{"gene":"CDK14","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2001,"finding":"Human PFTAIRE1 (CDK14) protein is localized to the cytoplasm when expressed as a GFP fusion in HeLa cells, as determined by fluorescence microscopy.","method":"GFP fusion protein expression and fluorescence microscopy in HeLa cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single localization experiment, single lab, no functional consequence linked","pmids":["11313143"],"is_preprint":false},{"year":1998,"finding":"Mouse Pftaire-1 (CDK14 ortholog) is expressed in late pachytene spermatocytes in the testis and in post-mitotic neuronal cells in the brain and embryo, suggesting roles in meiosis and neuron differentiation, as established by in situ hybridization.","method":"Northern blot and in situ hybridization in mouse tissues","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two orthogonal methods (Northern blot + in situ hybridization), single lab, localization without direct functional validation","pmids":["9547506"],"is_preprint":false},{"year":2007,"finding":"Human PFTK1 (CDK14) specifically interacts with cyclin D3 (CCND3) and forms a ternary complex with p21(Cip1); CCND3 is required for PFTK1 kinase activity, which is negatively regulated by p21(Cip1); Rb is a downstream phosphorylation substrate of the PFTK1/CCND3 complex; siRNA knockdown of PFTK1 causes G1 cell cycle arrest.","method":"Co-immunoprecipitation, siRNA knockdown, cell cycle analysis (flow cytometry), kinase assays in mammalian cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, kinase activity assays, siRNA phenotype with defined cell cycle readout, multiple orthogonal methods in one study","pmids":["17517622"],"is_preprint":false},{"year":2009,"finding":"Cyclin Y (CCNY) is a novel interacting partner of PFTK1 (CDK14) identified by yeast two-hybrid screen; the cyclin box of CCNY and the PFTAIRE motif of PFTK1 are both required for the interaction; binding of CCNY to PFTK1 enhances PFTK1 kinase activity and changes its intracellular localization; CCNY is enriched at the plasma membrane via an N-terminal myristoylation signal.","method":"Yeast two-hybrid screen, in vivo and in vitro binding assays, Northern blot, subcellular localization studies","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid discovery confirmed by in vivo and in vitro assays, domain mutagenesis, multiple orthogonal methods","pmids":["19524571"],"is_preprint":false},{"year":2010,"finding":"Caldesmon (CaD) is a downstream phosphorylation substrate of PFTK1 (CDK14); PFTK1 knockdown reduces CaD phosphorylation and causes dissociation of CaD from F-actin fibers, loss of actin stress fibers, and altered CaD subcellular localization in hepatocellular carcinoma cells.","method":"siRNA knockdown, immunofluorescence, co-localization analysis, phosphorylation assays in HCC cells","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined molecular phenotype (CaD phosphorylation, actin dynamics), single lab, two orthogonal methods","pmids":["21184254"],"is_preprint":false},{"year":2011,"finding":"PFTK1 (CDK14) phosphorylates TAGLN2 (transgelin2) at residues S83 and S163, inactivating its actin-binding function; in PFTK1-suppressed cells, unphosphorylated TAGLN2 exhibits strong actin-binding ability that inhibits actin cytoskeleton dynamics and cell motility; knockdown of TAGLN2 in PFTK1-suppressed cells rescues cell invasion and motility and restores actin polymerization. β-actin (ACTB) tyrosine phosphorylation is also affected by PFTK1.","method":"2D-PAGE mass spectrometry, siRNA knockdown, site-directed mutagenesis of TAGLN2, cell invasion/motility assays, actin polymerization assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phospho-proteomics discovery validated by mutagenesis at specific residues, epistasis (double KD rescue), multiple orthogonal methods in single study","pmids":["21577206"],"is_preprint":false},{"year":2014,"finding":"PFTK1 (CDK14) forms a direct complex with cyclin Y (CCNY) in HCC cells; this complex upregulates key components of noncanonical Wnt signaling (Dvl2 and Naked1) and activates Rho GTPases, leading to actin polymerization.","method":"Co-immunoprecipitation, exogenous expression, Rho GTPase activation assays, actin polymerization assays in HCC cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional readouts (Rho GTPase, actin), single lab","pmids":["24824184"],"is_preprint":false},{"year":2014,"finding":"CDK14 phosphorylates cyclin Y (CCNY) at Ser-71 and Ser-73, creating a phospho-degron that triggers CCNY ubiquitination by an SCF-Cul1 complex and its proteasomal degradation; mutation of these serines to alanine stabilizes CCNY and enhances CCNY/CDK14 activity on LRP6 phosphorylation, representing autoregulation of the cyclin Y/CDK14 pair.","method":"In vivo and in vitro phosphorylation mapping by mass spectrometry, Cul1 inactivation, site-directed mutagenesis (S71A/S73A), ubiquitination assays, LRP6 phosphorylation assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro + in vivo phosphorylation site mapping by MS, mutagenesis validation, functional consequence (ubiquitination, LRP6 phosphorylation), multiple orthogonal methods","pmids":["24794231"],"is_preprint":false},{"year":2014,"finding":"14-3-3 proteins (ε, β, η, τ isoforms) interact with cyclin Y (CCNY) via Ser-100 and Ser-326 residues, and this binding significantly enhances the association between CCNY and CDK14.","method":"Yeast two-hybrid screen, in vitro and in vivo binding assays, site-directed mutagenesis","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro and in vivo assays with mutagenesis, single lab","pmids":["24618387"],"is_preprint":false},{"year":2015,"finding":"CDK14 interacts with cyclin Y in spinal cord injury (SCI) rat model; CDK14 expression increases and peaks at 3 days post-SCI; CDK14 co-localizes with cyclin Y and with PCNA in astrocytes/glial cells, suggesting a role in reactive gliosis.","method":"Western blot, immunohistochemistry, double immunofluorescence, Co-immunoprecipitation in rat SCI model","journal":"Journal of molecular neuroscience : MN","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP confirms interaction in vivo, multiple staining methods, single lab with clear functional context","pmids":["26315607"],"is_preprint":false},{"year":2015,"finding":"PFTK1 (CDK14) knockdown in breast cancer cells attenuates Wnt/β-catenin signaling by reducing DVL2 levels and inhibiting β-catenin transcriptional targets (cyclin D1, MMP9, HEF1); PFTK1 interacts with cyclin B, and this complex increases DVL2 levels.","method":"Co-immunoprecipitation (cyclin B interaction), siRNA knockdown, Western blot, proliferation/migration/invasion assays in breast cancer cells","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for cyclin B interaction, siRNA with defined molecular pathway readouts, single lab","pmids":["26033031"],"is_preprint":false},{"year":2015,"finding":"PFTK1 (CDK14) knockdown in oligodendrocyte progenitor cell-derived OLN-93 cells promotes oligodendrocyte differentiation (increased CNPase, MOG, CGT, MBP markers); this effect is mediated through activation of the PI3K/AKT pathway but not the MAPK/ERK pathway, as AKT-specific inhibitor abrogates the differentiation-promoting effect of PFTK1 silencing.","method":"siRNA knockdown, qPCR, Western blot, AKT inhibitor epistasis in OLN-93 cells","journal":"Journal of molecular neuroscience : MN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis with pharmacological inhibitor, multiple differentiation marker readouts, single lab","pmids":["25355490"],"is_preprint":false},{"year":2016,"finding":"Caprin-2 positively regulates constitutive LRP5/6 Ser-1490 phosphorylation in a cell cycle-dependent manner (G2/M) by forming a quaternary complex with CDK14, Cyclin Y, and LRP5/6; Caprin-2 knockdown disrupts the CDK14–Cyclin Y interaction and the CDK14/Cyclin Y–LRP6 interaction.","method":"Co-immunoprecipitation, siRNA knockdown, cell cycle-dependent phosphorylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA epistasis, cell cycle-dependent phosphorylation assay, multiple orthogonal methods demonstrating quaternary complex","pmids":["27821587"],"is_preprint":false},{"year":2019,"finding":"FMF-04-159-2 is a potent covalent CDK14 inhibitor with TAIRE kinase-biased selectivity; covalent CDK14 inhibition affects cell-cycle regulation, particularly mitotic progression; phospho-proteomics under washout conditions identified putative CDK14-specific substrates.","method":"Covalent inhibitor development, phospho-proteomics, cell-cycle analysis with washout conditions","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — specific covalent inhibitor with biochemical characterization, unbiased phospho-proteomics, washout controls to deconvolute CDK14-specific effects","pmids":["30930164"],"is_preprint":false},{"year":2019,"finding":"Synthesis and SAR of covalent 4-amino-1H-pyrazole CDK14 inhibitors culminated in FMF-04-159-2, a potent, covalent CDK14 inhibitor with TAIRE kinase-biased selectivity profile.","method":"Medicinal chemistry synthesis, structure-activity relationship analysis, biochemical kinase selectivity profiling","journal":"Bioorganic & medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — chemical biology/SAR study, single paper, establishes inhibitor tool but limited biological mechanism","pmids":["31175010"],"is_preprint":false},{"year":2021,"finding":"In C. elegans, CDK-14 (mammalian CDK14 homolog) promotes axon regeneration via noncanonical Wnt signaling in a kinase-independent manner: CDK-14 binds MIG-5/Disheveled and activates EPHX-1 (ephexin RhoGEF), which activates CDC-42, inhibiting myosin phosphatase and maintaining MLC-4 phosphorylation. EGL-20/Wnt and MIG-1/Frizzled are required for efficient axon regeneration.","method":"Genetic epistasis (C. elegans), binding studies, GEF activity assays, phospho-mimetic rescue experiments in motor neurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple mutants and rescue experiments, identifies CDK14's kinase-independent mechanism, replicated across multiple genetic backgrounds","pmids":["34429379"],"is_preprint":false},{"year":2022,"finding":"CDK14 knockdown or pharmacological inhibition (FMF-04-159-2) reduces mammary basal cell colony-formation and regeneration capacity, inhibits MMTV-Wnt-1 mammary tumor progression, and suppresses TNBC progression and metastasis by attenuating Wnt/β-catenin signaling.","method":"Genetic knockdown, pharmacological inhibition (FMF-04-159-2), in vivo MMTV-Wnt-1 mouse model, in vitro colony-formation assays, Wnt signaling readouts","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological inhibition with concordant results, in vivo mouse model, defined pathway (Wnt/β-catenin) as mechanism","pmids":["36103813"],"is_preprint":false},{"year":2022,"finding":"CDK7/cyclin H (CAK complex) physically interacts with CDK14 in the cell nucleus and increases CDK14 phosphorylation; this activates CDK14 to phosphorylate Rb, inhibiting Rb function; overexpression of CDK7 with CDK14 strengthens colony formation and cisplatin resistance in ESCC cells.","method":"Co-immunoprecipitation, immunofluorescence co-localization, truncation mutant analysis, colony formation assays in ESCC cells","journal":"Annals of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and co-localization demonstrate CDK7-CDK14 interaction, functional consequence shown, single lab","pmids":["31930082"],"is_preprint":false},{"year":2023,"finding":"In Drosophila, Eip63E (CDK14 ortholog) regulates axogenesis; PFTK1 knockout mice show increased axonal outgrowth; PFTK1 phosphorylates GDP-bound inactive RhoA and this phosphorylation is required for RhoA activity, establishing RhoA as a CDK14 substrate mediating axon development.","method":"Drosophila genetic loss-of-function, PFTK1 knockout mouse model, RhoA phosphorylation assays in primary neuronal cultures, functional interaction studies","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cross-species validation (Drosophila + mouse KO), in vitro kinase assay showing RhoA as substrate, multiple orthogonal methods","pmids":["37907898"],"is_preprint":false},{"year":2023,"finding":"METTL1 adds internal m7G modifications to CDK14 mRNA, enhancing its stability and thereby promoting CRPC progression; the P300/SP1 complex binds the METTL1 promoter via SP1, mediating METTL1 transcriptional upregulation in CRPC.","method":"ChIP-qPCR, Co-IP, luciferase reporter assay, m7G AlkAniline-Seq, mRNA degradation assays, transcriptome sequencing","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including m7G-specific sequencing (AlkAniline-Seq), mRNA stability assays, ChIP, Co-IP in a single rigorous study","pmids":["37599359"],"is_preprint":false},{"year":2024,"finding":"CDK14 loss in the preformed fibrils (PFF) mouse model of Parkinson's disease mitigates grip strength deficits and reduces pS129 α-synuclein pathology in the cortex; Cdk14 depletion in primary neurons protects against propagation of toxic α-Syn species; pharmacological CDK14 inhibition (FMF-04-159-2) decreases total and pathologically aggregated α-Syn in human neurons, PFF-challenged rat neurons, and α-Syn-humanized mouse brains.","method":"Genetic Cdk14 knockout in PFF mouse model, primary neuron depletion assays, pharmacological inhibition in multiple model systems, pS129 α-Syn immunostaining","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological validation concordant across multiple model systems (mouse, rat neurons, human neurons), defined molecular phenotype (α-Syn aggregation)","pmids":["38575601"],"is_preprint":false},{"year":2024,"finding":"IGF2BP2 interacts with CDK14 mRNA, stabilizing it by inhibiting its degradation; CDK14 facilitates LRP6 and GSK3β phosphorylation, thereby regulating β-catenin levels and Wnt/β-catenin signaling during osteogenic differentiation.","method":"Co-IP (IGF2BP2-CDK14 mRNA interaction), siRNA knockdown, CDK14 inhibitor (FMF-04-159-2), Western blot for LRP6/GSK3β/β-catenin phosphorylation, osteogenesis assays","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNA-binding protein interaction with mRNA confirmed, pathway readouts established, single lab","pmids":["39447733"],"is_preprint":false},{"year":2024,"finding":"Gefitinib suppresses PFTK1 (CDK14) promoter methylation in a DNMT3B-dependent manner, upregulating CDK14 expression; CDK14 interacts with LRP6 and activates Wnt/β-catenin signaling to attenuate gefitinib-induced apoptosis and confer gefitinib resistance in NSCLC; FMF-04-159-2 reverses CDK14-mediated gefitinib resistance in vitro and in vivo.","method":"Promoter methylation analysis, DNMT3B manipulation, Co-IP (CDK14-LRP6), gain/loss-of-function assays, pharmacological inhibition in vitro and in vivo","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for CDK14-LRP6 interaction, epigenetic mechanism established, in vitro and in vivo pharmacological validation, single lab","pmids":["39702755"],"is_preprint":false},{"year":2025,"finding":"Genetic ablation of Cdk14 in mice impairs pulmonary vascular endothelial and alveolar epithelial cell proliferation, causes G2/M cell cycle arrest, and increases mortality and severity of bleomycin- or LPS-induced lung injury; RNA-seq reveals CDK14 knockdown controls STAT1 expression and interferon-signaling-associated genes; CDK14 disruption interferes with IFN-γ-induced lung repair.","method":"Cdk14 knockout mouse model, CDK14 covalent inhibitor FMF-04-159-2, RNA-seq, cell cycle analysis, in vivo lung injury models","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and pharmacological inhibition concordant, RNA-seq identifies mechanism (IFN-γ/STAT1 axis), in vivo phenotype with defined molecular pathway","pmids":["39827158"],"is_preprint":false},{"year":2025,"finding":"RNF213 ubiquitinates CDK14, inhibiting the CDK14-Pdgfrβ signaling pathway; maltol upregulates RNF213, thereby suppressing CDK14-Pdgfrβ signaling, M1 macrophage polarization, and NF-κB phosphorylation.","method":"In vitro and in vivo macrophage polarization assays, Western blot for CDK14-Pdgfrβ pathway, RNF213 overexpression/knockdown","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ubiquitination mechanism proposed with RNF213 as E3 ligase for CDK14, functional consequence shown, single lab","pmids":["40315161"],"is_preprint":false},{"year":2025,"finding":"IRX3 promotes CDK14 transcription by binding to its promoter (ChIP-confirmed); CDK14 then stabilizes β-catenin by restraining its ubiquitination and degradation, activating canonical Wnt/β-catenin signaling; LRP6 is identified as a crucial regulatory factor in IRX3-CDK14-mediated β-catenin stabilization in glioblastoma.","method":"ChIP assay, luciferase reporter assay, gain/loss-of-function in GBM cells, Western blot for β-catenin ubiquitination/stability","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional assays establish downstream mechanism, single lab","pmids":["41436436"],"is_preprint":false}],"current_model":"CDK14 (PFTK1/PFTAIRE1) is a cyclin-dependent serine/threonine kinase that is activated primarily by cyclin Y (and also cyclin D3 and cyclin B) to regulate cell cycle progression and Wnt signaling: at G2/M, the CDK14/cyclin Y complex—scaffolded by Caprin-2—phosphorylates LRP5/6 at Ser-1490, priming these Wnt co-receptors for subsequent Wnt-induced signaling; CDK14 can also activate noncanonical Wnt signaling via Rho GTPases; CDK14 phosphorylates substrates including Rb, TAGLN2, caldesmon (CaD), and RhoA to regulate actin dynamics, cell motility, and axogenesis; CDK14's own activity is autoregulated through CDK14-mediated phosphorylation of cyclin Y at Ser-71/73, triggering SCF-Cul1-dependent cyclin Y ubiquitination and degradation; 14-3-3 proteins enhance CDK14–cyclin Y association; CDK7 activates CDK14 by phosphorylation; in neurons, CDK14 can act in a kinase-independent manner via Disheveled to activate a RhoGEF-CDC42-myosin light chain phosphorylation axis promoting axon regeneration; CDK14 regulates α-synuclein levels and its inhibition is neuroprotective in synucleinopathy models; CDK14 mRNA stability is regulated by METTL1-mediated internal m7G modification and by IGF2BP2 binding."},"narrative":{"mechanistic_narrative":"CDK14 (PFTK1/PFTAIRE1) is a cyclin-dependent serine/threonine kinase that couples cell-cycle progression to Wnt signaling and actin cytoskeletal regulation [PMID:17517622, PMID:19524571, PMID:27821587]. Its kinase activity depends on association with a regulatory cyclin: cyclin D3 supports phosphorylation of Rb and is required for CDK14 activity, while siRNA depletion arrests cells in G1 [PMID:17517622], and a yeast two-hybrid-identified partner, cyclin Y, binds via the PFTAIRE motif, enhances kinase activity, and redirects CDK14 to the plasma membrane [PMID:19524571]. In a cell-cycle-dependent (G2/M) manner, a quaternary complex of CDK14, cyclin Y, the scaffold Caprin-2, and LRP5/6 drives constitutive LRP5/6 Ser-1490 phosphorylation, priming these Wnt co-receptors [PMID:27821587]; CDK14 also phosphorylates LRP6 and GSK3β to stabilize β-catenin and activate canonical Wnt/β-catenin signaling [PMID:24794231, PMID:39447733, PMID:41436436]. The cyclin Y/CDK14 pair is autoregulated: CDK14 phosphorylates cyclin Y at Ser-71/73 to create a phospho-degron triggering SCF-Cul1-dependent ubiquitination and degradation, while 14-3-3 proteins enhance the cyclin Y–CDK14 association and CDK7/cyclin H phosphorylates and activates CDK14 [PMID:24794231, PMID:24618387, PMID:31930082]. Beyond the cell cycle, CDK14 controls actin dynamics and motility by phosphorylating caldesmon and TAGLN2 (inactivating its actin-binding function) and by activating Rho GTPases through noncanonical Wnt components [PMID:21184254, PMID:21577206, PMID:24824184]; it phosphorylates GDP-bound RhoA to regulate axogenesis, and in C. elegans acts kinase-independently via Disheveled to drive a RhoGEF–CDC42–myosin light chain axis promoting axon regeneration [PMID:34429379, PMID:37907898]. CDK14 activity promotes tumor progression and therapy resistance via Wnt/β-catenin signaling across breast, esophageal, prostate, glioblastoma, and lung cancer models, and its inhibition is neuroprotective by reducing α-synuclein pathology in synucleinopathy models [PMID:36103813, PMID:38575601, PMID:39702755]. CDK14 abundance is post-transcriptionally controlled by METTL1-mediated m7G modification and IGF2BP2 binding to its mRNA, and by RNF213-mediated ubiquitination of the protein [PMID:37599359, PMID:39447733, PMID:40315161].","teleology":[{"year":1998,"claim":"Established the tissue and developmental expression pattern of the CDK14 ortholog, providing the first hint of roles in meiosis and post-mitotic neurons.","evidence":"Northern blot and in situ hybridization in mouse testis, brain, and embryo","pmids":["9547506"],"confidence":"Medium","gaps":["No molecular function or substrate identified","Expression correlation does not establish a mechanism"]},{"year":2001,"claim":"Localized the human protein to the cytoplasm, beginning the assignment of subcellular context to CDK14 function.","evidence":"GFP fusion expression and fluorescence microscopy in HeLa cells","pmids":["11313143"],"confidence":"Medium","gaps":["Single overexpression-based localization","No functional consequence linked","Later work showed cyclin Y can redirect localization to the membrane"]},{"year":2007,"claim":"Defined CDK14 as a bona fide cell-cycle kinase by identifying a cyclin partner (cyclin D3), a substrate (Rb), a negative regulator (p21), and a knockdown phenotype (G1 arrest).","evidence":"Reciprocal Co-IP, kinase assays, siRNA knockdown with flow-cytometry cell-cycle analysis in mammalian cells","pmids":["17517622"],"confidence":"High","gaps":["Did not establish which cyclin is the dominant physiological activator","No structural basis for activation"]},{"year":2009,"claim":"Identified cyclin Y as a CDK14 activating partner that enhances kinase activity and relocalizes the kinase, linking CDK14 to the membrane compartment.","evidence":"Yeast two-hybrid screen, in vivo/in vitro binding, domain mutagenesis, subcellular localization","pmids":["19524571"],"confidence":"High","gaps":["Membrane substrate not yet identified at this stage","Relationship between cyclin Y and cyclin D3 activation unresolved"]},{"year":2014,"claim":"Revealed a feedback loop and multiple regulatory inputs controlling the cyclin Y/CDK14 module, explaining how its activity is bounded and amplified.","evidence":"MS phospho-site mapping with S71A/S73A mutagenesis and ubiquitination assays (autoregulatory degron); yeast two-hybrid and binding assays (14-3-3); Co-IP and functional readouts (cyclin B, noncanonical Wnt/Rho GTPase) in HCC and other cells","pmids":["24794231","24618387","24824184"],"confidence":"High","gaps":["Physiological trigger for autophosphorylation-driven degradation unclear","Relative contributions of cyclin Y vs cyclin B in different tissues not resolved"]},{"year":2014,"claim":"Connected CDK14 to actin cytoskeletal control by identifying caldesmon and TAGLN2 as substrates whose phosphorylation governs actin binding, motility, and invasion.","evidence":"Phospho-proteomics, site-directed mutagenesis (TAGLN2 S83/S163), epistasis double-knockdown rescue, actin/invasion assays in HCC cells","pmids":["21184254","21577206"],"confidence":"High","gaps":["Direct kinase-substrate phosphorylation by purified CDK14 not fully established for caldesmon","In vivo relevance of these phospho-events untested"]},{"year":2016,"claim":"Established the scaffold and cell-cycle context for CDK14's canonical Wnt function: Caprin-2 assembles a CDK14/cyclin Y/LRP5/6 complex driving G2/M LRP5/6 Ser-1490 phosphorylation.","evidence":"Reciprocal Co-IP, siRNA epistasis, cell-cycle-dependent phosphorylation assays","pmids":["27821587"],"confidence":"High","gaps":["Structural arrangement of the quaternary complex unknown","How priming is coupled to ligand-induced signaling not detailed here"]},{"year":2019,"claim":"Provided a selective covalent chemical tool (FMF-04-159-2) and used it to deconvolute CDK14-specific substrates and confirm a mitotic-progression role.","evidence":"Covalent inhibitor development, SAR, washout phospho-proteomics, cell-cycle analysis","pmids":["30930164","31175010"],"confidence":"High","gaps":["Putative substrates from phospho-proteomics not individually validated","TAIRE-family cross-reactivity bounds interpretation"]},{"year":2021,"claim":"Uncovered a kinase-independent mode of CDK14 action in neurons, showing it can drive a Disheveled–RhoGEF–CDC42–MLC axis to promote axon regeneration.","evidence":"C. elegans genetic epistasis, binding studies, GEF activity assays, phospho-mimetic rescue in motor neurons","pmids":["34429379"],"confidence":"High","gaps":["Whether the kinase-independent mechanism operates in mammals not shown","Structural basis of CDK14–Disheveled binding undefined"]},{"year":2022,"claim":"Connected CDK14 activity to cancer dependency, demonstrating that genetic or pharmacological inhibition suppresses Wnt-driven mammary tumor and TNBC progression, and that CDK7 activates CDK14 to phosphorylate Rb and confer chemoresistance.","evidence":"Knockdown plus FMF-04-159-2, MMTV-Wnt-1 in vivo model, colony assays (breast); Co-IP, co-localization, truncation analysis, colony/cisplatin assays in ESCC","pmids":["36103813","31930082"],"confidence":"High","gaps":["Direct in vivo demonstration of CDK7-CDK14-Rb axis limited to one cancer type","Therapeutic window of CDK14 inhibition not defined"]},{"year":2023,"claim":"Identified RhoA as a direct CDK14 substrate in axogenesis and showed cross-species (Drosophila, mouse KO) requirement for CDK14 in axon development.","evidence":"Drosophila loss-of-function, PFTK1 knockout mice, RhoA phosphorylation assays in primary neurons","pmids":["37907898"],"confidence":"High","gaps":["Phospho-site on RhoA and structural consequence of phosphorylation not detailed","Reconciliation with kinase-independent regeneration mechanism open"]},{"year":2023,"claim":"Revealed post-transcriptional control of CDK14 abundance via METTL1-mediated internal m7G modification that stabilizes its mRNA to promote castration-resistant prostate cancer.","evidence":"m7G AlkAniline-Seq, mRNA degradation assays, ChIP-qPCR, Co-IP, luciferase reporter","pmids":["37599359"],"confidence":"High","gaps":["Whether m7G control operates outside CRPC unknown","Downstream CDK14 substrates in this context not mapped"]},{"year":2024,"claim":"Demonstrated CDK14 as a therapeutic target in synucleinopathy, with loss or inhibition reducing α-synuclein pathology, and extended Wnt regulation to osteogenesis under IGF2BP2-mediated mRNA stabilization.","evidence":"Cdk14 KO PFF mouse model and pharmacological inhibition across human/rat neurons (α-Syn); Co-IP, siRNA, inhibitor, and LRP6/GSK3β/β-catenin readouts in osteogenesis","pmids":["38575601","39447733"],"confidence":"High","gaps":["Molecular substrate linking CDK14 to α-Syn levels not identified","Whether α-Syn effect is Wnt-dependent unknown"]},{"year":2024,"claim":"Showed epigenetic and Wnt-mediated control of drug resistance: gefitinib derepresses CDK14 via DNMT3B-dependent promoter demethylation, and CDK14-LRP6-Wnt signaling attenuates apoptosis.","evidence":"Promoter methylation analysis, DNMT3B manipulation, Co-IP, in vitro/in vivo pharmacological inhibition in NSCLC","pmids":["39702755"],"confidence":"Medium","gaps":["Single-lab mechanism","Generality of methylation control across CDK14-driven cancers untested"]},{"year":2025,"claim":"Broadened CDK14's physiological roles to tissue repair and inflammation: it is required for endothelial/epithelial proliferation and lung repair via a STAT1/IFN axis, while RNF213-mediated ubiquitination restrains CDK14-Pdgfrβ signaling in macrophage polarization, and IRX3-driven transcription couples CDK14 to β-catenin stabilization in glioblastoma.","evidence":"Cdk14 KO mice with lung injury models and RNA-seq (STAT1/IFN); macrophage polarization assays with RNF213 manipulation; ChIP and β-catenin ubiquitination assays in GBM","pmids":["39827158","40315161","41436436"],"confidence":"Medium","gaps":["Direct CDK14 substrates in the STAT1/IFN and Pdgfrβ axes not defined","Single-lab mechanisms for RNF213 and IRX3 links"]},{"year":null,"claim":"It remains unresolved how CDK14 partitions between its distinct cyclin partners (D3, Y, B) and between kinase-dependent and kinase-independent modes across tissues, and which substrate connects it to α-synuclein homeostasis.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CDK14-cyclin or CDK14-substrate complexes in the corpus","Substrate linking CDK14 to α-Syn levels unidentified","Tissue-specific cyclin selection rules unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4,5,7,12,18]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,7,12,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,17]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,12,13,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,12,16,21,22,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[15,18]}],"complexes":["CDK14/cyclin Y","CDK14/cyclin D3/p21","CDK14/cyclin Y/Caprin-2/LRP5/6 quaternary complex","CDK7/cyclin H (CAK)"],"partners":["CCNY","CCND3","CAPRIN-2","LRP6","CDK7","14-3-3","DVL2","RHOA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94921","full_name":"Cyclin-dependent kinase 14","aliases":["Cell division protein kinase 14","Serine/threonine-protein kinase PFTAIRE-1","hPFTAIRE1"],"length_aa":469,"mass_kda":53.1,"function":"Serine/threonine-protein kinase involved in the control of the eukaryotic cell cycle, whose activity is controlled by an associated cyclin. Acts as a cell-cycle regulator of Wnt signaling pathway during G2/M phase by mediating the phosphorylation of LRP6 at 'Ser-1490', leading to the activation of the Wnt signaling pathway. Acts as a regulator of cell cycle progression and cell proliferation via its interaction with CCDN3. Phosphorylates RB1 in vitro, however the relevance of such result remains to be confirmed in vivo. May also play a role in meiosis, neuron differentiation and may indirectly act as a negative regulator of insulin-responsive glucose transport","subcellular_location":"Cell membrane; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O94921/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDK14","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDK14","total_profiled":1310},"omim":[{"mim_id":"610679","title":"CYCLIN-DEPENDENT KINASE 14; CDK14","url":"https://www.omim.org/entry/610679"},{"mim_id":"114550","title":"HEPATOCELLULAR CARCINOMA","url":"https://www.omim.org/entry/114550"}],"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/CDK14"},"hgnc":{"alias_symbol":["PFTAIRE1"],"prev_symbol":["PFTK1"]},"alphafold":{"accession":"O94921","domains":[{"cath_id":"3.30.200.20","chopping":"131-210","consensus_level":"high","plddt":83.6598,"start":131,"end":210},{"cath_id":"1.10.510.10","chopping":"214-436","consensus_level":"high","plddt":89.9936,"start":214,"end":436}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94921","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94921-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94921-F1-predicted_aligned_error_v6.png","plddt_mean":70.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDK14","jax_strain_url":"https://www.jax.org/strain/search?query=CDK14"},"sequence":{"accession":"O94921","fasta_url":"https://rest.uniprot.org/uniprotkb/O94921.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94921/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94921"}},"corpus_meta":[{"pmid":"30474270","id":"PMC_30474270","title":"LncRNA H19/miR-194/PFTK1 axis modulates the cell proliferation and migration of pancreatic cancer.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30474270","citation_count":78,"is_preprint":false},{"pmid":"21577206","id":"PMC_21577206","title":"A novel interplay between oncogenic PFTK1 protein kinase and tumor suppressor TAGLN2 in the control of liver cancer cell motility.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21577206","citation_count":78,"is_preprint":false},{"pmid":"29022909","id":"PMC_29022909","title":"miR-216a inhibits osteosarcoma cell proliferation, invasion and metastasis by targeting CDK14.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29022909","citation_count":77,"is_preprint":false},{"pmid":"19524571","id":"PMC_19524571","title":"Cyclin Y, a novel membrane-associated cyclin, interacts with PFTK1.","date":"2009","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/19524571","citation_count":77,"is_preprint":false},{"pmid":"29630731","id":"PMC_29630731","title":"Long non-coding RNA SNHG15 promotes CDK14 expression via miR-486 to accelerate non-small cell lung cancer cells progression and metastasis.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29630731","citation_count":71,"is_preprint":false},{"pmid":"30185212","id":"PMC_30185212","title":"The putative tumour suppressor miR-1-3p modulates prostate cancer cell aggressiveness by repressing E2F5 and PFTK1.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30185212","citation_count":65,"is_preprint":false},{"pmid":"17517622","id":"PMC_17517622","title":"Functional characterization of human PFTK1 as a cyclin-dependent kinase.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17517622","citation_count":58,"is_preprint":false},{"pmid":"30915884","id":"PMC_30915884","title":"The role of lncRNA MSC-AS1/miR-29b-3p axis-mediated CDK14 modulation in pancreatic cancer proliferation and Gemcitabine-induced apoptosis.","date":"2019","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30915884","citation_count":55,"is_preprint":false},{"pmid":"30119217","id":"PMC_30119217","title":"Long noncoding RNA OIP5-AS1 accelerates CDK14 expression to promote osteosarcoma tumorigenesis via targeting miR-223.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30119217","citation_count":53,"is_preprint":false},{"pmid":"37599359","id":"PMC_37599359","title":"P300/SP1 complex mediating elevated METTL1 regulates CDK14 mRNA stability via internal m7G modification in CRPC.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37599359","citation_count":51,"is_preprint":false},{"pmid":"28300591","id":"PMC_28300591","title":"miR-455 inhibits breast cancer cell proliferation through targeting CDK14.","date":"2017","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28300591","citation_count":45,"is_preprint":false},{"pmid":"24824184","id":"PMC_24824184","title":"PFTK1 interacts with cyclin Y to activate non-canonical Wnt signaling in hepatocellular carcinoma.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24824184","citation_count":44,"is_preprint":false},{"pmid":"26488471","id":"PMC_26488471","title":"PFTK1 Promotes Gastric Cancer Progression by Regulating Proliferation, Migration and Invasion.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26488471","citation_count":42,"is_preprint":false},{"pmid":"11313143","id":"PMC_11313143","title":"Identification and cellular localization of human PFTAIRE1.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11313143","citation_count":41,"is_preprint":false},{"pmid":"34247316","id":"PMC_34247316","title":"Hypoxia associated lncRNA HYPAL promotes proliferation of gastric cancer as ceRNA by sponging miR-431-5p to upregulate CDK14.","date":"2021","source":"Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association","url":"https://pubmed.ncbi.nlm.nih.gov/34247316","citation_count":40,"is_preprint":false},{"pmid":"30557834","id":"PMC_30557834","title":"MiR-542-3p, a microRNA targeting CDK14, suppresses cell proliferation, invasiveness, and tumorigenesis of epithelial ovarian cancer.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30557834","citation_count":38,"is_preprint":false},{"pmid":"30480816","id":"PMC_30480816","title":"Knockdown of NEAT1 repressed the malignant progression of glioma through sponging miR-107 and inhibiting CDK14.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30480816","citation_count":37,"is_preprint":false},{"pmid":"9547506","id":"PMC_9547506","title":"The identification and characterization of expression of Pftaire-1, a novel Cdk family member, suggest its function in the mouse testis and nervous system.","date":"1998","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/9547506","citation_count":35,"is_preprint":false},{"pmid":"29944887","id":"PMC_29944887","title":"Long noncoding RNA LINC00858 promotes osteosarcoma through regulating miR-139-CDK14 axis.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29944887","citation_count":32,"is_preprint":false},{"pmid":"22333595","id":"PMC_22333595","title":"Overexpression of PFTK1 predicts resistance to chemotherapy in patients with oesophageal squamous cell carcinoma.","date":"2012","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22333595","citation_count":29,"is_preprint":false},{"pmid":"26033031","id":"PMC_26033031","title":"Upregulated PFTK1 promotes tumor cell proliferation, migration, and invasion in breast cancer.","date":"2015","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26033031","citation_count":28,"is_preprint":false},{"pmid":"31930082","id":"PMC_31930082","title":"CDK14 involvement in proliferation migration and invasion of esophageal cancer.","date":"2019","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31930082","citation_count":28,"is_preprint":false},{"pmid":"30488589","id":"PMC_30488589","title":"LINC00707 contributes to hepatocellular carcinoma progression via sponging miR-206 to increase CDK14.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30488589","citation_count":26,"is_preprint":false},{"pmid":"26772918","id":"PMC_26772918","title":"PFTK1 regulates cell proliferation, migration and invasion in epithelial ovarian cancer.","date":"2016","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/26772918","citation_count":23,"is_preprint":false},{"pmid":"30930164","id":"PMC_30930164","title":"Discovery of Covalent CDK14 Inhibitors with Pan-TAIRE Family Specificity.","date":"2019","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/30930164","citation_count":23,"is_preprint":false},{"pmid":"36103813","id":"PMC_36103813","title":"CDK14 inhibition reduces mammary stem cell activity and suppresses triple negative breast cancer progression.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36103813","citation_count":22,"is_preprint":false},{"pmid":"27821587","id":"PMC_27821587","title":"Activation/Proliferation-associated Protein 2 (Caprin-2) Positively Regulates CDK14/Cyclin Y-mediated Lipoprotein Receptor-related Protein 5 and 6 (LRP5/6) Constitutive Phosphorylation.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27821587","citation_count":21,"is_preprint":false},{"pmid":"30600185","id":"PMC_30600185","title":"TCF3-activated LINC00152 exerts oncogenic role in osteosarcoma through regulating miR-1182/CDK14 axis.","date":"2018","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/30600185","citation_count":20,"is_preprint":false},{"pmid":"34031947","id":"PMC_34031947","title":"Hsa_circRNA_102229 facilitates the progression of triple-negative breast cancer via regulating the miR-152-3p/PFTK1 pathway.","date":"2021","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34031947","citation_count":19,"is_preprint":false},{"pmid":"27458094","id":"PMC_27458094","title":"Knockdown of PFTAIRE Protein Kinase 1 (PFTK1) Inhibits Proliferation, Invasion, and EMT in Colon Cancer Cells.","date":"2016","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/27458094","citation_count":18,"is_preprint":false},{"pmid":"26823712","id":"PMC_26823712","title":"Knockdown of PFTK1 inhibits tumor cell proliferation, invasion and epithelial-to-mesenchymal transition in pancreatic cancer.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26823712","citation_count":16,"is_preprint":false},{"pmid":"35307379","id":"PMC_35307379","title":"CircRNA_0078767 promotes osteosarcoma progression by increasing CDK14 expression through sponging microRNA-330-3p.","date":"2022","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/35307379","citation_count":16,"is_preprint":false},{"pmid":"21184254","id":"PMC_21184254","title":"Phosphorylation of Caldesmon by PFTAIRE1 kinase promotes actin binding and formation of stress fibers.","date":"2010","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21184254","citation_count":15,"is_preprint":false},{"pmid":"26234562","id":"PMC_26234562","title":"Knockdown of PFTK1 Inhibits the Migration of Glioma Cells.","date":"2015","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/26234562","citation_count":15,"is_preprint":false},{"pmid":"30058687","id":"PMC_30058687","title":"MiR-431 inhibits cell proliferation and induces cell apoptosis by targeting CDK14 in pancreatic cancer.","date":"2018","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30058687","citation_count":14,"is_preprint":false},{"pmid":"26315607","id":"PMC_26315607","title":"CDK14 Contributes to Reactive Gliosis via Interaction with Cyclin Y in Rat Model of Spinal Cord Injury.","date":"2015","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/26315607","citation_count":13,"is_preprint":false},{"pmid":"32605563","id":"PMC_32605563","title":"Upregulation of miR-1825 inhibits the progression of glioblastoma by suppressing CDK14 though Wnt/β-catenin signaling pathway.","date":"2020","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32605563","citation_count":13,"is_preprint":false},{"pmid":"24794231","id":"PMC_24794231","title":"Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation.","date":"2014","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/24794231","citation_count":12,"is_preprint":false},{"pmid":"33764714","id":"PMC_33764714","title":"LncRNA NORAD accelerates the progression of non-small cell lung cancer via targeting miRNA-455/CDK14 axis.","date":"2021","source":"Minerva medica","url":"https://pubmed.ncbi.nlm.nih.gov/33764714","citation_count":11,"is_preprint":false},{"pmid":"24618387","id":"PMC_24618387","title":"14-3-3 Binding to Cyclin Y contributes to cyclin Y/CDK14 association.","date":"2014","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/24618387","citation_count":11,"is_preprint":false},{"pmid":"34429379","id":"PMC_34429379","title":"CDK14 Promotes Axon Regeneration by Regulating the Noncanonical Wnt Signaling Pathway in a Kinase-Independent Manner.","date":"2021","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34429379","citation_count":10,"is_preprint":false},{"pmid":"25355490","id":"PMC_25355490","title":"Serine/threonine-protein kinase PFTK1 modulates oligodendrocyte differentiation via PI3K/AKT pathway.","date":"2014","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/25355490","citation_count":9,"is_preprint":false},{"pmid":"32602632","id":"PMC_32602632","title":"Long noncoding RNAs SET-binding factor 2-antisense RNA1 promotes cell growth through targeting miR-431-5p/CDK14 axis in human papillary thyroid cancer.","date":"2020","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32602632","citation_count":9,"is_preprint":false},{"pmid":"25680692","id":"PMC_25680692","title":"CDK14 expression is down-regulated by cigarette smoke in vivo and in vitro.","date":"2015","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/25680692","citation_count":8,"is_preprint":false},{"pmid":"35218724","id":"PMC_35218724","title":"Silencing of circ-CDK14 suppresses osteosarcoma progression through the miR-198/E2F2 axis.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35218724","citation_count":8,"is_preprint":false},{"pmid":"27458099","id":"PMC_27458099","title":"Knockdown of PFTK1 Expression by RNAi Inhibits the Proliferation and Invasion of Human Non-Small Lung Adenocarcinoma Cells.","date":"2016","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/27458099","citation_count":8,"is_preprint":false},{"pmid":"33871149","id":"PMC_33871149","title":"CDK14/β-catenin/TCF4/miR-26b positive feedback regulation modulating pancreatic cancer cell phenotypes in vitro and tumor growth in mice model in vivo.","date":"2021","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33871149","citation_count":7,"is_preprint":false},{"pmid":"33209486","id":"PMC_33209486","title":"The anti-tumor effect of miR-539-3p on colon cancer via regulating cell viability, motility, and nude mouse tumorigenicity with CDK14 inhibition.","date":"2020","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33209486","citation_count":7,"is_preprint":false},{"pmid":"39827158","id":"PMC_39827158","title":"CDK14 regulates the development and repair of lung.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39827158","citation_count":5,"is_preprint":false},{"pmid":"38575601","id":"PMC_38575601","title":"Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38575601","citation_count":5,"is_preprint":false},{"pmid":"34348465","id":"PMC_34348465","title":"Depletion of circRNA circ_CDK14 inhibits osteosarcoma progression by regulating the miR-520a-3p/GAB1 axis.","date":"2021","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/34348465","citation_count":5,"is_preprint":false},{"pmid":"34728797","id":"PMC_34728797","title":"Amygdala DCX and blood Cdk14 are implicated as cross-species indicators of individual differences in fear, extinction, and resilience to trauma exposure.","date":"2021","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/34728797","citation_count":5,"is_preprint":false},{"pmid":"40315161","id":"PMC_40315161","title":"Mechanistic Insights into Maltol-Mediated Reversal of Postmenopausal Osteoporosis via Regulation of CDK14 Ubiquitination in Macrophages.","date":"2025","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40315161","citation_count":4,"is_preprint":false},{"pmid":"39447733","id":"PMC_39447733","title":"CDK14 is regulated by IGF2BP2 and involved in osteogenic differentiation via Wnt/β-catenin signaling pathway in vitro.","date":"2024","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39447733","citation_count":3,"is_preprint":false},{"pmid":"37420040","id":"PMC_37420040","title":"miR-1-3p Inhibits Osteosarcoma Cell Proliferation and Cell Cycle Progression While Promoting Cell Apoptosis by Targeting CDK14 to Inactivate Wnt/Beta-Catenin Signaling.","date":"2023","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/37420040","citation_count":3,"is_preprint":false},{"pmid":"39702755","id":"PMC_39702755","title":"Methylation-modulated PFTK1 regulates gefitinib resistance via Wnt/β-catenin signaling in EGFR mutant non-small-cell lung cancer cells.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/39702755","citation_count":3,"is_preprint":false},{"pmid":"33061417","id":"PMC_33061417","title":"Downregulation of PFTK1 Inhibits Migration and Invasion of Non-Small Cell Lung Cancer.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33061417","citation_count":2,"is_preprint":false},{"pmid":"31175010","id":"PMC_31175010","title":"Synthesis and structure activity relationships of a series of 4-amino-1H-pyrazoles as covalent inhibitors of CDK14.","date":"2019","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/31175010","citation_count":2,"is_preprint":false},{"pmid":"37907898","id":"PMC_37907898","title":"PFTK1 kinase regulates axogenesis during development via RhoA activation.","date":"2023","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/37907898","citation_count":1,"is_preprint":false},{"pmid":"41436436","id":"PMC_41436436","title":"IRX3-CDK14 axis promotes glioblastoma progression by regulating LRP6-mediated canonical Wnt/β-catenin pathway.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41436436","citation_count":1,"is_preprint":false},{"pmid":"41016985","id":"PMC_41016985","title":"5-Hydroxytryptamine promotes non-small cell lung cancer metastasis via the SNRPG/WT1/CDK14 Axis.","date":"2025","source":"Molecular biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/41016985","citation_count":1,"is_preprint":false},{"pmid":"37906510","id":"PMC_37906510","title":"Acquired resistance to crizotinib in novel CDK14-ALK and CLTC-ALK fusions of ALK-positive large B-cell lymphoma identified by next-generation sequencing.","date":"2023","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37906510","citation_count":1,"is_preprint":false},{"pmid":"42080702","id":"PMC_42080702","title":"CDK14 is a critical regulator of haematopoietic stem and progenitor cell maintenance and post-transplantation proliferation.","date":"2026","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/42080702","citation_count":0,"is_preprint":false},{"pmid":"40696975","id":"PMC_40696975","title":"RETRACTION: Long Non-Coding RNA SNHG15 Promotes CDK14 Expression via miR-486 to Accelerate Non-Small Cell Lung Cancer Cells Progression and Metastasis.","date":"2025","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/40696975","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.08.663677","title":"Microbial Scl1 Activates TGFβR1 receptor kinase signalling to Drive Fibrosis – Inflammation Axis in Alcohol-Associated Liver Disease","date":"2025-07-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.08.663677","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33755,"output_tokens":6792,"usd":0.101572,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15887,"output_tokens":5466,"usd":0.108042,"stage2_stop_reason":"end_turn"},"total_usd":0.209614,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Human PFTAIRE1 (CDK14) protein is localized to the cytoplasm when expressed as a GFP fusion in HeLa cells, as determined by fluorescence microscopy.\",\n      \"method\": \"GFP fusion protein expression and fluorescence microscopy in HeLa cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment, single lab, no functional consequence linked\",\n      \"pmids\": [\"11313143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mouse Pftaire-1 (CDK14 ortholog) is expressed in late pachytene spermatocytes in the testis and in post-mitotic neuronal cells in the brain and embryo, suggesting roles in meiosis and neuron differentiation, as established by in situ hybridization.\",\n      \"method\": \"Northern blot and in situ hybridization in mouse tissues\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two orthogonal methods (Northern blot + in situ hybridization), single lab, localization without direct functional validation\",\n      \"pmids\": [\"9547506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human PFTK1 (CDK14) specifically interacts with cyclin D3 (CCND3) and forms a ternary complex with p21(Cip1); CCND3 is required for PFTK1 kinase activity, which is negatively regulated by p21(Cip1); Rb is a downstream phosphorylation substrate of the PFTK1/CCND3 complex; siRNA knockdown of PFTK1 causes G1 cell cycle arrest.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, cell cycle analysis (flow cytometry), kinase assays in mammalian cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, kinase activity assays, siRNA phenotype with defined cell cycle readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17517622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cyclin Y (CCNY) is a novel interacting partner of PFTK1 (CDK14) identified by yeast two-hybrid screen; the cyclin box of CCNY and the PFTAIRE motif of PFTK1 are both required for the interaction; binding of CCNY to PFTK1 enhances PFTK1 kinase activity and changes its intracellular localization; CCNY is enriched at the plasma membrane via an N-terminal myristoylation signal.\",\n      \"method\": \"Yeast two-hybrid screen, in vivo and in vitro binding assays, Northern blot, subcellular localization studies\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid discovery confirmed by in vivo and in vitro assays, domain mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"19524571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Caldesmon (CaD) is a downstream phosphorylation substrate of PFTK1 (CDK14); PFTK1 knockdown reduces CaD phosphorylation and causes dissociation of CaD from F-actin fibers, loss of actin stress fibers, and altered CaD subcellular localization in hepatocellular carcinoma cells.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, co-localization analysis, phosphorylation assays in HCC cells\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined molecular phenotype (CaD phosphorylation, actin dynamics), single lab, two orthogonal methods\",\n      \"pmids\": [\"21184254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PFTK1 (CDK14) phosphorylates TAGLN2 (transgelin2) at residues S83 and S163, inactivating its actin-binding function; in PFTK1-suppressed cells, unphosphorylated TAGLN2 exhibits strong actin-binding ability that inhibits actin cytoskeleton dynamics and cell motility; knockdown of TAGLN2 in PFTK1-suppressed cells rescues cell invasion and motility and restores actin polymerization. β-actin (ACTB) tyrosine phosphorylation is also affected by PFTK1.\",\n      \"method\": \"2D-PAGE mass spectrometry, siRNA knockdown, site-directed mutagenesis of TAGLN2, cell invasion/motility assays, actin polymerization assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phospho-proteomics discovery validated by mutagenesis at specific residues, epistasis (double KD rescue), multiple orthogonal methods in single study\",\n      \"pmids\": [\"21577206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PFTK1 (CDK14) forms a direct complex with cyclin Y (CCNY) in HCC cells; this complex upregulates key components of noncanonical Wnt signaling (Dvl2 and Naked1) and activates Rho GTPases, leading to actin polymerization.\",\n      \"method\": \"Co-immunoprecipitation, exogenous expression, Rho GTPase activation assays, actin polymerization assays in HCC cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional readouts (Rho GTPase, actin), single lab\",\n      \"pmids\": [\"24824184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDK14 phosphorylates cyclin Y (CCNY) at Ser-71 and Ser-73, creating a phospho-degron that triggers CCNY ubiquitination by an SCF-Cul1 complex and its proteasomal degradation; mutation of these serines to alanine stabilizes CCNY and enhances CCNY/CDK14 activity on LRP6 phosphorylation, representing autoregulation of the cyclin Y/CDK14 pair.\",\n      \"method\": \"In vivo and in vitro phosphorylation mapping by mass spectrometry, Cul1 inactivation, site-directed mutagenesis (S71A/S73A), ubiquitination assays, LRP6 phosphorylation assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro + in vivo phosphorylation site mapping by MS, mutagenesis validation, functional consequence (ubiquitination, LRP6 phosphorylation), multiple orthogonal methods\",\n      \"pmids\": [\"24794231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"14-3-3 proteins (ε, β, η, τ isoforms) interact with cyclin Y (CCNY) via Ser-100 and Ser-326 residues, and this binding significantly enhances the association between CCNY and CDK14.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro and in vivo binding assays, site-directed mutagenesis\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro and in vivo assays with mutagenesis, single lab\",\n      \"pmids\": [\"24618387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDK14 interacts with cyclin Y in spinal cord injury (SCI) rat model; CDK14 expression increases and peaks at 3 days post-SCI; CDK14 co-localizes with cyclin Y and with PCNA in astrocytes/glial cells, suggesting a role in reactive gliosis.\",\n      \"method\": \"Western blot, immunohistochemistry, double immunofluorescence, Co-immunoprecipitation in rat SCI model\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP confirms interaction in vivo, multiple staining methods, single lab with clear functional context\",\n      \"pmids\": [\"26315607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PFTK1 (CDK14) knockdown in breast cancer cells attenuates Wnt/β-catenin signaling by reducing DVL2 levels and inhibiting β-catenin transcriptional targets (cyclin D1, MMP9, HEF1); PFTK1 interacts with cyclin B, and this complex increases DVL2 levels.\",\n      \"method\": \"Co-immunoprecipitation (cyclin B interaction), siRNA knockdown, Western blot, proliferation/migration/invasion assays in breast cancer cells\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for cyclin B interaction, siRNA with defined molecular pathway readouts, single lab\",\n      \"pmids\": [\"26033031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PFTK1 (CDK14) knockdown in oligodendrocyte progenitor cell-derived OLN-93 cells promotes oligodendrocyte differentiation (increased CNPase, MOG, CGT, MBP markers); this effect is mediated through activation of the PI3K/AKT pathway but not the MAPK/ERK pathway, as AKT-specific inhibitor abrogates the differentiation-promoting effect of PFTK1 silencing.\",\n      \"method\": \"siRNA knockdown, qPCR, Western blot, AKT inhibitor epistasis in OLN-93 cells\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis with pharmacological inhibitor, multiple differentiation marker readouts, single lab\",\n      \"pmids\": [\"25355490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Caprin-2 positively regulates constitutive LRP5/6 Ser-1490 phosphorylation in a cell cycle-dependent manner (G2/M) by forming a quaternary complex with CDK14, Cyclin Y, and LRP5/6; Caprin-2 knockdown disrupts the CDK14–Cyclin Y interaction and the CDK14/Cyclin Y–LRP6 interaction.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, cell cycle-dependent phosphorylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA epistasis, cell cycle-dependent phosphorylation assay, multiple orthogonal methods demonstrating quaternary complex\",\n      \"pmids\": [\"27821587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FMF-04-159-2 is a potent covalent CDK14 inhibitor with TAIRE kinase-biased selectivity; covalent CDK14 inhibition affects cell-cycle regulation, particularly mitotic progression; phospho-proteomics under washout conditions identified putative CDK14-specific substrates.\",\n      \"method\": \"Covalent inhibitor development, phospho-proteomics, cell-cycle analysis with washout conditions\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — specific covalent inhibitor with biochemical characterization, unbiased phospho-proteomics, washout controls to deconvolute CDK14-specific effects\",\n      \"pmids\": [\"30930164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Synthesis and SAR of covalent 4-amino-1H-pyrazole CDK14 inhibitors culminated in FMF-04-159-2, a potent, covalent CDK14 inhibitor with TAIRE kinase-biased selectivity profile.\",\n      \"method\": \"Medicinal chemistry synthesis, structure-activity relationship analysis, biochemical kinase selectivity profiling\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — chemical biology/SAR study, single paper, establishes inhibitor tool but limited biological mechanism\",\n      \"pmids\": [\"31175010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In C. elegans, CDK-14 (mammalian CDK14 homolog) promotes axon regeneration via noncanonical Wnt signaling in a kinase-independent manner: CDK-14 binds MIG-5/Disheveled and activates EPHX-1 (ephexin RhoGEF), which activates CDC-42, inhibiting myosin phosphatase and maintaining MLC-4 phosphorylation. EGL-20/Wnt and MIG-1/Frizzled are required for efficient axon regeneration.\",\n      \"method\": \"Genetic epistasis (C. elegans), binding studies, GEF activity assays, phospho-mimetic rescue experiments in motor neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple mutants and rescue experiments, identifies CDK14's kinase-independent mechanism, replicated across multiple genetic backgrounds\",\n      \"pmids\": [\"34429379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDK14 knockdown or pharmacological inhibition (FMF-04-159-2) reduces mammary basal cell colony-formation and regeneration capacity, inhibits MMTV-Wnt-1 mammary tumor progression, and suppresses TNBC progression and metastasis by attenuating Wnt/β-catenin signaling.\",\n      \"method\": \"Genetic knockdown, pharmacological inhibition (FMF-04-159-2), in vivo MMTV-Wnt-1 mouse model, in vitro colony-formation assays, Wnt signaling readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological inhibition with concordant results, in vivo mouse model, defined pathway (Wnt/β-catenin) as mechanism\",\n      \"pmids\": [\"36103813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDK7/cyclin H (CAK complex) physically interacts with CDK14 in the cell nucleus and increases CDK14 phosphorylation; this activates CDK14 to phosphorylate Rb, inhibiting Rb function; overexpression of CDK7 with CDK14 strengthens colony formation and cisplatin resistance in ESCC cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, truncation mutant analysis, colony formation assays in ESCC cells\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and co-localization demonstrate CDK7-CDK14 interaction, functional consequence shown, single lab\",\n      \"pmids\": [\"31930082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Drosophila, Eip63E (CDK14 ortholog) regulates axogenesis; PFTK1 knockout mice show increased axonal outgrowth; PFTK1 phosphorylates GDP-bound inactive RhoA and this phosphorylation is required for RhoA activity, establishing RhoA as a CDK14 substrate mediating axon development.\",\n      \"method\": \"Drosophila genetic loss-of-function, PFTK1 knockout mouse model, RhoA phosphorylation assays in primary neuronal cultures, functional interaction studies\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cross-species validation (Drosophila + mouse KO), in vitro kinase assay showing RhoA as substrate, multiple orthogonal methods\",\n      \"pmids\": [\"37907898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL1 adds internal m7G modifications to CDK14 mRNA, enhancing its stability and thereby promoting CRPC progression; the P300/SP1 complex binds the METTL1 promoter via SP1, mediating METTL1 transcriptional upregulation in CRPC.\",\n      \"method\": \"ChIP-qPCR, Co-IP, luciferase reporter assay, m7G AlkAniline-Seq, mRNA degradation assays, transcriptome sequencing\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including m7G-specific sequencing (AlkAniline-Seq), mRNA stability assays, ChIP, Co-IP in a single rigorous study\",\n      \"pmids\": [\"37599359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDK14 loss in the preformed fibrils (PFF) mouse model of Parkinson's disease mitigates grip strength deficits and reduces pS129 α-synuclein pathology in the cortex; Cdk14 depletion in primary neurons protects against propagation of toxic α-Syn species; pharmacological CDK14 inhibition (FMF-04-159-2) decreases total and pathologically aggregated α-Syn in human neurons, PFF-challenged rat neurons, and α-Syn-humanized mouse brains.\",\n      \"method\": \"Genetic Cdk14 knockout in PFF mouse model, primary neuron depletion assays, pharmacological inhibition in multiple model systems, pS129 α-Syn immunostaining\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological validation concordant across multiple model systems (mouse, rat neurons, human neurons), defined molecular phenotype (α-Syn aggregation)\",\n      \"pmids\": [\"38575601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP2 interacts with CDK14 mRNA, stabilizing it by inhibiting its degradation; CDK14 facilitates LRP6 and GSK3β phosphorylation, thereby regulating β-catenin levels and Wnt/β-catenin signaling during osteogenic differentiation.\",\n      \"method\": \"Co-IP (IGF2BP2-CDK14 mRNA interaction), siRNA knockdown, CDK14 inhibitor (FMF-04-159-2), Western blot for LRP6/GSK3β/β-catenin phosphorylation, osteogenesis assays\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNA-binding protein interaction with mRNA confirmed, pathway readouts established, single lab\",\n      \"pmids\": [\"39447733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Gefitinib suppresses PFTK1 (CDK14) promoter methylation in a DNMT3B-dependent manner, upregulating CDK14 expression; CDK14 interacts with LRP6 and activates Wnt/β-catenin signaling to attenuate gefitinib-induced apoptosis and confer gefitinib resistance in NSCLC; FMF-04-159-2 reverses CDK14-mediated gefitinib resistance in vitro and in vivo.\",\n      \"method\": \"Promoter methylation analysis, DNMT3B manipulation, Co-IP (CDK14-LRP6), gain/loss-of-function assays, pharmacological inhibition in vitro and in vivo\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for CDK14-LRP6 interaction, epigenetic mechanism established, in vitro and in vivo pharmacological validation, single lab\",\n      \"pmids\": [\"39702755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic ablation of Cdk14 in mice impairs pulmonary vascular endothelial and alveolar epithelial cell proliferation, causes G2/M cell cycle arrest, and increases mortality and severity of bleomycin- or LPS-induced lung injury; RNA-seq reveals CDK14 knockdown controls STAT1 expression and interferon-signaling-associated genes; CDK14 disruption interferes with IFN-γ-induced lung repair.\",\n      \"method\": \"Cdk14 knockout mouse model, CDK14 covalent inhibitor FMF-04-159-2, RNA-seq, cell cycle analysis, in vivo lung injury models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and pharmacological inhibition concordant, RNA-seq identifies mechanism (IFN-γ/STAT1 axis), in vivo phenotype with defined molecular pathway\",\n      \"pmids\": [\"39827158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF213 ubiquitinates CDK14, inhibiting the CDK14-Pdgfrβ signaling pathway; maltol upregulates RNF213, thereby suppressing CDK14-Pdgfrβ signaling, M1 macrophage polarization, and NF-κB phosphorylation.\",\n      \"method\": \"In vitro and in vivo macrophage polarization assays, Western blot for CDK14-Pdgfrβ pathway, RNF213 overexpression/knockdown\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ubiquitination mechanism proposed with RNF213 as E3 ligase for CDK14, functional consequence shown, single lab\",\n      \"pmids\": [\"40315161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRX3 promotes CDK14 transcription by binding to its promoter (ChIP-confirmed); CDK14 then stabilizes β-catenin by restraining its ubiquitination and degradation, activating canonical Wnt/β-catenin signaling; LRP6 is identified as a crucial regulatory factor in IRX3-CDK14-mediated β-catenin stabilization in glioblastoma.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, gain/loss-of-function in GBM cells, Western blot for β-catenin ubiquitination/stability\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional assays establish downstream mechanism, single lab\",\n      \"pmids\": [\"41436436\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDK14 (PFTK1/PFTAIRE1) is a cyclin-dependent serine/threonine kinase that is activated primarily by cyclin Y (and also cyclin D3 and cyclin B) to regulate cell cycle progression and Wnt signaling: at G2/M, the CDK14/cyclin Y complex—scaffolded by Caprin-2—phosphorylates LRP5/6 at Ser-1490, priming these Wnt co-receptors for subsequent Wnt-induced signaling; CDK14 can also activate noncanonical Wnt signaling via Rho GTPases; CDK14 phosphorylates substrates including Rb, TAGLN2, caldesmon (CaD), and RhoA to regulate actin dynamics, cell motility, and axogenesis; CDK14's own activity is autoregulated through CDK14-mediated phosphorylation of cyclin Y at Ser-71/73, triggering SCF-Cul1-dependent cyclin Y ubiquitination and degradation; 14-3-3 proteins enhance CDK14–cyclin Y association; CDK7 activates CDK14 by phosphorylation; in neurons, CDK14 can act in a kinase-independent manner via Disheveled to activate a RhoGEF-CDC42-myosin light chain phosphorylation axis promoting axon regeneration; CDK14 regulates α-synuclein levels and its inhibition is neuroprotective in synucleinopathy models; CDK14 mRNA stability is regulated by METTL1-mediated internal m7G modification and by IGF2BP2 binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDK14 (PFTK1/PFTAIRE1) is a cyclin-dependent serine/threonine kinase that couples cell-cycle progression to Wnt signaling and actin cytoskeletal regulation [#2, #3, #12]. Its kinase activity depends on association with a regulatory cyclin: cyclin D3 supports phosphorylation of Rb and is required for CDK14 activity, while siRNA depletion arrests cells in G1 [#2], and a yeast two-hybrid-identified partner, cyclin Y, binds via the PFTAIRE motif, enhances kinase activity, and redirects CDK14 to the plasma membrane [#3]. In a cell-cycle-dependent (G2/M) manner, a quaternary complex of CDK14, cyclin Y, the scaffold Caprin-2, and LRP5/6 drives constitutive LRP5/6 Ser-1490 phosphorylation, priming these Wnt co-receptors [#12]; CDK14 also phosphorylates LRP6 and GSK3\\u03b2 to stabilize \\u03b2-catenin and activate canonical Wnt/\\u03b2-catenin signaling [#7, #21, #25]. The cyclin Y/CDK14 pair is autoregulated: CDK14 phosphorylates cyclin Y at Ser-71/73 to create a phospho-degron triggering SCF-Cul1-dependent ubiquitination and degradation, while 14-3-3 proteins enhance the cyclin Y\\u2013CDK14 association and CDK7/cyclin H phosphorylates and activates CDK14 [#7, #8, #17]. Beyond the cell cycle, CDK14 controls actin dynamics and motility by phosphorylating caldesmon and TAGLN2 (inactivating its actin-binding function) and by activating Rho GTPases through noncanonical Wnt components [#4, #5, #6]; it phosphorylates GDP-bound RhoA to regulate axogenesis, and in C. elegans acts kinase-independently via Disheveled to drive a RhoGEF\\u2013CDC42\\u2013myosin light chain axis promoting axon regeneration [#15, #18]. CDK14 activity promotes tumor progression and therapy resistance via Wnt/\\u03b2-catenin signaling across breast, esophageal, prostate, glioblastoma, and lung cancer models, and its inhibition is neuroprotective by reducing \\u03b1-synuclein pathology in synucleinopathy models [#16, #20, #22]. CDK14 abundance is post-transcriptionally controlled by METTL1-mediated m7G modification and IGF2BP2 binding to its mRNA, and by RNF213-mediated ubiquitination of the protein [#19, #21, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the tissue and developmental expression pattern of the CDK14 ortholog, providing the first hint of roles in meiosis and post-mitotic neurons.\",\n      \"evidence\": \"Northern blot and in situ hybridization in mouse testis, brain, and embryo\",\n      \"pmids\": [\"9547506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function or substrate identified\", \"Expression correlation does not establish a mechanism\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Localized the human protein to the cytoplasm, beginning the assignment of subcellular context to CDK14 function.\",\n      \"evidence\": \"GFP fusion expression and fluorescence microscopy in HeLa cells\",\n      \"pmids\": [\"11313143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single overexpression-based localization\", \"No functional consequence linked\", \"Later work showed cyclin Y can redirect localization to the membrane\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined CDK14 as a bona fide cell-cycle kinase by identifying a cyclin partner (cyclin D3), a substrate (Rb), a negative regulator (p21), and a knockdown phenotype (G1 arrest).\",\n      \"evidence\": \"Reciprocal Co-IP, kinase assays, siRNA knockdown with flow-cytometry cell-cycle analysis in mammalian cells\",\n      \"pmids\": [\"17517622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which cyclin is the dominant physiological activator\", \"No structural basis for activation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified cyclin Y as a CDK14 activating partner that enhances kinase activity and relocalizes the kinase, linking CDK14 to the membrane compartment.\",\n      \"evidence\": \"Yeast two-hybrid screen, in vivo/in vitro binding, domain mutagenesis, subcellular localization\",\n      \"pmids\": [\"19524571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane substrate not yet identified at this stage\", \"Relationship between cyclin Y and cyclin D3 activation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a feedback loop and multiple regulatory inputs controlling the cyclin Y/CDK14 module, explaining how its activity is bounded and amplified.\",\n      \"evidence\": \"MS phospho-site mapping with S71A/S73A mutagenesis and ubiquitination assays (autoregulatory degron); yeast two-hybrid and binding assays (14-3-3); Co-IP and functional readouts (cyclin B, noncanonical Wnt/Rho GTPase) in HCC and other cells\",\n      \"pmids\": [\"24794231\", \"24618387\", \"24824184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger for autophosphorylation-driven degradation unclear\", \"Relative contributions of cyclin Y vs cyclin B in different tissues not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CDK14 to actin cytoskeletal control by identifying caldesmon and TAGLN2 as substrates whose phosphorylation governs actin binding, motility, and invasion.\",\n      \"evidence\": \"Phospho-proteomics, site-directed mutagenesis (TAGLN2 S83/S163), epistasis double-knockdown rescue, actin/invasion assays in HCC cells\",\n      \"pmids\": [\"21184254\", \"21577206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase-substrate phosphorylation by purified CDK14 not fully established for caldesmon\", \"In vivo relevance of these phospho-events untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the scaffold and cell-cycle context for CDK14's canonical Wnt function: Caprin-2 assembles a CDK14/cyclin Y/LRP5/6 complex driving G2/M LRP5/6 Ser-1490 phosphorylation.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA epistasis, cell-cycle-dependent phosphorylation assays\",\n      \"pmids\": [\"27821587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural arrangement of the quaternary complex unknown\", \"How priming is coupled to ligand-induced signaling not detailed here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided a selective covalent chemical tool (FMF-04-159-2) and used it to deconvolute CDK14-specific substrates and confirm a mitotic-progression role.\",\n      \"evidence\": \"Covalent inhibitor development, SAR, washout phospho-proteomics, cell-cycle analysis\",\n      \"pmids\": [\"30930164\", \"31175010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Putative substrates from phospho-proteomics not individually validated\", \"TAIRE-family cross-reactivity bounds interpretation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a kinase-independent mode of CDK14 action in neurons, showing it can drive a Disheveled\\u2013RhoGEF\\u2013CDC42\\u2013MLC axis to promote axon regeneration.\",\n      \"evidence\": \"C. elegans genetic epistasis, binding studies, GEF activity assays, phospho-mimetic rescue in motor neurons\",\n      \"pmids\": [\"34429379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the kinase-independent mechanism operates in mammals not shown\", \"Structural basis of CDK14\\u2013Disheveled binding undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected CDK14 activity to cancer dependency, demonstrating that genetic or pharmacological inhibition suppresses Wnt-driven mammary tumor and TNBC progression, and that CDK7 activates CDK14 to phosphorylate Rb and confer chemoresistance.\",\n      \"evidence\": \"Knockdown plus FMF-04-159-2, MMTV-Wnt-1 in vivo model, colony assays (breast); Co-IP, co-localization, truncation analysis, colony/cisplatin assays in ESCC\",\n      \"pmids\": [\"36103813\", \"31930082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vivo demonstration of CDK7-CDK14-Rb axis limited to one cancer type\", \"Therapeutic window of CDK14 inhibition not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified RhoA as a direct CDK14 substrate in axogenesis and showed cross-species (Drosophila, mouse KO) requirement for CDK14 in axon development.\",\n      \"evidence\": \"Drosophila loss-of-function, PFTK1 knockout mice, RhoA phosphorylation assays in primary neurons\",\n      \"pmids\": [\"37907898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-site on RhoA and structural consequence of phosphorylation not detailed\", \"Reconciliation with kinase-independent regeneration mechanism open\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed post-transcriptional control of CDK14 abundance via METTL1-mediated internal m7G modification that stabilizes its mRNA to promote castration-resistant prostate cancer.\",\n      \"evidence\": \"m7G AlkAniline-Seq, mRNA degradation assays, ChIP-qPCR, Co-IP, luciferase reporter\",\n      \"pmids\": [\"37599359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether m7G control operates outside CRPC unknown\", \"Downstream CDK14 substrates in this context not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated CDK14 as a therapeutic target in synucleinopathy, with loss or inhibition reducing \\u03b1-synuclein pathology, and extended Wnt regulation to osteogenesis under IGF2BP2-mediated mRNA stabilization.\",\n      \"evidence\": \"Cdk14 KO PFF mouse model and pharmacological inhibition across human/rat neurons (\\u03b1-Syn); Co-IP, siRNA, inhibitor, and LRP6/GSK3\\u03b2/\\u03b2-catenin readouts in osteogenesis\",\n      \"pmids\": [\"38575601\", \"39447733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate linking CDK14 to \\u03b1-Syn levels not identified\", \"Whether \\u03b1-Syn effect is Wnt-dependent unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed epigenetic and Wnt-mediated control of drug resistance: gefitinib derepresses CDK14 via DNMT3B-dependent promoter demethylation, and CDK14-LRP6-Wnt signaling attenuates apoptosis.\",\n      \"evidence\": \"Promoter methylation analysis, DNMT3B manipulation, Co-IP, in vitro/in vivo pharmacological inhibition in NSCLC\",\n      \"pmids\": [\"39702755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanism\", \"Generality of methylation control across CDK14-driven cancers untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened CDK14's physiological roles to tissue repair and inflammation: it is required for endothelial/epithelial proliferation and lung repair via a STAT1/IFN axis, while RNF213-mediated ubiquitination restrains CDK14-Pdgfr\\u03b2 signaling in macrophage polarization, and IRX3-driven transcription couples CDK14 to \\u03b2-catenin stabilization in glioblastoma.\",\n      \"evidence\": \"Cdk14 KO mice with lung injury models and RNA-seq (STAT1/IFN); macrophage polarization assays with RNF213 manipulation; ChIP and \\u03b2-catenin ubiquitination assays in GBM\",\n      \"pmids\": [\"39827158\", \"40315161\", \"41436436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CDK14 substrates in the STAT1/IFN and Pdgfr\\u03b2 axes not defined\", \"Single-lab mechanisms for RNF213 and IRX3 links\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CDK14 partitions between its distinct cyclin partners (D3, Y, B) and between kinase-dependent and kinase-independent modes across tissues, and which substrate connects it to \\u03b1-synuclein homeostasis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CDK14-cyclin or CDK14-substrate complexes in the corpus\", \"Substrate linking CDK14 to \\u03b1-Syn levels unidentified\", \"Tissue-specific cyclin selection rules unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 5, 7, 12, 18]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 7, 12, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 12, 13, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 12, 16, 21, 22, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [15, 18]}\n    ],\n    \"complexes\": [\n      \"CDK14/cyclin Y\",\n      \"CDK14/cyclin D3/p21\",\n      \"CDK14/cyclin Y/Caprin-2/LRP5/6 quaternary complex\",\n      \"CDK7/cyclin H (CAK)\"\n    ],\n    \"partners\": [\n      \"CCNY\",\n      \"CCND3\",\n      \"Caprin-2\",\n      \"LRP6\",\n      \"CDK7\",\n      \"14-3-3\",\n      \"DVL2\",\n      \"RhoA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}