro and in vivo tumor growth assays Cell death & disease Medium 33500384
2023 DYRK1A promotes viral entry of SARS-CoV, SARS-CoV-2, and MERS-CoV in a kinase-independent manner by regulating ACE2 and DPP4 transcription; DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer. Genome-wide CRISPR/Cas9 screen; kinase-dead mutant rescue; ATAC-seq for chromatin accessibility; ACE2/DPP4 expression assays; viral entry assays in human and non-human primate cells PLoS biology High 37310920
2023 DYRK1A identifies ABLIM3 (a cytoskeletal protein) as a synaptic substrate in hippocampal mossy fiber-PV interneuron synapses; DYRK1A recruits feedforward inhibition of CA3 and CA2 via PV interneurons to promote social recognition; Ablim3 downregulation rescues PV IN-mediated inhibition and social behavior in Dyrk1a heterozygous mice. Genetic epistasis; viral knockdown of Ablim3 in dentate granule cells; chemogenetic activation of PV INs; electrophysiology; behavioral assays in Dyrk1a+/- mice Neuron High 37797581
1997 The murine Dyrk protein localizes to the cell nucleus, can self-associate (via leucine zipper), and maps to distal chromosome 16 (syntenic with human 21q22.2). Two-hybrid self-interaction assay; subcellular fractionation/immunostaining; chromosomal mapping by interspecific backcross Biochemical and biophysical research communications Medium 9070862
1999 DYRK1A is activated by tyrosine autophosphorylation in the activation loop (between subdomains VII and VIII) and subsequently phosphorylates exogenous substrates exclusively on serine/threonine residues; this dual-specificity mechanism is a defining biochemical property of the DYRK family. In vitro kinase assay; autophosphorylation analysis; substrate specificity profiling Progress in nucleic acid research and molecular biology High 9932450
2018 DYRK1A phosphorylates α-synuclein at serine 129 (Ser129), and Dyrk1a knockdown reduces P-α-synuclein (Ser129) levels and activates the PI3K/AKT pathway, reducing dopaminergic neuron apoptosis in a Parkinson's disease model. AAV-shRNA knockdown of Dyrk1a in vivo; Western blot for P-α-synuclein Ser129; apoptosis markers; transcriptome and metabolome sequencing Parkinson's disease Low 37469393
2018 DYRK1A stabilizes the c-MET receptor through SPRY2, leading to prolonged activation of ERK signaling in pancreatic ductal adenocarcinoma; DYRK1A protein level positively correlates with c-MET levels. Knockdown experiments in PDAC cell lines; DYRK1A genetic reduction in mouse PDAC models; co-expression and protein stability analysis; ERK signaling measurement Gut Medium 30343272

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Molecular and cellular biology 281 12192061
2001 The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. The Biochemical journal 273 11311121
2010 DYRK family of protein kinases: evolutionary relationships, biochemical properties, and functional roles. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 256 21048044
2011 DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes & development 249 21498570
2009 Polar gradients of the DYRK-family kinase Pom1 couple cell length with the cell cycle. Nature 243 19474792
2010 The role of DYRK1A in neurodegenerative diseases. The FEBS journal 221 21156028
2009 Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation. The FEBS journal 216 19796173
1999 Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity. Progress in nucleic acid research and molecular biology 201 9932450
2010 DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. The Journal of biological chemistry 193 20167603
2010 MNB/DYRK1A as a multiple regulator of neuronal development. The FEBS journal 178 21156027
2010 Activation, regulation, and inhibition of DYRK1A. The FEBS journal 171 21126318
2015 Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nature communications 170 26496802
2009 Function and regulation of Dyrk1A: towards understanding Down syndrome. Cellular and molecular life sciences : CMLS 167 19685005
2016 Inhibition of DYRK1A Stimulates Human β-Cell Proliferation. Diabetes 166 26953159
2002 Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. The Journal of biological chemistry 155 12138125
1999 Human minibrain homologue (MNBH/DYRK1): characterization, alternative splicing, differential tissue expression, and overexpression in Down syndrome. Genomics 147 10329007
2001 Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells. The Journal of biological chemistry 145 11518709
2016 DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome. Frontiers in behavioral neuroscience 144 27375444
2015 DYRK1A in neurodegeneration and cancer: Molecular basis and clinical implications. Pharmacology & therapeutics 130 25795597
2018 DYRK1A and cognition: A lifelong relationship. Pharmacology & therapeutics 128 30268771
2008 The protein kinase DYRK1A regulates caspase-9-mediated apoptosis during retina development. Developmental cell 111 19081073
2017 Dyrk1 inhibition improves Alzheimer's disease-like pathology. Aging cell 99 28779511
2014 Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage. Neurobiology of disease 98 24801365
2018 Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics. Journal of medicinal chemistry 97 29985601
2015 DYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis. Molecular & cellular oncology 92 27308401
2005 The C. elegans DYRK Kinase MBK-2 Marks Oocyte Proteins for Degradation in Response to Meiotic Maturation. Current biology : CB 92 16338136
2021 DYRK1A inhibitors for disease therapy: Current status and perspectives. European journal of medicinal chemistry 88 34954592
2012 Emerging role of DYRK family protein kinases as regulators of protein stability in cell cycle control. Cell cycle (Georgetown, Tex.) 86 22918246
2014 DYRK1A: a potential drug target for multiple Down syndrome neuropathologies. CNS & neurological disorders drug targets 78 24152332
2020 The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities. Cancers 77 32751160
2021 DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3. The Journal of clinical investigation 72 33393494
2021 GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways. International journal of molecular sciences 71 34445804
2011 Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation. The Journal of biological chemistry 68 21965663
1999 Cloning and characterization of DYRK1B, a novel member of the DYRK family of protein kinases. Biochemical and biophysical research communications 67 9918863
2003 The MNB/DYRK1A protein kinase: genetic and biochemical properties. Journal of neural transmission. Supplementum 66 15068246
2003 The MNB/DYRK1A protein kinase: neurobiological functions and Down syndrome implications. Journal of neural transmission. Supplementum 65 15068245
2020 DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis. Cellular and molecular life sciences : CMLS 62 32870330
2018 DYRK1A Protein, A Promising Therapeutic Target to Improve Cognitive Deficits in Down Syndrome. Brain sciences 62 30332747
2021 Dyrk1a from Gene Function in Development and Physiology to Dosage Correction across Life Span in Down Syndrome. Genes 59 34828439
2018 DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth. Gut 59 30343272
2015 DYRK protein kinases. Current biology : CB 58 26079075
2016 DYRK1A inhibition as potential treatment for Alzheimer's disease. Future medicinal chemistry 57 27073990
2012 DYRK1A kinase inhibitors with emphasis on cancer. Mini reviews in medicinal chemistry 57 23016545
2022 The Omnipresence of DYRK1A in Human Diseases. International journal of molecular sciences 56 36012629
2018 Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation. Journal of medicinal chemistry 56 30059217
2017 Clinical phenotype of ASD-associated DYRK1A haploinsufficiency. Molecular autism 56 29034068
2015 The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. eLife 55 25998054
2016 Dyrk1a regulates the cardiomyocyte cell cycle via D-cyclin-dependent Rb/E2f-signalling. Cardiovascular research 54 27056896
2017 Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: a survey of recent patent literature. Expert opinion on therapeutic patents 52 28766366
2022 The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target. Oncogene 51 35220406
2015 Selectivity Profiling and Biological Activity of Novel β-Carbolines as Potent and Selective DYRK1 Kinase Inhibitors. PloS one 50 26192590
2021 Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease. Nature communications 49 34344863
2021 DYRK1A Inhibitors as Potential Therapeutics for β-Cell Regeneration for Diabetes. Journal of medicinal chemistry 47 33682417
2020 Pharmacologic and genetic approaches define human pancreatic β cell mitogenic targets of DYRK1A inhibitors. JCI insight 45 31821176
2014 Dyrk1A induces pancreatic β cell mass expansion and improves glucose tolerance. Cell cycle (Georgetown, Tex.) 44 24870561
2021 DYRK1a mediates BAFF-induced noncanonical NF-κB activation to promote autoimmunity and B-cell leukemogenesis. Blood 43 34255829
2017 Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK & CLK Kinases. Marine drugs 41 29039762
2019 Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice. Acta neuropathologica communications 40 30885273
2018 DYRK1A Kinase Positively Regulates Angiogenic Responses in Endothelial Cells. Cell reports 40 29742440
2018 DYRK1A kinase inhibition with emphasis on neurodegeneration: A comprehensive evolution story-cum-perspective. European journal of medicinal chemistry 40 30243157
2017 Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits. Molecular genetics & genomic medicine 40 28944229
2017 DYRK1A-haploinsufficiency in mice causes autistic-like features and febrile seizures. Neurobiology of disease 40 29223763
1998 Expression of the mnb (dyrk) protein in adult and embryonic mouse tissues. Biochemical and biophysical research communications 39 9878567
2023 Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases. Journal of medicinal chemistry 37 36876904
2005 Regulation of the proapoptotic activity of huntingtin interacting protein 1 by Dyrk1 and caspase-3 in hippocampal neuroprogenitor cells. Journal of neuroscience research 37 15906374
2019 Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice. Molecular neurobiology 35 31240602
1997 The murine Dyrk protein maps to chromosome 16, localizes to the nucleus, and can form multimers. Biochemical and biophysical research communications 33 9070862
2018 DYRK1A interacts with histone acetyl transferase p300 and CBP and localizes to enhancers. Nucleic acids research 32 30137413
2016 Understanding the Multifaceted Role of Human Down Syndrome Kinase DYRK1A. Advances in protein chemistry and structural biology 32 27567487
2004 Regulation of Dyrk1A kinase activity by 14-3-3. Biochemical and biophysical research communications 32 15369779
2021 TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression. Cell death & disease 31 33500384
2023 Function and inhibition of DYRK1A: Emerging roles of treating multiple human diseases. Biochemical pharmacology 30 36990324
2013 Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) enhances tau expression. Journal of Alzheimer's disease : JAD 30 23948904
2012 Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal organization, and neuronal morphology. Cytoskeleton (Hoboken, N.J.) 30 22359282
2017 Emerging Roles of DYRK Kinases in Embryogenesis and Hedgehog Pathway Control. Journal of developmental biology 29 29615569
2022 APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer's pathology in trisomy 21 neurons. Molecular psychiatry 28 35194165
2022 Inhibition of DYRK1a Enhances Cardiomyocyte Cycling After Myocardial Infarction. Circulation research 28 35369706
2020 The novel DYRK1A inhibitor KVN93 regulates cognitive function, amyloid-beta pathology, and neuroinflammation. Free radical biology & medicine 28 32896600
2020 An atypical DYRK kinase connects quorum-sensing with posttranscriptional gene regulation in Trypanosoma brucei. eLife 26 32213288
2018 Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design. Molecules (Basel, Switzerland) 26 29364148
2021 Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors. Journal of medicinal chemistry 25 33975430
2022 New insights into the roles for DYRK family in mammalian development and congenital diseases. Genes & diseases 24 37396550
2015 Design and synthesis of a potent inhibitor of class 1 DYRK kinases as a suppressor of adipogenesis. Bioorganic & medicinal chemistry 24 26145823
2023 DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner. PLoS biology 23 37310920
2023 Leucettinibs, a Class of DYRK/CLK Kinase Inhibitors Inspired by the Marine Sponge Natural Product Leucettamine B. Journal of medicinal chemistry 23 37487467
2011 Dyrk1A Positively Stimulates ASK1-JNK Signaling Pathway during Apoptotic Cell Death. Experimental neurobiology 22 22110360
2023 Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β. Frontiers in immunology 21 37435081
2021 Protein phosphatase PPM1B inhibits DYRK1A kinase through dephosphorylation of pS258 and reduces toxic tau aggregation. The Journal of biological chemistry 21 33380426
2021 DYRK1A Negatively Regulates CDK5-SOX2 Pathway and Self-Renewal of Glioblastoma Stem Cells. International journal of molecular sciences 20 33924599
2021 DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis. Cells 20 34571911
2020 DYRK kinase Pom1 drives F-BAR protein Cdc15 from the membrane to promote medial division. Molecular biology of the cell 20 32101481
2023 An inhibitory circuit-based enhancer of DYRK1A function reverses Dyrk1a-associated impairment in social recognition. Neuron 19 37797581
2023 DYRK1A Inhibitors and Perspectives for the Treatment of Alzheimer's Disease. Current medicinal chemistry 18 35726411
2021 K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR. Cell death & disease 18 34117217
2024 Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging. Nature communications 17 38862481
2023 Insights from the protein interaction Universe of the multifunctional "Goldilocks" kinase DYRK1A. Frontiers in cell and developmental biology 17 37900285
2020 DYRK1A suppression restrains Mcl-1 expression and sensitizes NSCLC cells to Bcl-2 inhibitors. Cancer biology & medicine 17 32587776
2023 Resveratrol induces DNA damage-mediated cancer cell senescence through the DLC1-DYRK1A-EGFR axis. Food & function 16 36651299
2015 Luciferin and derivatives as a DYRK selective scaffold for the design of protein kinase inhibitors. European journal of medicinal chemistry 16 25768698
2023 Dyrk1a Phosphorylation of α-Synuclein Mediating Apoptosis of Dopaminergic Neurons in Parkinson's Disease. Parkinson's disease 15 37469393

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