{"gene":"DYRK2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2007,"finding":"DYRK2 directly phosphorylates p53 at Ser46 in the nucleus upon genotoxic stress, inducing p53AIP1 expression and apoptotic cell death in a Ser46 phosphorylation-dependent manner. DYRK2 translocates from cytoplasm to nucleus upon DNA damage to execute this phosphorylation.","method":"In vitro kinase assay, phospho-specific antibody detection, siRNA knockdown, nuclear translocation by fractionation/immunofluorescence, apoptosis assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro phosphorylation assay, functional mutagenesis of Ser46, multiple orthogonal methods, replicated across subsequent studies","pmids":["17349958"],"is_preprint":false},{"year":2009,"finding":"DYRK2 serves as a scaffold for an E3 ubiquitin ligase complex containing EDD, DDB1, and VPRBP (EDVP complex). siRNA depletion of DYRK2 disrupts formation of the EDD-DDB1-VPRBP complex. DYRK2 kinase activity, while dispensable for scaffold function, is required for phosphorylation and subsequent ubiquitin-mediated degradation of the substrate katanin p60.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, kinase-dead mutant analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, kinase-dead mutant dissection, siRNA rescue, replicated in multiple subsequent studies on the EDVP complex","pmids":["19287380"],"is_preprint":false},{"year":2009,"finding":"ATM phosphorylates DYRK2 at Thr-33 and Ser-369 upon genotoxic stress, enabling DYRK2 to dissociate from MDM2 and escape proteasomal degradation. Under basal conditions, nuclear DYRK2 is ubiquitinated by MDM2 and constitutively degraded. A functional nuclear localization signal was identified at the N-terminal domain of DYRK2.","method":"Co-immunoprecipitation, proteasome inhibitor treatment, phospho-site mutagenesis, siRNA knockdown, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, phospho-mutants, fractionation) in single rigorous study, mechanistically detailed","pmids":["19965871"],"is_preprint":false},{"year":2012,"finding":"DYRK2 functions as a priming kinase for c-Jun and c-Myc, phosphorylating them to enable subsequent GSK3β phosphorylation and βTrCP-mediated ubiquitin degradation. Knockdown of DYRK2 stabilizes unphosphorylated c-Jun and c-Myc, shortens G1 phase, and accelerates cell proliferation. Co-depletion of c-Jun or c-Myc completely reverses the pro-proliferative effect of DYRK2 knockdown.","method":"siRNA knockdown, phospho-specific Western blot, cell cycle analysis, in vivo xenograft, epistasis by co-knockdown","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis by double knockdown, in vivo confirmation, multiple orthogonal methods, mechanistically detailed","pmids":["22307329"],"is_preprint":false},{"year":2012,"finding":"SIAH2 E3 ligase interacts with DYRK2 and promotes its polyubiquitination and proteasomal degradation. Conversely, DYRK2 phosphorylates SIAH2 at five residues (Ser16, Thr26, Ser28, Ser68, and Thr119), modulating SIAH2 subcellular localization and its ability to degrade PHD3 and stabilize HIF-1α. Under hypoxia, SIAH2-dependent DYRK2 degradation impairs DYRK2-mediated Ser46 phosphorylation of p53.","method":"Co-immunoprecipitation, in vitro kinase assay, phosphomimetic/phospho-mutant constructs, ubiquitination assay, subcellular fractionation, siRNA knockdown","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro phosphorylation, phospho-mutant functional analysis, multiple orthogonal methods in single study","pmids":["22878263"],"is_preprint":false},{"year":2013,"finding":"DYRK2 controls EMT in breast cancer by phosphorylating Snail, priming it for GSK3β phosphorylation and subsequent βTrCP-mediated ubiquitin degradation. Knockdown of DYRK2 stabilizes Snail, promotes EMT, and increases cancer invasion in vitro and in vivo.","method":"siRNA knockdown, Western blot for Snail stability, invasion assays, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional knockdown with defined phenotype, biochemical mechanism inferred from substrate phosphorylation, but in vitro kinase assay not described in abstract","pmids":["23791882"],"is_preprint":false},{"year":2013,"finding":"DYRK2 phosphorylates TERT (the catalytic subunit of telomerase), leading to its association with the EDD-DDB1-VprBP E3 ligase complex, ubiquitination, and proteasomal degradation. This regulation occurs specifically at the G2/M phase. Endogenous DYRK2 depletion results in constitutive telomerase activation.","method":"Co-immunoprecipitation, in vitro kinase assay, cell cycle synchronization, ubiquitination assay, siRNA knockdown, telomerase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, Co-IP, ubiquitination assay, cell cycle-specific functional analysis in one study","pmids":["23362280"],"is_preprint":false},{"year":2014,"finding":"DYRK2 phosphorylates hPXR (human pregnane X receptor), and this phosphorylation facilitates subsequent ubiquitination of hPXR by the E3 ligase UBR5, leading to hPXR proteasomal degradation. DYRK2 knockdown phenocopies UBR5 knockdown, resulting in hPXR accumulation and increased hPXR transcriptional activity.","method":"Kinome-wide siRNA screen, MS analysis, co-immunoprecipitation, ubiquitination assay, knockdown rescue","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinome screen + biochemical validation, siRNA phenocopy, single lab","pmids":["24438055"],"is_preprint":false},{"year":2015,"finding":"DYRK2 negatively regulates virus-triggered type I interferon induction by phosphorylating TBK1 at Ser527, which primes TBK1 for recruitment of NLRP4 and the E3 ubiquitin ligase DTX4, leading to K48-linked ubiquitination and degradation of TBK1. This function is dependent on DYRK2 kinase activity.","method":"Co-immunoprecipitation, in vitro kinase assay, phospho-site mutagenesis, ubiquitination assay, siRNA knockdown, viral infection assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with phospho-site mutagenesis, ubiquitination assay, Co-IP, multiple orthogonal methods in single study","pmids":["26407194"],"is_preprint":false},{"year":2017,"finding":"Centrosomal protein Cep78 directly interacts with VprBP, specifically binding EDD-DYRK2-DDB1VprBP but not CRL4VprBP, and inhibits its E3 ligase activity. EDD-DYRK2-DDB1VprBP ubiquitinates CP110 (a novel centrosomal substrate) after DYRK2-mediated phosphorylation of CP110. Cep78 inhibits the final ubiquitin transfer step from EDD to CP110 without affecting CP110 phosphorylation or VprBP binding. Deregulation of this complex perturbs centriole length and cilia assembly.","method":"Co-immunoprecipitation, ubiquitination assay, in vitro kinase assay, RNAi knockdown, centrosome/cilia imaging","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, Co-IP, ubiquitination assay, defined substrate and inhibitor mechanism, multiple orthogonal methods","pmids":["28242748"],"is_preprint":false},{"year":2017,"finding":"DYRK2 directly interacts with RNF8, and this interaction is required for DNA damage-induced monoubiquitination of γ-H2AX. DYRK2 depletion impairs γ-H2AX ubiquitination, suppresses 53BP1 foci formation at DSBs, and reduces homologous recombination efficiency.","method":"High-throughput screening, co-immunoprecipitation, siRNA knockdown, γ-H2AX ubiquitination assay, homologous recombination reporter assay, foci imaging","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional knockdown with defined molecular readout (γ-H2AX ubiquitination), HR assay, single lab","pmids":["28194753"],"is_preprint":false},{"year":2019,"finding":"p38 MAPK directly phosphorylates Snail at Ser107, which suppresses DYRK2-mediated phosphorylation of Snail at Ser104. DYRK2 phosphorylation of Snail at Ser104 is critical for subsequent GSK3β-dependent phosphorylation and βTrCP-mediated ubiquitination and degradation of Snail.","method":"In vitro kinase assay, phospho-site mutagenesis, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with phospho-site mutagenesis defining the regulatory hierarchy, single lab but multiple orthogonal biochemical methods","pmids":["31209060"],"is_preprint":false},{"year":2019,"finding":"KLF4 transcriptionally represses the DYRK2 gene in CML leukemia stem/progenitor cells. Loss of KLF4 elevates DYRK2, which in turn depletes c-Myc protein and activates p53, impairing survival and self-renewal. Stabilization of DYRK2 protein by inhibiting SIAH2 with vitamin K3 promotes apoptosis and abrogates self-renewal in CML stem/progenitor cells.","method":"Klf4 conditional knockout mouse model, DYRK2 expression analysis, p53/c-Myc protein quantification, small-molecule SIAH2 inhibitor, colony/sphere-forming assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined molecular pathway, small-molecule validation, but mechanistic link relies partly on established DYRK2 substrates","pmids":["31515251"],"is_preprint":false},{"year":2020,"finding":"DYRK2 phosphorylates HSF1, promoting its nuclear stability and transcriptional activity in triple-negative breast cancer cells. DYRK2 depletion reduces HSF1 activity and sensitizes TNBC cells to proteotoxic stress.","method":"siRNA knockdown, phospho-specific Western blot, HSF1 transcriptional activity assays, proteotoxic stress sensitivity assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with HSF1 activity readout, phosphorylation evidence, single lab","pmids":["33268814"],"is_preprint":false},{"year":2020,"finding":"Loss of Dyrk2 in mice causes suppression of Hedgehog (Hh) signaling, skeletal abnormalities, abnormal ciliary morphology, and defective trafficking of Hh pathway components. Transcriptome analysis revealed downregulation of Aurora kinase A (Aurka) and other cilia disassembly genes following Dyrk2 deletion, identifying DYRK2 as a ciliogenesis-related kinase necessary for Hh signaling during embryogenesis.","method":"Dyrk2 knockout mice, in vivo phenotype analysis, RNA-seq, immunofluorescence for cilia morphology and Hh component localization","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model with defined molecular and developmental phenotype, transcriptome + imaging, single lab but rigorous in vivo study","pmids":["32758357"],"is_preprint":false},{"year":2021,"finding":"DYRK2 phosphorylates CDC25A on at least 7 residues, leading to its proteasomal degradation independent of known CDC25A E3 ubiquitin ligases. In turn, CDC25A controls DYRK2 phosphorylation at residues outside its activation loop, affecting DYRK2 localization and activity. This mutual regulatory feedback loop influences cell cycle progression and the DNA damage response.","method":"Co-immunoprecipitation, phospho-site mapping, in vitro kinase assay, siRNA knockdown, phosphoproteomic analysis, cell cycle analysis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, phospho-site identification, reciprocal regulation demonstrated, multiple orthogonal methods","pmids":["34363019"],"is_preprint":false},{"year":2021,"finding":"Dyrk2-deficient mice display congenital malformations including lung hypoplasia, with disrupted Foxf1 expression gradient in lung mesenchyme and reduced Foxf1 target genes necessary for proper airway and alveolar development. Restoring Shh signaling in ex vivo Dyrk2-deficient lung culture rescues Foxf1 and target gene expression.","method":"Dyrk2 conditional knockout mice, RNA-seq, ex vivo lung culture, in situ hybridization, immunofluorescence","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined transcriptional pathway, ex vivo rescue experiment, single lab","pmids":["34671097"],"is_preprint":false},{"year":2022,"finding":"DYRK2 promotes neddylation of cullins by forming a complex with NAE1 (a component of NEDD8-activating enzyme E1) and maintaining NAE1 protein level by suppressing its polyubiquitylation. Deletion of DYRK2 leads to persistent DNA double-strand breaks and genome instability.","method":"Co-immunoprecipitation, neddylation assay, DSB analysis (γ-H2AX), DYRK2 knockout cells, ubiquitination assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating complex, functional KO with defined molecular readout, single lab","pmids":["35582972"],"is_preprint":false},{"year":2022,"finding":"Using a potent selective DYRK2 inhibitor (C17) and quantitative phosphoproteomics, 4E-BP1 and STIM1 were identified as novel DYRK2 substrates. DYRK2 phosphorylates 4E-BP1 at multiple sites to regulate protein synthesis. DYRK2 phosphorylates STIM1, substantially increasing STIM1 interaction with the ORAI1 channel and promoting store-operated calcium entry.","method":"Structure-based inhibitor design with co-crystal structures, quantitative phosphoproteomics, in vitro kinase assay, Co-IP (STIM1-ORAI1), calcium entry assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — co-crystal structure-guided inhibitor, phosphoproteomics substrate identification, in vitro kinase validation, Co-IP, functional calcium assay; multiple orthogonal methods","pmids":["35439114"],"is_preprint":false},{"year":2022,"finding":"DYRK2 binds Twist and promotes its proteasomal degradation via ubiquitination in colorectal cancer cells, reducing EMT and chemoresistance. Co-immunoprecipitation confirmed direct DYRK2-Twist interaction.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot, siRNA knockdown/overexpression, in vivo xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, ubiquitination assay, multiple functional assays, but specific phosphorylation site on Twist not established in abstract","pmids":["36577753"],"is_preprint":false},{"year":2013,"finding":"DYRK2 negatively regulates cardiomyocyte growth by acting as a priming kinase for GSK-3β-mediated phosphorylation of eIF2Bε at Ser535, thereby inhibiting eIF2Bε activity and protein synthesis. DYRK2 overexpression increases phospho-eIF2Bε, reduces cardiomyocyte size, and diminishes hypertrophic response to adrenergic stimulation.","method":"Transgenic mouse overexpression, adenoviral overexpression, siRNA knockdown in cardiomyocytes, phospho-specific Western blot, isoproterenol stimulation, aortic banding model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic/adenoviral gain and loss of function, phospho-specific readout, in vivo and in vitro, single lab","pmids":["24023715"],"is_preprint":false},{"year":2024,"finding":"DYRK2 acts as a ciliary kinase that positively regulates Hedgehog signaling by phosphorylating GLI2 and GLI3 on evolutionarily conserved serine residues at the ciliary base downstream of Smoothened activation. This phosphorylation induces dissociation of GLI2/GLI3 from the suppressor SUFU and their nuclear translocation. Loss of Dyrk2 in mice causes skeletal malformation, and DYRK2-mediated phosphorylation controls limb cell proliferation.","method":"Dyrk2 knockout mice, in vitro kinase assay with phospho-site identification, interactome analysis, Co-IP (GLI-SUFU), transcriptome analysis, immunofluorescence for ciliary localization and nuclear translocation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with site identification, Co-IP for SUFU dissociation, genetic KO mouse, interactome + transcriptome, multiple orthogonal methods","pmids":["38968120"],"is_preprint":false},{"year":2025,"finding":"DYRK2 phosphorylates USP28, promoting its ubiquitination and proteasomal degradation in a kinase activity-independent manner. Conversely, USP28 deubiquitinates DYRK2, stabilizing its protein levels and enhancing its kinase activity. The 521–541 region of DYRK2, particularly residue T525, is required for USP28-mediated DYRK2 stabilization. This feedback loop modulates p53 Ser46 phosphorylation and apoptotic responses to DNA damage.","method":"Co-immunoprecipitation, ubiquitination assay, kinase-dead mutant analysis, site-directed mutagenesis (T525), deubiquitinase assay, p53-Ser46 phospho-specific Western blot","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination and deubiquitinase assays, site-directed mutagenesis, single lab","pmids":["40858801"],"is_preprint":false},{"year":2018,"finding":"HIV-1 Vpr localizes to the centrosome through DCAF1 binding and forms a complex with EDD-DYRK2-DDB1DCAF1, enhancing ubiquitination and degradation of CP110 (an EDD-DYRK2-DDB1 substrate), leading to centriole elongation and increased microtubule nucleation. Cep78 expression overcomes the Vpr-mediated CP110 degradation.","method":"Co-immunoprecipitation, ubiquitination assay, immunofluorescence for centrosome/centriole length, γ-tubulin recruitment assay, HIV-1 infection of T lymphocytes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional imaging, viral infection validation, mechanistically extends known DYRK2 complex biology","pmids":["29724823"],"is_preprint":false},{"year":2016,"finding":"Diminished DYRK2 leads to mTOR stabilization by reducing Thr631 phosphorylation of mTOR, which is required for mTOR ubiquitination and degradation. Ectopic DYRK2 expression promotes mTOR phosphorylation at Thr631 and its subsequent degradation, activating the mTORC1 pathway when DYRK2 is depleted.","method":"Ectopic DYRK2 overexpression, phospho-specific Western blot (mTOR Thr631), ubiquitination assay, siRNA knockdown, xenograft model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — phospho-specific western blot, ubiquitination assay, overexpression and knockdown, single lab","pmids":["27746162"],"is_preprint":false},{"year":2026,"finding":"DYRK2 interacts with CDK1 (identified by mass spectrometry and co-immunoprecipitation) and promotes inhibitory phosphorylation of CDK1 at Thr14, thereby inhibiting CDK1 activity and causing G2/M phase arrest in renal tubular epithelial cells under fibrotic conditions. Silencing DYRK2 restores CDK1 activity and cell cycle progression, and attenuates renal fibrosis.","method":"LC–MS/MS interactomics, co-immunoprecipitation, phospho-specific Western blot (CDK1 Thr14), siRNA knockdown, RNA-seq, in vivo fibrosis mouse models","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS + Co-IP for interaction, phospho-specific readout, KO functional phenotype, single lab","pmids":["41933287"],"is_preprint":false},{"year":2025,"finding":"Two DYRK2 variants identified in CAKUT patients disrupted EDD-DYRK2-DDB1VprBP complex formation without affecting DYRK2 kinase activity, establishing that DYRK2's scaffold function in the EDVP complex is genetically separable from its catalytic activity and is required for proper ciliogenesis relevant to kidney development.","method":"Co-immunoprecipitation of variant proteins, kinase activity assay, Shh signaling in RPE-1 cells, trio exome sequencing","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with variants, preprint, single lab, limited functional follow-up on DYRK2-specific mechanism","pmids":["40777246"],"is_preprint":true},{"year":2012,"finding":"In zebrafish, DYRK2 phosphorylates CRMP2 (Dpysl2) and CRMP4 (Dpysl3), and this phosphorylation is required (together with Cdk5) for proper positioning of Rohon-Beard sensory neurons and neural crest cells during neurulation. Phosphorylation-mimicking forms of Dpysl2/Dpysl3 rescue the ectopic cell positioning phenotype seen in cdk5/dyrk2 double morphants.","method":"Morpholino knockdown in zebrafish, cell transplantation, phosphomimetic rescue experiments","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double morphant), phosphomimetic rescue, in vivo cell transplantation, zebrafish ortholog","pmids":["22898304"],"is_preprint":false},{"year":2005,"finding":"In C. elegans, the DYRK2 ortholog MBK-2 directly phosphorylates OMA-1 at T239, which is required for OMA-1 function in the 1-cell embryo and for its timely degradation after the first mitotic division. Phosphorylation at T239 by MBK-2 facilitates subsequent phosphorylation of OMA-1 by GSK-3 at T339 in vitro, and both phosphorylations are required for correctly-timed OMA-1 degradation in vivo.","method":"In vitro kinase assay, phospho-site mutagenesis, RNAi, in vivo developmental analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, in vivo genetic validation, mechanistic cascade defined, C. elegans DYRK2 ortholog","pmids":["16289132"],"is_preprint":false},{"year":2008,"finding":"In C. elegans, the DYRK2 ortholog MBK-2 primes MEX-5 at T186 for subsequent polo kinase-dependent phosphorylation. Phosphorylation of MEX-5 at T186 by MBK-2 greatly enhances MEX-5 phosphorylation by polo kinases in vitro. T186 phosphorylation is required for polo kinase binding via polo box domains and is essential for MEX-5 function in regulating embryonic polarity.","method":"In vitro kinase assay, phospho-site mutagenesis, genetic analysis, polo box domain binding assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, mutagenesis, binding domain analysis, in vivo genetic validation, C. elegans DYRK2 ortholog","pmids":["18199581"],"is_preprint":false},{"year":2016,"finding":"Reduced DYRK2 expression increases KLF4 expression in breast cancer cells through androgen receptor (AR)-dependent transcriptional regulation of the KLF4 promoter, which depends on DYRK2 kinase activity. Elevated KLF4 then induces cancer stem-like properties.","method":"siRNA knockdown, KLF4 promoter luciferase assay, AR chromatin immunoprecipitation, kinase-dead mutant, sphere-forming assays, xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter assay, ChIP, kinase-dead mutant, multiple functional assays, single lab","pmids":["27721402"],"is_preprint":false},{"year":2024,"finding":"DYRK2 promotes ubiquitination and degradation of Twist1 in breast cancer cells by phosphorylating Twist1 (decreased Twist1 phosphorylation and increased ubiquitination observed after DYRK2 overexpression). Twist1 degradation reduces GSTP1 promoter binding by Twist1, suppressing GSTP1 transcription and reversing chemoresistance to docetaxel.","method":"Western blot, ubiquitination assay, lentiviral DYRK2 overexpression, phospho-specific western blot, promoter binding analysis, in vivo xenograft","journal":"Journal of molecular histology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ubiquitination assay and phospho-western blot without explicit in vitro kinase assay described in abstract, single lab, single study","pmids":["39641870"],"is_preprint":false}],"current_model":"DYRK2 is a dual-specificity serine/threonine kinase that (1) directly phosphorylates p53 at Ser46 to induce apoptosis after DNA damage (stabilized in the nucleus by ATM-mediated phosphorylation at Thr33/Ser369, which dissociates it from MDM2-mediated degradation); (2) acts as a scaffold for the EDD-DDB1-VPRBP (EDVP) E3 ubiquitin ligase complex and provides priming phosphorylation of substrates including katanin p60, TERT, and CP110 for their ubiquitin-mediated degradation; (3) functions as a priming kinase for GSK3β on substrates including c-Jun, c-Myc, Snail, and eIF2Bε, targeting them for proteasomal degradation and thereby regulating G1/S transition, EMT, and protein synthesis; (4) phosphorylates TBK1 at Ser527 to promote its K48-linked ubiquitination and degradation, suppressing antiviral type I interferon signaling; (5) acts as a ciliary kinase that phosphorylates GLI2/GLI3 downstream of Smoothened to dissociate them from SUFU and drive Hedgehog pathway activation during embryogenesis; and (6) engages additional substrates including STIM1 (regulating store-operated calcium entry), 4E-BP1 (regulating protein synthesis), CDC25A (mutual feedback regulation of cell cycle), NAE1 (regulating neddylation and genome stability), HSF1 (promoting proteotoxic stress survival), and CDK1 (inhibitory Thr14 phosphorylation in renal fibrosis)."},"narrative":{"mechanistic_narrative":"DYRK2 is a dual-specificity serine/threonine kinase that acts as a master priming kinase, marking diverse substrates for processive phosphorylation and ubiquitin-mediated degradation to control apoptosis, cell-cycle progression, EMT, ciliary signaling, and protein synthesis [PMID:17349958, PMID:19287380, PMID:22307329]. In the DNA damage response it translocates to the nucleus and directly phosphorylates p53 at Ser46 to induce p53AIP1-dependent apoptosis [PMID:17349958]; its nuclear pool is gated by competing modifications, with ATM phosphorylation at Thr33/Ser369 freeing it from MDM2-mediated degradation, while SIAH2 and USP28 oppose to set DYRK2 abundance and thereby p53-Ser46 output [PMID:19965871, PMID:22878263, PMID:40858801]. DYRK2 serves as the kinase-bearing scaffold of the EDD-DDB1-VPRBP (EDVP) E3 ligase, a function genetically separable from catalysis; it phosphorylates and primes substrates including katanin p60, TERT, and the centriolar protein CP110 for EDVP-mediated ubiquitination [PMID:19287380, PMID:23362280, PMID:28242748]. As a priming kinase upstream of GSK3β and βTrCP, DYRK2 phosphorylates c-Jun, c-Myc, Snail, and eIF2Bε to drive their proteasomal degradation, thereby restraining G1/S transition and proliferation, suppressing EMT, and limiting protein synthesis and cardiomyocyte growth [PMID:22307329, PMID:23791882, PMID:31209060, PMID:24023715]. DYRK2 phosphorylates TBK1 at Ser527 to prime its K48-linked ubiquitination and degradation, dampening type I interferon induction [PMID:26407194]. It also functions as a ciliary kinase that phosphorylates GLI2/GLI3 downstream of Smoothened, dissociating them from SUFU to activate Hedgehog signaling during skeletal and lung development [PMID:32758357, PMID:38968120]. Additional characterized substrates and partners include CDC25A and CDK1 (cell-cycle control), STIM1 and 4E-BP1, NAE1 (cullin neddylation and genome stability), and HSF1 (proteotoxic stress survival) [PMID:34363019, PMID:35439114, PMID:35582972, PMID:33268814, PMID:41933287]. DYRK2 scaffold-disrupting variants identified in CAKUT patients link its EDVP function to kidney development [PMID:40777246].","teleology":[{"year":2007,"claim":"Established DYRK2 as a direct effector of the DNA damage apoptotic program by identifying p53-Ser46 as a physiological substrate, answering how genotoxic stress couples to apoptotic p53 output.","evidence":"In vitro kinase assay, Ser46 phospho-specific detection, siRNA, nuclear translocation by fractionation/IF, apoptosis assays","pmids":["17349958"],"confidence":"High","gaps":["Upstream signal triggering nuclear translocation not defined here","Did not address non-apoptotic DYRK2 functions"]},{"year":2009,"claim":"Revealed a non-catalytic role: DYRK2 acts as the scaffold organizing the EDD-DDB1-VPRBP E3 ligase, while its kinase activity primes substrates such as katanin p60 for degradation, separating scaffold from catalytic functions.","evidence":"Reciprocal Co-IP, siRNA, ubiquitination assay, kinase-dead mutant dissection","pmids":["19287380"],"confidence":"High","gaps":["Full substrate repertoire of EDVP complex not defined","Stoichiometry/architecture of complex not resolved"]},{"year":2009,"claim":"Defined how nuclear DYRK2 abundance is controlled, showing ATM phosphorylation (Thr33/Ser369) dissociates DYRK2 from MDM2 to stabilize it for the p53 response.","evidence":"Co-IP, proteasome inhibition, phospho-site mutagenesis, siRNA, fractionation","pmids":["19965871"],"confidence":"High","gaps":["Whether ATM phosphorylates DYRK2 directly vs indirectly","Quantitative contribution to apoptotic threshold unclear"]},{"year":2012,"claim":"Identified the priming-kinase paradigm for proliferation control, showing DYRK2 primes c-Jun and c-Myc for GSK3β/βTrCP degradation to restrain G1 and proliferation.","evidence":"siRNA, phospho-Western, cell-cycle analysis, xenograft, epistasis by co-knockdown","pmids":["22307329"],"confidence":"High","gaps":["Phospho-sites on c-Jun/c-Myc not fully mapped here","Context dependence across cell types not addressed"]},{"year":2012,"claim":"Showed DYRK2 itself is regulated by SIAH2-mediated degradation and reciprocally phosphorylates SIAH2, linking DYRK2 stability to hypoxia and HIF-1α signaling.","evidence":"Co-IP, in vitro kinase assay, phospho-mutants, ubiquitination assay, fractionation, siRNA","pmids":["22878263"],"confidence":"High","gaps":["In vivo relevance of SIAH2-DYRK2 axis under hypoxia not established","Functional consequence of each SIAH2 phospho-site unclear"]},{"year":2013,"claim":"Extended the priming-kinase role to EMT and telomere maintenance, showing DYRK2 primes Snail for degradation and phosphorylates TERT for EDVP-mediated, G2/M-restricted degradation.","evidence":"siRNA, Western for substrate stability, invasion/telomerase assays, in vitro kinase assay, cell-cycle synchronization, xenograft","pmids":["23791882","23362280"],"confidence":"High","gaps":["Snail study did not show direct in vitro kinase assay","Cell-cycle gating mechanism for TERT phosphorylation not defined"]},{"year":2014,"claim":"Showed DYRK2 priming feeds non-GSK3β degradation pathways, phosphorylating hPXR to enable UBR5-mediated degradation, broadening the E3-ligase partnerships it serves.","evidence":"Kinome-wide siRNA screen, MS, Co-IP, ubiquitination assay, knockdown rescue","pmids":["24438055"],"confidence":"Medium","gaps":["hPXR phospho-sites not mapped","Physiological/pharmacological relevance not tested in vivo"]},{"year":2015,"claim":"Placed DYRK2 in innate antiviral signaling, showing TBK1-Ser527 phosphorylation primes NLRP4/DTX4-mediated K48 ubiquitination and TBK1 degradation to suppress type I interferon.","evidence":"Co-IP, in vitro kinase assay, phospho-site mutagenesis, ubiquitination assay, siRNA, viral infection","pmids":["26407194"],"confidence":"High","gaps":["Upstream regulation of DYRK2 during infection unknown","In vivo antiviral phenotype not established here"]},{"year":2017,"claim":"Defined CP110 as an EDVP substrate and Cep78 as a complex inhibitor acting at the ubiquitin-transfer step, linking the DYRK2-EDVP axis to centriole length and cilia assembly.","evidence":"Co-IP, in vitro kinase assay, ubiquitination assay, RNAi, centrosome/cilia imaging","pmids":["28242748"],"confidence":"High","gaps":["How Cep78 selectively blocks transfer mechanistically unclear","Physiological signals controlling CP110 turnover unknown"]},{"year":2017,"claim":"Connected DYRK2 to double-strand break repair, showing its RNF8 interaction is required for γ-H2AX monoubiquitination, 53BP1 foci, and homologous recombination.","evidence":"High-throughput screen, Co-IP, siRNA, γ-H2AX ubiquitination assay, HR reporter, foci imaging","pmids":["28194753"],"confidence":"Medium","gaps":["Whether DYRK2 phosphorylates RNF8 or another DDR factor unclear","Single lab, no reciprocal in vivo validation"]},{"year":2019,"claim":"Resolved a regulatory hierarchy on Snail, showing p38 MAPK phosphorylation at Ser107 suppresses DYRK2 priming at Ser104, controlling whether Snail is degraded.","evidence":"In vitro kinase assay, phospho-site mutagenesis, Co-IP, ubiquitination assay","pmids":["31209060"],"confidence":"High","gaps":["In vivo relevance of p38-DYRK2 antagonism not tested","Generalizability to other DYRK2 substrates unclear"]},{"year":2019,"claim":"Embedded DYRK2 in a transcriptional circuit in leukemia stem cells, showing KLF4 represses DYRK2 and that restoring DYRK2 depletes c-Myc and activates p53 to impair self-renewal.","evidence":"Klf4 conditional KO mouse, protein quantification, SIAH2 small-molecule inhibitor, colony/sphere assays","pmids":["31515251"],"confidence":"Medium","gaps":["Mechanistic link partly inferred from known substrates","Direct vs indirect DYRK2 effects on p53 in this context not dissected"]},{"year":2020,"claim":"Identified DYRK2 as a positive regulator of the proteotoxic stress response, phosphorylating HSF1 to sustain its nuclear stability and transcriptional activity in TNBC.","evidence":"siRNA, phospho-Western, HSF1 activity assays, proteotoxic stress sensitivity","pmids":["33268814"],"confidence":"Medium","gaps":["HSF1 phospho-sites not defined","Whether this is degradative or stabilizing priming unclear"]},{"year":2020,"claim":"Established DYRK2 as a ciliogenesis-related kinase required for Hedgehog signaling in vivo, with loss causing skeletal defects and abnormal ciliary morphology and Hh trafficking.","evidence":"Dyrk2 KO mice, RNA-seq, immunofluorescence for cilia and Hh components","pmids":["32758357"],"confidence":"High","gaps":["Direct ciliary substrate not yet identified in this study","Mechanism linking DYRK2 to Aurka downregulation unclear"]},{"year":2021,"claim":"Revealed a mutual DYRK2-CDC25A feedback loop, with DYRK2 driving CDC25A degradation independent of known E3s while CDC25A modulates DYRK2 localization and activity, integrating cell cycle and DDR.","evidence":"Co-IP, phospho-site mapping, in vitro kinase assay, siRNA, phosphoproteomics, cell-cycle analysis","pmids":["34363019"],"confidence":"High","gaps":["E3 ligase mediating CDC25A degradation downstream of DYRK2 unidentified","Net directionality of feedback under different conditions unclear"]},{"year":2021,"claim":"Linked DYRK2 to lung organogenesis through Shh, showing Dyrk2 loss disrupts the Foxf1 gradient and that restoring Shh rescues Foxf1 target expression.","evidence":"Dyrk2 conditional KO mice, RNA-seq, ex vivo lung culture, in situ hybridization, IF","pmids":["34671097"],"confidence":"Medium","gaps":["Direct ciliary substrate not defined in this study","Cell-type specificity of Shh defect not fully resolved"]},{"year":2022,"claim":"Connected DYRK2 to neddylation and genome stability, showing it complexes with NAE1 and stabilizes it, with DYRK2 loss causing persistent DSBs.","evidence":"Co-IP, neddylation assay, γ-H2AX DSB analysis, KO cells, ubiquitination assay","pmids":["35582972"],"confidence":"Medium","gaps":["Whether DYRK2 phosphorylates NAE1 directly unclear","Single lab without orthogonal in vivo validation"]},{"year":2022,"claim":"Used a structure-guided selective inhibitor and phosphoproteomics to identify 4E-BP1 and STIM1 as DYRK2 substrates, linking DYRK2 to protein synthesis and store-operated calcium entry.","evidence":"Co-crystal structure-guided inhibitor (C17), quantitative phosphoproteomics, in vitro kinase assay, STIM1-ORAI1 Co-IP, calcium assay","pmids":["35439114"],"confidence":"High","gaps":["Physiological contexts requiring these substrates not defined","Whether 4E-BP1/STIM1 phosphorylation triggers degradation or activity change varies and is incompletely resolved"]},{"year":2022,"claim":"Showed HIV-1 Vpr hijacks the EDD-DYRK2-DDB1 complex via DCAF1 to enhance CP110 degradation, driving centriole elongation, illustrating viral subversion of DYRK2-EDVP biology.","evidence":"Co-IP, ubiquitination assay, centriole/centrosome imaging, γ-tubulin assay, HIV-1 infection of T cells","pmids":["29724823"],"confidence":"Medium","gaps":["Consequence for viral replication/pathogenesis not established","Whether Vpr alters DYRK2 kinase activity unclear"]},{"year":2024,"claim":"Defined the direct ciliary mechanism of Hedgehog activation, showing DYRK2 phosphorylates GLI2/GLI3 at conserved serines at the ciliary base to dissociate them from SUFU and promote nuclear translocation.","evidence":"Dyrk2 KO mice, in vitro kinase assay with site ID, interactome, GLI-SUFU Co-IP, transcriptome, IF","pmids":["38968120"],"confidence":"High","gaps":["How Smoothened activation triggers DYRK2 ciliary activity unclear","Crosstalk with other GLI-regulating kinases not resolved"]},{"year":2025,"claim":"Identified a USP28-DYRK2 reciprocal feedback loop, where DYRK2 promotes USP28 degradation while USP28 deubiquitinates and stabilizes DYRK2 (via T525), tuning the p53-Ser46 apoptotic response.","evidence":"Co-IP, ubiquitination/deubiquitinase assays, kinase-dead and T525 mutants, p53-Ser46 phospho-Western","pmids":["40858801"],"confidence":"Medium","gaps":["In vivo relevance of the loop not tested","Single lab without independent confirmation"]},{"year":2025,"claim":"Provided human genetic evidence that DYRK2's EDVP scaffold function, separable from catalysis, is required for ciliogenesis relevant to kidney development, via CAKUT-associated variants.","evidence":"Co-IP of variant proteins, kinase activity assay, Shh signaling in RPE-1 cells, trio exome sequencing (preprint)","pmids":["40777246"],"confidence":"Low","gaps":["Preprint, single lab with limited functional follow-up","Causality of variants for CAKUT not formally established","No animal modeling of the variants"]},{"year":2026,"claim":"Linked DYRK2 to renal fibrosis, showing it phosphorylates CDK1 at inhibitory Thr14 to cause G2/M arrest in tubular epithelial cells, with silencing attenuating fibrosis.","evidence":"LC-MS/MS interactomics, Co-IP, CDK1-Thr14 phospho-Western, siRNA, RNA-seq, in vivo fibrosis models","pmids":["41933287"],"confidence":"Medium","gaps":["Whether DYRK2 phosphorylates CDK1 directly vs via Wee1/Myt1 unclear","Single lab; therapeutic translatability untested"]},{"year":null,"claim":"How DYRK2's many activating and inhibitory inputs (ATM, SIAH2, USP28, CDC25A, p38) are integrated to select among its competing substrate programs and subcellular pools in a given context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of context-specific substrate selection","Spatial regulation between nucleus, cytoplasm, and cilium incompletely mapped","Whether scaffold vs kinase functions are co-regulated unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,8,11,15,18,21,25]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,6,8,15,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,9,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[14,21]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[9,23]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,6,15,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,17,18]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,16,21]}],"complexes":["EDD-DDB1-VPRBP (EDVP) E3 ubiquitin ligase complex"],"partners":["EDD","DDB1","VPRBP","MDM2","SIAH2","USP28","RNF8","NAE1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92630","full_name":"Dual specificity tyrosine-phosphorylation-regulated kinase 2","aliases":[],"length_aa":601,"mass_kda":66.7,"function":"Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser-641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates TERT at 'Ser-457', promoting TERT ubiquitination by the EDVP complex. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q92630/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DYRK2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DYRK2","total_profiled":1310},"omim":[{"mim_id":"613482","title":"CYCLIN L2; CCNL2","url":"https://www.omim.org/entry/613482"},{"mim_id":"603497","title":"DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 3; DYRK3","url":"https://www.omim.org/entry/603497"},{"mim_id":"603496","title":"DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 2; DYRK2","url":"https://www.omim.org/entry/603496"},{"mim_id":"600855","title":"DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 1A; DYRK1A","url":"https://www.omim.org/entry/600855"},{"mim_id":"191170","title":"TUMOR PROTEIN p53; TP53","url":"https://www.omim.org/entry/191170"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DYRK2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q92630","domains":[{"cath_id":"1.10.510.10","chopping":"161-196_203-303","consensus_level":"medium","plddt":97.0153,"start":161,"end":303},{"cath_id":"1.10.510.10","chopping":"304-536","consensus_level":"medium","plddt":97.331,"start":304,"end":536}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92630","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92630-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92630-F1-predicted_aligned_error_v6.png","plddt_mean":75.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DYRK2","jax_strain_url":"https://www.jax.org/strain/search?query=DYRK2"},"sequence":{"accession":"Q92630","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92630.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92630/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92630"}},"corpus_meta":[{"pmid":"17349958","id":"PMC_17349958","title":"DYRK2 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Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3β-βTrCP-Induced Snail Degradation.","date":"2019","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31209060","citation_count":44,"is_preprint":false},{"pmid":"31505048","id":"PMC_31505048","title":"Multiple functions of DYRK2 in cancer and tissue development.","date":"2019","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/31505048","citation_count":42,"is_preprint":false},{"pmid":"28260923","id":"PMC_28260923","title":"Decrease of miR-622 expression suppresses migration and invasion by targeting regulation of DYRK2 in colorectal cancer cells.","date":"2017","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/28260923","citation_count":42,"is_preprint":false},{"pmid":"32462403","id":"PMC_32462403","title":"Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases.","date":"2020","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/32462403","citation_count":40,"is_preprint":false},{"pmid":"31515251","id":"PMC_31515251","title":"A KLF4-DYRK2-mediated pathway regulating self-renewal in CML stem cells.","date":"2019","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/31515251","citation_count":39,"is_preprint":false},{"pmid":"25603354","id":"PMC_25603354","title":"Engagement of DYRK2 in proper control for cell division.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/25603354","citation_count":38,"is_preprint":false},{"pmid":"20836251","id":"PMC_20836251","title":"Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors.","date":"2010","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/20836251","citation_count":38,"is_preprint":false},{"pmid":"22898304","id":"PMC_22898304","title":"Dpysl2 (CRMP2) and Dpysl3 (CRMP4) phosphorylation by Cdk5 and DYRK2 is required for proper positioning of Rohon-Beard neurons and neural crest cells during neurulation in zebrafish.","date":"2012","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22898304","citation_count":36,"is_preprint":false},{"pmid":"24438055","id":"PMC_24438055","title":"Stability of the human pregnane X receptor is regulated by E3 ligase UBR5 and serine/threonine kinase DYRK2.","date":"2014","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/24438055","citation_count":35,"is_preprint":false},{"pmid":"33268814","id":"PMC_33268814","title":"The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/33268814","citation_count":32,"is_preprint":false},{"pmid":"25712377","id":"PMC_25712377","title":"DYRK2 regulates epithelial-mesenchymal-transition and chemosensitivity through Snail degradation in ovarian serous adenocarcinoma.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25712377","citation_count":32,"is_preprint":false},{"pmid":"32758357","id":"PMC_32758357","title":"The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32758357","citation_count":32,"is_preprint":false},{"pmid":"34363019","id":"PMC_34363019","title":"A novel CDC25A/DYRK2 regulatory switch modulates cell cycle and survival.","date":"2021","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/34363019","citation_count":31,"is_preprint":false},{"pmid":"19596956","id":"PMC_19596956","title":"DYRK2 expression may be a predictive marker for chemotherapy in non-small cell lung 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pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/38889633","citation_count":6,"is_preprint":false},{"pmid":"35781054","id":"PMC_35781054","title":"Grass carp (Ctenopharyngodon idella) DYRK2 modulates cell apoptosis through phosphorylating p53.","date":"2022","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35781054","citation_count":6,"is_preprint":false},{"pmid":"36104345","id":"PMC_36104345","title":"A pan-cancer analysis of the oncogenic role of dual-specificity tyrosine (Y)-phosphorylation- regulated kinase 2 (DYRK2) in human tumors.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36104345","citation_count":6,"is_preprint":false},{"pmid":"38033250","id":"PMC_38033250","title":"Discovery of Potent, Selective, and Orally Bioavailable DYRK2 Inhibitors for the Treatment of Prostate Cancer.","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38033250","citation_count":6,"is_preprint":false},{"pmid":"37886981","id":"PMC_37886981","title":"Functional Roles of DYRK2 as a Tumor Regulator.","date":"2023","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37886981","citation_count":5,"is_preprint":false},{"pmid":"33368138","id":"PMC_33368138","title":"Frequent DYRK2 gene amplification in micropapillary element of lung adenocarcinoma - an implication in progression in EGFR-mutated lung adenocarcinoma.","date":"2020","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/33368138","citation_count":5,"is_preprint":false},{"pmid":"38727863","id":"PMC_38727863","title":"CircCOX6A1 suppresses osteogenic differentiation and aggravates osteoporosis via miR-512-3p/DYRK2 axis.","date":"2024","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/38727863","citation_count":4,"is_preprint":false},{"pmid":"35347031","id":"PMC_35347031","title":"Combination of DYRK2 and TERT Expression Is a Powerful Predictive Marker for Early-stage Breast Cancer Recurrence.","date":"2022","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35347031","citation_count":4,"is_preprint":false},{"pmid":"32964102","id":"PMC_32964102","title":"Determination of genetic variation within the DYRK2 gene and its associations with milk traits in cattle.","date":"2020","source":"Archives animal breeding","url":"https://pubmed.ncbi.nlm.nih.gov/32964102","citation_count":4,"is_preprint":false},{"pmid":"38656683","id":"PMC_38656683","title":"The diverse functions of DYRK2 in response to cellular stress.","date":"2024","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/38656683","citation_count":3,"is_preprint":false},{"pmid":"40858801","id":"PMC_40858801","title":"A novel feedback loop between DYRK2 and USP28 regulates cancer homeostasis and DNA damage signaling.","date":"2025","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/40858801","citation_count":2,"is_preprint":false},{"pmid":"39641870","id":"PMC_39641870","title":"DYRK2 controls GSTPI expression through ubiquitination and degradation of Twist1 to reduce chemotherapy resistance caused by EMT in breast cancer.","date":"2024","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/39641870","citation_count":2,"is_preprint":false},{"pmid":"39561721","id":"PMC_39561721","title":"DYRK2 regulates epithelial-mesenchymal transition restriction in pancreatic cancer liver metastasis by inhibiting Twist.","date":"2024","source":"Digestion","url":"https://pubmed.ncbi.nlm.nih.gov/39561721","citation_count":2,"is_preprint":false},{"pmid":"40145237","id":"PMC_40145237","title":"Benzamide Derivatives of Thioacridine as DYRK2 and DYRK3 Dual 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/40777246","citation_count":1,"is_preprint":false},{"pmid":"41524942","id":"PMC_41524942","title":"The dual fate of DYRK2 in cancer: balancing the light and dark side of tumorigenesis.","date":"2026","source":"Cancer metastasis reviews","url":"https://pubmed.ncbi.nlm.nih.gov/41524942","citation_count":1,"is_preprint":false},{"pmid":"41673049","id":"PMC_41673049","title":"A physics-informed graph neural network to approximate docking-based binding affinity for DYRK2 in Alzheimer's drug repurposing.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41673049","citation_count":1,"is_preprint":false},{"pmid":"41933287","id":"PMC_41933287","title":"DYRK2 drives renal fibrosis through CDK1-dependent G2/M phase dysregulation in tubular epithelial cells.","date":"2026","source":"Cellular & molecular biology 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ciliogenesis","date":"2025-07-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.16.665151","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39222,"output_tokens":8776,"usd":0.124653,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18478,"output_tokens":7172,"usd":0.135845,"stage2_stop_reason":"end_turn"},"total_usd":0.260498,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"DYRK2 directly phosphorylates p53 at Ser46 in the nucleus upon genotoxic stress, inducing p53AIP1 expression and apoptotic cell death in a Ser46 phosphorylation-dependent manner. DYRK2 translocates from cytoplasm to nucleus upon DNA damage to execute this phosphorylation.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody detection, siRNA knockdown, nuclear translocation by fractionation/immunofluorescence, apoptosis assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro phosphorylation assay, functional mutagenesis of Ser46, multiple orthogonal methods, replicated across subsequent studies\",\n      \"pmids\": [\"17349958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DYRK2 serves as a scaffold for an E3 ubiquitin ligase complex containing EDD, DDB1, and VPRBP (EDVP complex). siRNA depletion of DYRK2 disrupts formation of the EDD-DDB1-VPRBP complex. DYRK2 kinase activity, while dispensable for scaffold function, is required for phosphorylation and subsequent ubiquitin-mediated degradation of the substrate katanin p60.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, kinase-dead mutant analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, kinase-dead mutant dissection, siRNA rescue, replicated in multiple subsequent studies on the EDVP complex\",\n      \"pmids\": [\"19287380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATM phosphorylates DYRK2 at Thr-33 and Ser-369 upon genotoxic stress, enabling DYRK2 to dissociate from MDM2 and escape proteasomal degradation. Under basal conditions, nuclear DYRK2 is ubiquitinated by MDM2 and constitutively degraded. A functional nuclear localization signal was identified at the N-terminal domain of DYRK2.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor treatment, phospho-site mutagenesis, siRNA knockdown, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, phospho-mutants, fractionation) in single rigorous study, mechanistically detailed\",\n      \"pmids\": [\"19965871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DYRK2 functions as a priming kinase for c-Jun and c-Myc, phosphorylating them to enable subsequent GSK3β phosphorylation and βTrCP-mediated ubiquitin degradation. Knockdown of DYRK2 stabilizes unphosphorylated c-Jun and c-Myc, shortens G1 phase, and accelerates cell proliferation. Co-depletion of c-Jun or c-Myc completely reverses the pro-proliferative effect of DYRK2 knockdown.\",\n      \"method\": \"siRNA knockdown, phospho-specific Western blot, cell cycle analysis, in vivo xenograft, epistasis by co-knockdown\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis by double knockdown, in vivo confirmation, multiple orthogonal methods, mechanistically detailed\",\n      \"pmids\": [\"22307329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SIAH2 E3 ligase interacts with DYRK2 and promotes its polyubiquitination and proteasomal degradation. Conversely, DYRK2 phosphorylates SIAH2 at five residues (Ser16, Thr26, Ser28, Ser68, and Thr119), modulating SIAH2 subcellular localization and its ability to degrade PHD3 and stabilize HIF-1α. Under hypoxia, SIAH2-dependent DYRK2 degradation impairs DYRK2-mediated Ser46 phosphorylation of p53.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phosphomimetic/phospho-mutant constructs, ubiquitination assay, subcellular fractionation, siRNA knockdown\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro phosphorylation, phospho-mutant functional analysis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22878263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DYRK2 controls EMT in breast cancer by phosphorylating Snail, priming it for GSK3β phosphorylation and subsequent βTrCP-mediated ubiquitin degradation. Knockdown of DYRK2 stabilizes Snail, promotes EMT, and increases cancer invasion in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, Western blot for Snail stability, invasion assays, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional knockdown with defined phenotype, biochemical mechanism inferred from substrate phosphorylation, but in vitro kinase assay not described in abstract\",\n      \"pmids\": [\"23791882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DYRK2 phosphorylates TERT (the catalytic subunit of telomerase), leading to its association with the EDD-DDB1-VprBP E3 ligase complex, ubiquitination, and proteasomal degradation. This regulation occurs specifically at the G2/M phase. Endogenous DYRK2 depletion results in constitutive telomerase activation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, cell cycle synchronization, ubiquitination assay, siRNA knockdown, telomerase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, Co-IP, ubiquitination assay, cell cycle-specific functional analysis in one study\",\n      \"pmids\": [\"23362280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DYRK2 phosphorylates hPXR (human pregnane X receptor), and this phosphorylation facilitates subsequent ubiquitination of hPXR by the E3 ligase UBR5, leading to hPXR proteasomal degradation. DYRK2 knockdown phenocopies UBR5 knockdown, resulting in hPXR accumulation and increased hPXR transcriptional activity.\",\n      \"method\": \"Kinome-wide siRNA screen, MS analysis, co-immunoprecipitation, ubiquitination assay, knockdown rescue\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinome screen + biochemical validation, siRNA phenocopy, single lab\",\n      \"pmids\": [\"24438055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DYRK2 negatively regulates virus-triggered type I interferon induction by phosphorylating TBK1 at Ser527, which primes TBK1 for recruitment of NLRP4 and the E3 ubiquitin ligase DTX4, leading to K48-linked ubiquitination and degradation of TBK1. This function is dependent on DYRK2 kinase activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phospho-site mutagenesis, ubiquitination assay, siRNA knockdown, viral infection assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with phospho-site mutagenesis, ubiquitination assay, Co-IP, multiple orthogonal methods in single study\",\n      \"pmids\": [\"26407194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Centrosomal protein Cep78 directly interacts with VprBP, specifically binding EDD-DYRK2-DDB1VprBP but not CRL4VprBP, and inhibits its E3 ligase activity. EDD-DYRK2-DDB1VprBP ubiquitinates CP110 (a novel centrosomal substrate) after DYRK2-mediated phosphorylation of CP110. Cep78 inhibits the final ubiquitin transfer step from EDD to CP110 without affecting CP110 phosphorylation or VprBP binding. Deregulation of this complex perturbs centriole length and cilia assembly.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, in vitro kinase assay, RNAi knockdown, centrosome/cilia imaging\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, Co-IP, ubiquitination assay, defined substrate and inhibitor mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"28242748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DYRK2 directly interacts with RNF8, and this interaction is required for DNA damage-induced monoubiquitination of γ-H2AX. DYRK2 depletion impairs γ-H2AX ubiquitination, suppresses 53BP1 foci formation at DSBs, and reduces homologous recombination efficiency.\",\n      \"method\": \"High-throughput screening, co-immunoprecipitation, siRNA knockdown, γ-H2AX ubiquitination assay, homologous recombination reporter assay, foci imaging\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional knockdown with defined molecular readout (γ-H2AX ubiquitination), HR assay, single lab\",\n      \"pmids\": [\"28194753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p38 MAPK directly phosphorylates Snail at Ser107, which suppresses DYRK2-mediated phosphorylation of Snail at Ser104. DYRK2 phosphorylation of Snail at Ser104 is critical for subsequent GSK3β-dependent phosphorylation and βTrCP-mediated ubiquitination and degradation of Snail.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with phospho-site mutagenesis defining the regulatory hierarchy, single lab but multiple orthogonal biochemical methods\",\n      \"pmids\": [\"31209060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KLF4 transcriptionally represses the DYRK2 gene in CML leukemia stem/progenitor cells. Loss of KLF4 elevates DYRK2, which in turn depletes c-Myc protein and activates p53, impairing survival and self-renewal. Stabilization of DYRK2 protein by inhibiting SIAH2 with vitamin K3 promotes apoptosis and abrogates self-renewal in CML stem/progenitor cells.\",\n      \"method\": \"Klf4 conditional knockout mouse model, DYRK2 expression analysis, p53/c-Myc protein quantification, small-molecule SIAH2 inhibitor, colony/sphere-forming assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined molecular pathway, small-molecule validation, but mechanistic link relies partly on established DYRK2 substrates\",\n      \"pmids\": [\"31515251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DYRK2 phosphorylates HSF1, promoting its nuclear stability and transcriptional activity in triple-negative breast cancer cells. DYRK2 depletion reduces HSF1 activity and sensitizes TNBC cells to proteotoxic stress.\",\n      \"method\": \"siRNA knockdown, phospho-specific Western blot, HSF1 transcriptional activity assays, proteotoxic stress sensitivity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with HSF1 activity readout, phosphorylation evidence, single lab\",\n      \"pmids\": [\"33268814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of Dyrk2 in mice causes suppression of Hedgehog (Hh) signaling, skeletal abnormalities, abnormal ciliary morphology, and defective trafficking of Hh pathway components. Transcriptome analysis revealed downregulation of Aurora kinase A (Aurka) and other cilia disassembly genes following Dyrk2 deletion, identifying DYRK2 as a ciliogenesis-related kinase necessary for Hh signaling during embryogenesis.\",\n      \"method\": \"Dyrk2 knockout mice, in vivo phenotype analysis, RNA-seq, immunofluorescence for cilia morphology and Hh component localization\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model with defined molecular and developmental phenotype, transcriptome + imaging, single lab but rigorous in vivo study\",\n      \"pmids\": [\"32758357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DYRK2 phosphorylates CDC25A on at least 7 residues, leading to its proteasomal degradation independent of known CDC25A E3 ubiquitin ligases. In turn, CDC25A controls DYRK2 phosphorylation at residues outside its activation loop, affecting DYRK2 localization and activity. This mutual regulatory feedback loop influences cell cycle progression and the DNA damage response.\",\n      \"method\": \"Co-immunoprecipitation, phospho-site mapping, in vitro kinase assay, siRNA knockdown, phosphoproteomic analysis, cell cycle analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, phospho-site identification, reciprocal regulation demonstrated, multiple orthogonal methods\",\n      \"pmids\": [\"34363019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Dyrk2-deficient mice display congenital malformations including lung hypoplasia, with disrupted Foxf1 expression gradient in lung mesenchyme and reduced Foxf1 target genes necessary for proper airway and alveolar development. Restoring Shh signaling in ex vivo Dyrk2-deficient lung culture rescues Foxf1 and target gene expression.\",\n      \"method\": \"Dyrk2 conditional knockout mice, RNA-seq, ex vivo lung culture, in situ hybridization, immunofluorescence\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined transcriptional pathway, ex vivo rescue experiment, single lab\",\n      \"pmids\": [\"34671097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DYRK2 promotes neddylation of cullins by forming a complex with NAE1 (a component of NEDD8-activating enzyme E1) and maintaining NAE1 protein level by suppressing its polyubiquitylation. Deletion of DYRK2 leads to persistent DNA double-strand breaks and genome instability.\",\n      \"method\": \"Co-immunoprecipitation, neddylation assay, DSB analysis (γ-H2AX), DYRK2 knockout cells, ubiquitination assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating complex, functional KO with defined molecular readout, single lab\",\n      \"pmids\": [\"35582972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Using a potent selective DYRK2 inhibitor (C17) and quantitative phosphoproteomics, 4E-BP1 and STIM1 were identified as novel DYRK2 substrates. DYRK2 phosphorylates 4E-BP1 at multiple sites to regulate protein synthesis. DYRK2 phosphorylates STIM1, substantially increasing STIM1 interaction with the ORAI1 channel and promoting store-operated calcium entry.\",\n      \"method\": \"Structure-based inhibitor design with co-crystal structures, quantitative phosphoproteomics, in vitro kinase assay, Co-IP (STIM1-ORAI1), calcium entry assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — co-crystal structure-guided inhibitor, phosphoproteomics substrate identification, in vitro kinase validation, Co-IP, functional calcium assay; multiple orthogonal methods\",\n      \"pmids\": [\"35439114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DYRK2 binds Twist and promotes its proteasomal degradation via ubiquitination in colorectal cancer cells, reducing EMT and chemoresistance. Co-immunoprecipitation confirmed direct DYRK2-Twist interaction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot, siRNA knockdown/overexpression, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, ubiquitination assay, multiple functional assays, but specific phosphorylation site on Twist not established in abstract\",\n      \"pmids\": [\"36577753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DYRK2 negatively regulates cardiomyocyte growth by acting as a priming kinase for GSK-3β-mediated phosphorylation of eIF2Bε at Ser535, thereby inhibiting eIF2Bε activity and protein synthesis. DYRK2 overexpression increases phospho-eIF2Bε, reduces cardiomyocyte size, and diminishes hypertrophic response to adrenergic stimulation.\",\n      \"method\": \"Transgenic mouse overexpression, adenoviral overexpression, siRNA knockdown in cardiomyocytes, phospho-specific Western blot, isoproterenol stimulation, aortic banding model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic/adenoviral gain and loss of function, phospho-specific readout, in vivo and in vitro, single lab\",\n      \"pmids\": [\"24023715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DYRK2 acts as a ciliary kinase that positively regulates Hedgehog signaling by phosphorylating GLI2 and GLI3 on evolutionarily conserved serine residues at the ciliary base downstream of Smoothened activation. This phosphorylation induces dissociation of GLI2/GLI3 from the suppressor SUFU and their nuclear translocation. Loss of Dyrk2 in mice causes skeletal malformation, and DYRK2-mediated phosphorylation controls limb cell proliferation.\",\n      \"method\": \"Dyrk2 knockout mice, in vitro kinase assay with phospho-site identification, interactome analysis, Co-IP (GLI-SUFU), transcriptome analysis, immunofluorescence for ciliary localization and nuclear translocation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with site identification, Co-IP for SUFU dissociation, genetic KO mouse, interactome + transcriptome, multiple orthogonal methods\",\n      \"pmids\": [\"38968120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DYRK2 phosphorylates USP28, promoting its ubiquitination and proteasomal degradation in a kinase activity-independent manner. Conversely, USP28 deubiquitinates DYRK2, stabilizing its protein levels and enhancing its kinase activity. The 521–541 region of DYRK2, particularly residue T525, is required for USP28-mediated DYRK2 stabilization. This feedback loop modulates p53 Ser46 phosphorylation and apoptotic responses to DNA damage.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, kinase-dead mutant analysis, site-directed mutagenesis (T525), deubiquitinase assay, p53-Ser46 phospho-specific Western blot\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination and deubiquitinase assays, site-directed mutagenesis, single lab\",\n      \"pmids\": [\"40858801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HIV-1 Vpr localizes to the centrosome through DCAF1 binding and forms a complex with EDD-DYRK2-DDB1DCAF1, enhancing ubiquitination and degradation of CP110 (an EDD-DYRK2-DDB1 substrate), leading to centriole elongation and increased microtubule nucleation. Cep78 expression overcomes the Vpr-mediated CP110 degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, immunofluorescence for centrosome/centriole length, γ-tubulin recruitment assay, HIV-1 infection of T lymphocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional imaging, viral infection validation, mechanistically extends known DYRK2 complex biology\",\n      \"pmids\": [\"29724823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Diminished DYRK2 leads to mTOR stabilization by reducing Thr631 phosphorylation of mTOR, which is required for mTOR ubiquitination and degradation. Ectopic DYRK2 expression promotes mTOR phosphorylation at Thr631 and its subsequent degradation, activating the mTORC1 pathway when DYRK2 is depleted.\",\n      \"method\": \"Ectopic DYRK2 overexpression, phospho-specific Western blot (mTOR Thr631), ubiquitination assay, siRNA knockdown, xenograft model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — phospho-specific western blot, ubiquitination assay, overexpression and knockdown, single lab\",\n      \"pmids\": [\"27746162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DYRK2 interacts with CDK1 (identified by mass spectrometry and co-immunoprecipitation) and promotes inhibitory phosphorylation of CDK1 at Thr14, thereby inhibiting CDK1 activity and causing G2/M phase arrest in renal tubular epithelial cells under fibrotic conditions. Silencing DYRK2 restores CDK1 activity and cell cycle progression, and attenuates renal fibrosis.\",\n      \"method\": \"LC–MS/MS interactomics, co-immunoprecipitation, phospho-specific Western blot (CDK1 Thr14), siRNA knockdown, RNA-seq, in vivo fibrosis mouse models\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS + Co-IP for interaction, phospho-specific readout, KO functional phenotype, single lab\",\n      \"pmids\": [\"41933287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Two DYRK2 variants identified in CAKUT patients disrupted EDD-DYRK2-DDB1VprBP complex formation without affecting DYRK2 kinase activity, establishing that DYRK2's scaffold function in the EDVP complex is genetically separable from its catalytic activity and is required for proper ciliogenesis relevant to kidney development.\",\n      \"method\": \"Co-immunoprecipitation of variant proteins, kinase activity assay, Shh signaling in RPE-1 cells, trio exome sequencing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with variants, preprint, single lab, limited functional follow-up on DYRK2-specific mechanism\",\n      \"pmids\": [\"40777246\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, DYRK2 phosphorylates CRMP2 (Dpysl2) and CRMP4 (Dpysl3), and this phosphorylation is required (together with Cdk5) for proper positioning of Rohon-Beard sensory neurons and neural crest cells during neurulation. Phosphorylation-mimicking forms of Dpysl2/Dpysl3 rescue the ectopic cell positioning phenotype seen in cdk5/dyrk2 double morphants.\",\n      \"method\": \"Morpholino knockdown in zebrafish, cell transplantation, phosphomimetic rescue experiments\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double morphant), phosphomimetic rescue, in vivo cell transplantation, zebrafish ortholog\",\n      \"pmids\": [\"22898304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In C. elegans, the DYRK2 ortholog MBK-2 directly phosphorylates OMA-1 at T239, which is required for OMA-1 function in the 1-cell embryo and for its timely degradation after the first mitotic division. Phosphorylation at T239 by MBK-2 facilitates subsequent phosphorylation of OMA-1 by GSK-3 at T339 in vitro, and both phosphorylations are required for correctly-timed OMA-1 degradation in vivo.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis, RNAi, in vivo developmental analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, in vivo genetic validation, mechanistic cascade defined, C. elegans DYRK2 ortholog\",\n      \"pmids\": [\"16289132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In C. elegans, the DYRK2 ortholog MBK-2 primes MEX-5 at T186 for subsequent polo kinase-dependent phosphorylation. Phosphorylation of MEX-5 at T186 by MBK-2 greatly enhances MEX-5 phosphorylation by polo kinases in vitro. T186 phosphorylation is required for polo kinase binding via polo box domains and is essential for MEX-5 function in regulating embryonic polarity.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis, genetic analysis, polo box domain binding assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, mutagenesis, binding domain analysis, in vivo genetic validation, C. elegans DYRK2 ortholog\",\n      \"pmids\": [\"18199581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Reduced DYRK2 expression increases KLF4 expression in breast cancer cells through androgen receptor (AR)-dependent transcriptional regulation of the KLF4 promoter, which depends on DYRK2 kinase activity. Elevated KLF4 then induces cancer stem-like properties.\",\n      \"method\": \"siRNA knockdown, KLF4 promoter luciferase assay, AR chromatin immunoprecipitation, kinase-dead mutant, sphere-forming assays, xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter assay, ChIP, kinase-dead mutant, multiple functional assays, single lab\",\n      \"pmids\": [\"27721402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DYRK2 promotes ubiquitination and degradation of Twist1 in breast cancer cells by phosphorylating Twist1 (decreased Twist1 phosphorylation and increased ubiquitination observed after DYRK2 overexpression). Twist1 degradation reduces GSTP1 promoter binding by Twist1, suppressing GSTP1 transcription and reversing chemoresistance to docetaxel.\",\n      \"method\": \"Western blot, ubiquitination assay, lentiviral DYRK2 overexpression, phospho-specific western blot, promoter binding analysis, in vivo xenograft\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ubiquitination assay and phospho-western blot without explicit in vitro kinase assay described in abstract, single lab, single study\",\n      \"pmids\": [\"39641870\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DYRK2 is a dual-specificity serine/threonine kinase that (1) directly phosphorylates p53 at Ser46 to induce apoptosis after DNA damage (stabilized in the nucleus by ATM-mediated phosphorylation at Thr33/Ser369, which dissociates it from MDM2-mediated degradation); (2) acts as a scaffold for the EDD-DDB1-VPRBP (EDVP) E3 ubiquitin ligase complex and provides priming phosphorylation of substrates including katanin p60, TERT, and CP110 for their ubiquitin-mediated degradation; (3) functions as a priming kinase for GSK3β on substrates including c-Jun, c-Myc, Snail, and eIF2Bε, targeting them for proteasomal degradation and thereby regulating G1/S transition, EMT, and protein synthesis; (4) phosphorylates TBK1 at Ser527 to promote its K48-linked ubiquitination and degradation, suppressing antiviral type I interferon signaling; (5) acts as a ciliary kinase that phosphorylates GLI2/GLI3 downstream of Smoothened to dissociate them from SUFU and drive Hedgehog pathway activation during embryogenesis; and (6) engages additional substrates including STIM1 (regulating store-operated calcium entry), 4E-BP1 (regulating protein synthesis), CDC25A (mutual feedback regulation of cell cycle), NAE1 (regulating neddylation and genome stability), HSF1 (promoting proteotoxic stress survival), and CDK1 (inhibitory Thr14 phosphorylation in renal fibrosis).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DYRK2 is a dual-specificity serine/threonine kinase that acts as a master priming kinase, marking diverse substrates for processive phosphorylation and ubiquitin-mediated degradation to control apoptosis, cell-cycle progression, EMT, ciliary signaling, and protein synthesis [#0, #1, #3]. In the DNA damage response it translocates to the nucleus and directly phosphorylates p53 at Ser46 to induce p53AIP1-dependent apoptosis [#0]; its nuclear pool is gated by competing modifications, with ATM phosphorylation at Thr33/Ser369 freeing it from MDM2-mediated degradation, while SIAH2 and USP28 oppose to set DYRK2 abundance and thereby p53-Ser46 output [#2, #4, #22]. DYRK2 serves as the kinase-bearing scaffold of the EDD-DDB1-VPRBP (EDVP) E3 ligase, a function genetically separable from catalysis; it phosphorylates and primes substrates including katanin p60, TERT, and the centriolar protein CP110 for EDVP-mediated ubiquitination [#1, #6, #9]. As a priming kinase upstream of GSK3\\u03b2 and \\u03b2TrCP, DYRK2 phosphorylates c-Jun, c-Myc, Snail, and eIF2B\\u03b5 to drive their proteasomal degradation, thereby restraining G1/S transition and proliferation, suppressing EMT, and limiting protein synthesis and cardiomyocyte growth [#3, #5, #11, #20]. DYRK2 phosphorylates TBK1 at Ser527 to prime its K48-linked ubiquitination and degradation, dampening type I interferon induction [#8]. It also functions as a ciliary kinase that phosphorylates GLI2/GLI3 downstream of Smoothened, dissociating them from SUFU to activate Hedgehog signaling during skeletal and lung development [#14, #21]. Additional characterized substrates and partners include CDC25A and CDK1 (cell-cycle control), STIM1 and 4E-BP1, NAE1 (cullin neddylation and genome stability), and HSF1 (proteotoxic stress survival) [#15, #18, #17, #13, #25]. DYRK2 scaffold-disrupting variants identified in CAKUT patients link its EDVP function to kidney development [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established DYRK2 as a direct effector of the DNA damage apoptotic program by identifying p53-Ser46 as a physiological substrate, answering how genotoxic stress couples to apoptotic p53 output.\",\n      \"evidence\": \"In vitro kinase assay, Ser46 phospho-specific detection, siRNA, nuclear translocation by fractionation/IF, apoptosis assays\",\n      \"pmids\": [\"17349958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal triggering nuclear translocation not defined here\", \"Did not address non-apoptotic DYRK2 functions\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a non-catalytic role: DYRK2 acts as the scaffold organizing the EDD-DDB1-VPRBP E3 ligase, while its kinase activity primes substrates such as katanin p60 for degradation, separating scaffold from catalytic functions.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA, ubiquitination assay, kinase-dead mutant dissection\",\n      \"pmids\": [\"19287380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire of EDVP complex not defined\", \"Stoichiometry/architecture of complex not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined how nuclear DYRK2 abundance is controlled, showing ATM phosphorylation (Thr33/Ser369) dissociates DYRK2 from MDM2 to stabilize it for the p53 response.\",\n      \"evidence\": \"Co-IP, proteasome inhibition, phospho-site mutagenesis, siRNA, fractionation\",\n      \"pmids\": [\"19965871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATM phosphorylates DYRK2 directly vs indirectly\", \"Quantitative contribution to apoptotic threshold unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the priming-kinase paradigm for proliferation control, showing DYRK2 primes c-Jun and c-Myc for GSK3\\u03b2/\\u03b2TrCP degradation to restrain G1 and proliferation.\",\n      \"evidence\": \"siRNA, phospho-Western, cell-cycle analysis, xenograft, epistasis by co-knockdown\",\n      \"pmids\": [\"22307329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-sites on c-Jun/c-Myc not fully mapped here\", \"Context dependence across cell types not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed DYRK2 itself is regulated by SIAH2-mediated degradation and reciprocally phosphorylates SIAH2, linking DYRK2 stability to hypoxia and HIF-1\\u03b1 signaling.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, phospho-mutants, ubiquitination assay, fractionation, siRNA\",\n      \"pmids\": [\"22878263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of SIAH2-DYRK2 axis under hypoxia not established\", \"Functional consequence of each SIAH2 phospho-site unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the priming-kinase role to EMT and telomere maintenance, showing DYRK2 primes Snail for degradation and phosphorylates TERT for EDVP-mediated, G2/M-restricted degradation.\",\n      \"evidence\": \"siRNA, Western for substrate stability, invasion/telomerase assays, in vitro kinase assay, cell-cycle synchronization, xenograft\",\n      \"pmids\": [\"23791882\", \"23362280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Snail study did not show direct in vitro kinase assay\", \"Cell-cycle gating mechanism for TERT phosphorylation not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed DYRK2 priming feeds non-GSK3\\u03b2 degradation pathways, phosphorylating hPXR to enable UBR5-mediated degradation, broadening the E3-ligase partnerships it serves.\",\n      \"evidence\": \"Kinome-wide siRNA screen, MS, Co-IP, ubiquitination assay, knockdown rescue\",\n      \"pmids\": [\"24438055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"hPXR phospho-sites not mapped\", \"Physiological/pharmacological relevance not tested in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed DYRK2 in innate antiviral signaling, showing TBK1-Ser527 phosphorylation primes NLRP4/DTX4-mediated K48 ubiquitination and TBK1 degradation to suppress type I interferon.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, phospho-site mutagenesis, ubiquitination assay, siRNA, viral infection\",\n      \"pmids\": [\"26407194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream regulation of DYRK2 during infection unknown\", \"In vivo antiviral phenotype not established here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined CP110 as an EDVP substrate and Cep78 as a complex inhibitor acting at the ubiquitin-transfer step, linking the DYRK2-EDVP axis to centriole length and cilia assembly.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, ubiquitination assay, RNAi, centrosome/cilia imaging\",\n      \"pmids\": [\"28242748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Cep78 selectively blocks transfer mechanistically unclear\", \"Physiological signals controlling CP110 turnover unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected DYRK2 to double-strand break repair, showing its RNF8 interaction is required for \\u03b3-H2AX monoubiquitination, 53BP1 foci, and homologous recombination.\",\n      \"evidence\": \"High-throughput screen, Co-IP, siRNA, \\u03b3-H2AX ubiquitination assay, HR reporter, foci imaging\",\n      \"pmids\": [\"28194753\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DYRK2 phosphorylates RNF8 or another DDR factor unclear\", \"Single lab, no reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved a regulatory hierarchy on Snail, showing p38 MAPK phosphorylation at Ser107 suppresses DYRK2 priming at Ser104, controlling whether Snail is degraded.\",\n      \"evidence\": \"In vitro kinase assay, phospho-site mutagenesis, Co-IP, ubiquitination assay\",\n      \"pmids\": [\"31209060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of p38-DYRK2 antagonism not tested\", \"Generalizability to other DYRK2 substrates unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Embedded DYRK2 in a transcriptional circuit in leukemia stem cells, showing KLF4 represses DYRK2 and that restoring DYRK2 depletes c-Myc and activates p53 to impair self-renewal.\",\n      \"evidence\": \"Klf4 conditional KO mouse, protein quantification, SIAH2 small-molecule inhibitor, colony/sphere assays\",\n      \"pmids\": [\"31515251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link partly inferred from known substrates\", \"Direct vs indirect DYRK2 effects on p53 in this context not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified DYRK2 as a positive regulator of the proteotoxic stress response, phosphorylating HSF1 to sustain its nuclear stability and transcriptional activity in TNBC.\",\n      \"evidence\": \"siRNA, phospho-Western, HSF1 activity assays, proteotoxic stress sensitivity\",\n      \"pmids\": [\"33268814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HSF1 phospho-sites not defined\", \"Whether this is degradative or stabilizing priming unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established DYRK2 as a ciliogenesis-related kinase required for Hedgehog signaling in vivo, with loss causing skeletal defects and abnormal ciliary morphology and Hh trafficking.\",\n      \"evidence\": \"Dyrk2 KO mice, RNA-seq, immunofluorescence for cilia and Hh components\",\n      \"pmids\": [\"32758357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ciliary substrate not yet identified in this study\", \"Mechanism linking DYRK2 to Aurka downregulation unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a mutual DYRK2-CDC25A feedback loop, with DYRK2 driving CDC25A degradation independent of known E3s while CDC25A modulates DYRK2 localization and activity, integrating cell cycle and DDR.\",\n      \"evidence\": \"Co-IP, phospho-site mapping, in vitro kinase assay, siRNA, phosphoproteomics, cell-cycle analysis\",\n      \"pmids\": [\"34363019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating CDC25A degradation downstream of DYRK2 unidentified\", \"Net directionality of feedback under different conditions unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked DYRK2 to lung organogenesis through Shh, showing Dyrk2 loss disrupts the Foxf1 gradient and that restoring Shh rescues Foxf1 target expression.\",\n      \"evidence\": \"Dyrk2 conditional KO mice, RNA-seq, ex vivo lung culture, in situ hybridization, IF\",\n      \"pmids\": [\"34671097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ciliary substrate not defined in this study\", \"Cell-type specificity of Shh defect not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected DYRK2 to neddylation and genome stability, showing it complexes with NAE1 and stabilizes it, with DYRK2 loss causing persistent DSBs.\",\n      \"evidence\": \"Co-IP, neddylation assay, \\u03b3-H2AX DSB analysis, KO cells, ubiquitination assay\",\n      \"pmids\": [\"35582972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DYRK2 phosphorylates NAE1 directly unclear\", \"Single lab without orthogonal in vivo validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Used a structure-guided selective inhibitor and phosphoproteomics to identify 4E-BP1 and STIM1 as DYRK2 substrates, linking DYRK2 to protein synthesis and store-operated calcium entry.\",\n      \"evidence\": \"Co-crystal structure-guided inhibitor (C17), quantitative phosphoproteomics, in vitro kinase assay, STIM1-ORAI1 Co-IP, calcium assay\",\n      \"pmids\": [\"35439114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts requiring these substrates not defined\", \"Whether 4E-BP1/STIM1 phosphorylation triggers degradation or activity change varies and is incompletely resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed HIV-1 Vpr hijacks the EDD-DYRK2-DDB1 complex via DCAF1 to enhance CP110 degradation, driving centriole elongation, illustrating viral subversion of DYRK2-EDVP biology.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, centriole/centrosome imaging, \\u03b3-tubulin assay, HIV-1 infection of T cells\",\n      \"pmids\": [\"29724823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Consequence for viral replication/pathogenesis not established\", \"Whether Vpr alters DYRK2 kinase activity unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the direct ciliary mechanism of Hedgehog activation, showing DYRK2 phosphorylates GLI2/GLI3 at conserved serines at the ciliary base to dissociate them from SUFU and promote nuclear translocation.\",\n      \"evidence\": \"Dyrk2 KO mice, in vitro kinase assay with site ID, interactome, GLI-SUFU Co-IP, transcriptome, IF\",\n      \"pmids\": [\"38968120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Smoothened activation triggers DYRK2 ciliary activity unclear\", \"Crosstalk with other GLI-regulating kinases not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a USP28-DYRK2 reciprocal feedback loop, where DYRK2 promotes USP28 degradation while USP28 deubiquitinates and stabilizes DYRK2 (via T525), tuning the p53-Ser46 apoptotic response.\",\n      \"evidence\": \"Co-IP, ubiquitination/deubiquitinase assays, kinase-dead and T525 mutants, p53-Ser46 phospho-Western\",\n      \"pmids\": [\"40858801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of the loop not tested\", \"Single lab without independent confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided human genetic evidence that DYRK2's EDVP scaffold function, separable from catalysis, is required for ciliogenesis relevant to kidney development, via CAKUT-associated variants.\",\n      \"evidence\": \"Co-IP of variant proteins, kinase activity assay, Shh signaling in RPE-1 cells, trio exome sequencing (preprint)\",\n      \"pmids\": [\"40777246\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single lab with limited functional follow-up\", \"Causality of variants for CAKUT not formally established\", \"No animal modeling of the variants\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked DYRK2 to renal fibrosis, showing it phosphorylates CDK1 at inhibitory Thr14 to cause G2/M arrest in tubular epithelial cells, with silencing attenuating fibrosis.\",\n      \"evidence\": \"LC-MS/MS interactomics, Co-IP, CDK1-Thr14 phospho-Western, siRNA, RNA-seq, in vivo fibrosis models\",\n      \"pmids\": [\"41933287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DYRK2 phosphorylates CDK1 directly vs via Wee1/Myt1 unclear\", \"Single lab; therapeutic translatability untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DYRK2's many activating and inhibitory inputs (ATM, SIAH2, USP28, CDC25A, p38) are integrated to select among its competing substrate programs and subcellular pools in a given context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of context-specific substrate selection\", \"Spatial regulation between nucleus, cytoplasm, and cilium incompletely mapped\", \"Whether scaffold vs kinase functions are co-regulated unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 8, 11, 15, 18, 21, 25]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 6, 8, 15, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 9, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [14, 21]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [9, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 6, 15, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 17, 18]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 16, 21]}\n    ],\n    \"complexes\": [\n      \"EDD-DDB1-VPRBP (EDVP) E3 ubiquitin ligase complex\"\n    ],\n    \"partners\": [\n      \"EDD\",\n      \"DDB1\",\n      \"VPRBP\",\n      \"MDM2\",\n      \"SIAH2\",\n      \"USP28\",\n      \"RNF8\",\n      \"NAE1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}