{"gene":"CDC14A","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2002,"finding":"Human CDC14A phosphatase localizes to interphase centrosomes (not mitotic centrosomes), and this localization is independent of microtubules and phosphatase activity but requires active nuclear export via a nuclear export signal (NES). Disrupting the NES relocalizes CDC14A to nucleoli. Conditional overproduction of CDC14A (but not phosphatase-dead or NES-deficient mutants, or CDC14B) causes premature centrosome splitting and supernumerary mitotic spindles. siRNA-mediated knockdown of CDC14A impairs centrosome separation and cytokinesis, causing aberrant chromosome segregation.","method":"siRNA knockdown, conditional overexpression, NES mutagenesis, immunofluorescence localization, live-cell imaging","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and cell-biological approaches (siRNA KD, OE, phosphatase-dead and NES mutants), multiple orthogonal methods, replicated by Kaiser et al. same year","pmids":["11901424"],"is_preprint":false},{"year":2002,"finding":"Human CDC14A is selective for CDK substrates in vitro. CDC14A dynamically localizes to interphase (but not mitotic) centrosomes, whereas CDC14B localizes to the interphase nucleolus. Overexpression of CDC14A causes loss of pericentrin and γ-tubulin from centrosomes, mitotic spindle defects, chromosome segregation errors, and failure to complete cytokinesis.","method":"In vitro phosphatase assay with CDK substrates, immunofluorescence, overexpression in human cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro substrate specificity assay combined with cell-biological localization and overexpression phenotype; independently corroborated by Mailand et al. 2002","pmids":["12134069"],"is_preprint":false},{"year":2001,"finding":"Human CDC14A (hCdc14a) dephosphorylates hCdh1, reversing cyclin B-Cdc2-mediated phosphorylation that prevents hCdh1 from activating the APC. hCdc14a activates APC(Cdh1) but does not affect APC(Cdc20) activity. hCdc14a localizes to centrosomes in HeLa cells.","method":"In vitro phosphatase assay, APC activity reconstitution, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of dephosphorylation and APC activation, single lab with multiple orthogonal assays","pmids":["11598127"],"is_preprint":false},{"year":2000,"finding":"Human CDC14A and CDC14B interact with tumor suppressor p53 both in vitro and in vivo; this interaction requires the N-termini of the hCdc14 proteins and the C-terminus of p53. Both phosphatases specifically dephosphorylate p53 at the p34(Cdc2)/Clb phosphorylation site Ser315.","method":"In vitro binding assay, co-immunoprecipitation, in vitro phosphatase assay with p53","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal in vitro and in vivo binding plus in vitro dephosphorylation, single lab","pmids":["10644693"],"is_preprint":false},{"year":2007,"finding":"Human CDC14A binds directly to the atypical MAPK ERK3 via ERK3's unique C-terminal domain. CDC14A can remove CDK-mediated phosphorylation from ERK3 in vitro. CDC14A forms a stable complex with ERK3 in human cells independently of its phosphatase activity, mediated by CDC14A's C-terminal regulatory domain. CDC14A upregulation redistributes the ERK3 substrate MK5 from nucleus to cytoplasm and stabilizes ERK3-cyclin D3 complex formation.","method":"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, in vitro phosphatase assay, subcellular localization imaging","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by pulldown and Co-IP, in vitro phosphatase activity shown, single lab","pmids":["18235225"],"is_preprint":false},{"year":2007,"finding":"RN-tre, a Rab5 GTPase-activating protein, is identified as a substrate of human CDC14A. A substrate-trapping mutant (CDC14A C278S) stably associates with RN-tre in human cells. RN-tre undergoes cell cycle-dependent phosphorylation peaking at mitosis, which CDC14A reverses in vitro and in vivo. RN-tre is a direct CDK substrate and CDC14A dephosphorylates proline-directed CDK phosphorylation sites. RN-tre phosphorylation modulates its catalytic activity.","method":"Substrate-trapping Co-IP, in vitro phosphatase assay, tungstate competition, cell cycle phosphorylation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate trapping plus in vitro and in vivo dephosphorylation demonstrated, single lab","pmids":["17371873"],"is_preprint":false},{"year":2010,"finding":"Human CDC14A associates with the actin cytoskeleton of human cells. Ablation of CDC14A phosphatase activity (phosphatase-dead knock-in) diminishes stress fibers, increases cell migration speed, and reduces cell adhesion. CDC14A colocalizes with its substrate KIBRA at the cell leading edge, and KIBRA overexpression rescues CDC14A phosphatase-dead phenotypes.","method":"Phosphatase-dead knock-in at native locus, immunofluorescence, cell migration assays, adhesion assays, co-localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — native locus PD mutation in two independent cell lines, multiple orthogonal functional assays, substrate rescue experiment","pmids":["26747605"],"is_preprint":false},{"year":2017,"finding":"Human CDC14A dephosphorylates eplin (epithelial protein lost in neoplasm) at ERK-phosphorylated sites Ser362 and Ser604, counteracting EGF-induced actin cytoskeleton rearrangements. CDC14A phosphatase-dead (PD) cells and eplin knockout cells both show reduced E-cadherin and α/β-catenin at cell-cell adhesions.","method":"Phospho-proteome profiling, proximity-dependent biotin identification (BioID), in vitro and in vivo dephosphorylation assays, phosphatase-dead knock-in cell lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phosphoproteomics combined with BioID substrate identification and in vitro/in vivo dephosphorylation validation, single lab with multiple orthogonal methods","pmids":["28465438"],"is_preprint":false},{"year":2018,"finding":"Human CDC14A regulates primary cilia length by dephosphorylating the actin-binding protein drebrin at CDK5-phosphorylated Ser142, and by regulating recruitment of the actin organizer Arp2 to centrosomes. CDC14A phosphatase-dead RPE1 cells have longer cilia than wild-type, while CDC14A overexpression reduces cilia formation. CDC14A also regulates endocytosis and targeting of myosin Va vesicles to the basal body during ciliogenesis.","method":"Phosphatase-dead knock-in, phospho-proteome analysis, immunofluorescence, cilia length measurement, overexpression","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — phospho-proteomics substrate identification with phosphatase-dead cells, multiple orthogonal methods, single lab","pmids":["30467237"],"is_preprint":false},{"year":2018,"finding":"CDC14A phosphatase activity is essential in vivo for hearing and male fertility in mammals. CRISPR/Cas9 phosphatase-dead (p.C278S) mouse Cdc14a mutations cause deafness and male infertility. CDC14A protein localizes to inner ear hair cell kinocilia, basal bodies, and stereocilia. Auditory hair cells develop normally but degenerate postnatally in mutants. In males, degeneration of seminiferous tubules and spermiation defects lead to low sperm count and abnormal sperm motility/morphology.","method":"CRISPR/Cas9 phosphatase-dead and truncating knock-in mouse models, zebrafish mutants, immunofluorescence localization, histology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphatase-dead knock-in (not just null) in mouse and zebrafish, multiple alleles, human genetic validation, orthogonal species","pmids":["29293958"],"is_preprint":false},{"year":2016,"finding":"Biallelic loss-of-function mutations in CDC14A (nonsense alleles) cause severe-to-profound sensorineural deafness in humans. CDC14A protein is strongly expressed in kinocilia of inner ear hair cells in mouse. Morpholino knockdown of cdc14a in zebrafish reduces kinocilium length in inner ear hair cells, indicating that CDC14A is required for proper kinocilium growth/maintenance in hair bundles.","method":"Human genetic linkage analysis and whole-exome sequencing, mouse immunofluorescence, zebrafish morpholino knockdown and kinocilium length measurement","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with specific ciliary phenotype readout plus human genetics, single lab; kinocilia length phenotype not fully replicated in germ-line mutants per Imtiaz et al. 2018","pmids":["27259055"],"is_preprint":false},{"year":2010,"finding":"Vertebrate cells with CDC14A gene deletion (chicken DT40, human HCT116, human RPE1) are DNA damage checkpoint proficient and arrest normally in G2 after irradiation with normal Chk1/Chk2 activation. However, CDC14A-KO cells show persistent γ-H2AX foci and slower resolution of DNA double-strand breaks, indicating CDC14A is required for efficient DNA repair but not checkpoint signaling.","method":"Gene knockout (targeted deletion) in three cell lines, irradiation assay, γ-H2AX foci quantification, comet assay, immunoblot for checkpoint kinase activation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout validated in three independent vertebrate cell lines with multiple orthogonal assays, checkpoint negative result clearly established","pmids":["20479464"],"is_preprint":false},{"year":2015,"finding":"CDC14A and CDC14B redundantly regulate DNA double-strand break repair in mammalian cells. CDC14B-KO MEFs show DSB repair defects at late passages when CDC14A levels are also low. Combined loss of both CDC14A and CDC14B impairs both homologous recombination and non-homologous end joining. Cdh1 is a downstream target of Cdc14B in DSB repair.","method":"Knockout MEFs, siRNA knockdown, IR-induced DSB repair assays (γ-H2AX, HR and NHEJ reporters), immunoblot","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout cells with specific repair pathway readouts, single lab, Cdh1 substrate link is supporting but not fully characterized here","pmids":["26283732"],"is_preprint":false},{"year":2010,"finding":"Human CDC14A modulates the G2/M transition: increasing CDC14A levels delays mitotic entry by inhibiting Cdk1-cyclin B1 activity, whereas depleting CDC14A accelerates mitotic entry. CDC14A directly binds to and dephosphorylates Cdc25B, inhibiting its catalytic activity. CDC14A also regulates Cdc25A activity at the G2/M transition.","method":"Overexpression and siRNA knockdown in human cells, in vitro phosphatase assay with Cdc25B, cell cycle analysis, Cdk1 kinase activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro dephosphorylation of Cdc25B plus cellular gain- and loss-of-function with cell cycle readouts, single lab","pmids":["20956543"],"is_preprint":false},{"year":2012,"finding":"Human CDC14A binds to Wee1 at its amino-terminal domain and dephosphorylates Wee1 at CDK-phosphorylated Ser123 and Ser139, preventing Plk1-mediated phosphorylation and subsequent Wee1 degradation at mitotic entry. CDC14A depletion significantly reduces Wee1 protein levels.","method":"Co-immunoprecipitation, in vitro phosphatase assay with recombinant Wee1, siRNA depletion, phospho-site mutagenesis, Wee1 stability assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro dephosphorylation with identified sites, Co-IP, siRNA phenotype, single lab","pmids":["23051732"],"is_preprint":false},{"year":2012,"finding":"CDC14A and CDC14B phosphatases associate with KIBRA in human cells and dephosphorylate CDK1-phosphorylated KIBRA in vitro and in cells. CDK1 phosphorylates KIBRA at Ser542 and Ser931. Phospho-regulation of KIBRA by CDK1 and CDC14 is involved in mitotic exit under spindle stress.","method":"Co-immunoprecipitation, in vitro kinase/phosphatase assays, site-directed mutagenesis, inducible expression, cell cycle analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo dephosphorylation with identified sites, Co-IP, single lab","pmids":["22784093"],"is_preprint":false},{"year":2009,"finding":"Mouse CDC14A concentrates in the nucleus of meiotically incompetent oocytes but disperses throughout meiotically competent oocytes. Between metaphase I and metaphase II, CDC14A co-localizes with the central portion of the meiotic spindle. Antibody microinjection against CDC14A specifically delays exit from meiosis I and generates eggs with chromosome alignment abnormalities and elevated aneuploidy. Overexpression of CDC14A delays meiotic progression after meiosis resumption.","method":"Immunofluorescence localization in mouse oocytes, antibody microinjection, overexpression, chromosome spread analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody microinjection loss-of-function with specific meiosis I exit defect, single lab","pmids":["19270517"],"is_preprint":false},{"year":2010,"finding":"Human CDC14A (like budding yeast Cdc14) can act as a CTD phosphatase for RNA polymerase II, targeting CTD phosphorylation at Ser2 and Ser5, consistent with a conserved role in transcriptional repression.","method":"In vitro CTD phosphatase assay with human CDC14A","journal":"Nature cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro assay, briefly described as conservation evidence in a study primarily focused on yeast Cdc14","pmids":["22020438"],"is_preprint":false},{"year":2004,"finding":"Xenopus CDC14A (XCdc14alpha) localizes to the nucleolus in interphase and to mitotic centrosomes. XCdc14beta localizes primarily to centrosomes. Antibody injection against XCdc14alpha/beta into Xenopus embryos at the two-cell stage blocks division of injected blastomeres, demonstrating a requirement for CDC14A/B activity in vertebrate cell division. XCdc14alpha is phosphorylated both meiotically and mitotically.","method":"GFP tagging, immunofluorescence, antibody microinjection into Xenopus embryos","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct antibody loss-of-function with cell division arrest phenotype in Xenopus embryos, single lab","pmids":["15251038"],"is_preprint":false},{"year":2010,"finding":"ERK3 C-terminal phosphorylation sites (Ser684, Ser688, Thr698, Ser705), all proline-directed, are phosphorylated by cyclin B-Cdk1. CDC14A and CDC14B both bind ERK3 and reverse this C-terminal phosphorylation in mitosis. Alanine substitution of these four sites decreases ERK3 half-life in mitosis, linking CDC14A/B-opposed phosphorylation to ERK3 stabilization.","method":"Mass spectrometry site identification, in vitro kinase/phosphatase assays with purified proteins, co-immunoprecipitation, pulse-chase stability assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phosphorylation/dephosphorylation with identified sites, Co-IP binding, stability assay, single lab","pmids":["20236090"],"is_preprint":false},{"year":2005,"finding":"Human CDC14A rescues flp1-deficient fission yeast strains, demonstrating functional homology. CDC14A interacts in vivo with S. pombe Cdc25 and dephosphorylates Cdc25 both in vitro and in vivo, suggesting CDC14A can inhibit Cdc25 activity.","method":"Complementation assay in fission yeast, co-immunoprecipitation, in vitro phosphatase assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — heterologous complementation plus in vitro and in vivo dephosphorylation, single lab","pmids":["15911625"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of Cdc14 (S. cerevisiae, relevant to the conserved family including CDC14A) reveals two tandem DSP-like domains. The C-terminal domain contains the catalytic PTP motif; the N-terminal domain contributes to substrate specificity but lacks catalytic activity. The active site is at the interface of both domains. The structure reveals a hydrophobic pocket specifying the pSer-Pro motif, explaining selectivity for proline-directed phosphorylation.","method":"X-ray crystallography, kinetic analysis, peptide substrate binding","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with kinetic analyses; structural basis for substrate specificity defined; foundational for the whole Cdc14 family including CDC14A","pmids":["12853468"],"is_preprint":false},{"year":2004,"finding":"Detailed kinetic and mechanistic analysis of Cdc14 phosphatase (including hCdc14a with substrate hCdh1) reveals: general acid-independent mechanism for substrates with pKa < 7, and general acid-dependent mechanism for substrates with pKa > 7. Asp253 functions as the general acid during phosphoenzyme formation and as the general base during hydrolysis. Asp50, Asp129, Glu168, Glu171, and Asp177 are required for efficient dephosphorylation of hCdh1.","method":"Kinetic analysis, mutagenesis of active-site residues, pre-steady-state kinetics, pH-dependence studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous enzymological dissection with mutagenesis, multiple kinetic methods, includes human CDC14A substrate (hCdh1)","pmids":["15128740"],"is_preprint":false},{"year":2011,"finding":"Cdc14 family phosphatases, including CDC14A homologs, have a strong and conserved preference for phosphoserine over phosphothreonine at proline-directed (CDK) sites. An invariant active-site residue sterically restricts phosphothreonine binding, responsible for phosphoserine selectivity. Optimal substrates additionally possess a basic residue at the +3 position. This selectivity is demonstrated both in vitro with purified proteins and in vivo using serine-to-threonine substitutions.","method":"In vitro phosphatase assays with phosphopeptides and phosphoprotein substrates, site-directed mutagenesis of active-site residue and substrate sites, in vivo analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical substrate specificity defined by multiple methods including mutagenesis; shown to be conserved across Cdc14 family","pmids":["22117071"],"is_preprint":false}],"current_model":"Human CDC14A is a proline-directed dual-specificity phosphatase that selectively dephosphorylates phosphoserine-containing CDK substrates; it localizes to interphase centrosomes (requiring nuclear export via a NES), the cell leading edge (actin cytoskeleton), kinocilia/basal bodies of inner ear hair cells, and the meiotic spindle midzone, where its phosphatase activity is required for centrosome separation, cell migration/adhesion (via dephosphorylation of eplin and KIBRA), primary cilia length regulation (via drebrin and Arp2 at centrosomes), hearing and male fertility in vivo, and efficient DNA double-strand break repair, while also dephosphorylating substrates including hCdh1, p53-Ser315, Cdc25B, Wee1, ERK3, and RN-tre to modulate CDK activity and G2/M entry."},"narrative":{"mechanistic_narrative":"CDC14A is a dual-specificity protein phosphatase that selectively reverses CDK-mediated phosphorylation, with a strong intrinsic preference for phosphoserine over phosphothreonine at proline-directed (pSer-Pro) sites favoring a basic residue at +3 [PMID:12134069, PMID:22117071]. This selectivity is structurally encoded: the family adopts two tandem DSP-like domains in which the C-terminal domain carries the catalytic PTP motif while the N-terminal domain shapes substrate specificity, creating a hydrophobic pocket that reads the pSer-Pro motif, and active-site residues including Asp253 act as both general acid and general base during catalysis [PMID:12853468, PMID:15128740]. In human cells CDC14A localizes to interphase centrosomes through active nuclear export via an NES, and its dosage and activity control centrosome separation, spindle integrity, and cytokinesis [PMID:11901424, PMID:12134069]. Beyond mitotic regulation, CDC14A acts on the actin cytoskeleton at the cell leading edge, where its phosphatase activity supports stress fibers, adhesion, and restrains migration through substrates including KIBRA and eplin, the latter dephosphorylated at ERK sites to maintain E-cadherin/catenin-based cell-cell adhesion [PMID:26747605, PMID:28465438]. CDC14A also regulates primary cilium length via dephosphorylation of the actin-binding protein drebrin at CDK5-phosphorylated Ser142 and control of Arp2 recruitment to centrosomes [PMID:30467237]. It modulates the G2/M transition by opposing CDK1-cyclin B1, dephosphorylating and inhibiting Cdc25B and stabilizing Wee1 through dephosphorylation of Ser123/Ser139 [PMID:20956543, PMID:23051732]. Through dephosphorylation of hCdh1 at the inhibitory CDK site, CDC14A activates APC(Cdh1) but not APC(Cdc20) [PMID:11598127]. CDC14A is also required for efficient repair of DNA double-strand breaks, acting redundantly with CDC14B in both homologous recombination and non-homologous end joining without affecting checkpoint signaling [PMID:20479464, PMID:26283732]. In vivo, CDC14A phosphatase activity is essential for hearing and male fertility: it localizes to inner ear hair cell kinocilia and basal bodies, and biallelic loss-of-function or phosphatase-dead mutations cause sensorineural deafness in humans and deafness with male infertility in mice [PMID:29293958, PMID:27259055].","teleology":[{"year":2000,"claim":"Established CDC14A as a phosphatase physically coupled to a key cell-cycle/tumor-suppressor substrate, showing it reverses CDK-type phosphorylation on a defined site.","evidence":"in vitro binding, co-IP, and in vitro phosphatase assays mapping p53 Ser315 dephosphorylation","pmids":["10644693"],"confidence":"Medium","gaps":["Functional consequence of p53 Ser315 dephosphorylation in cells not established","single-lab in vitro dephosphorylation"]},{"year":2001,"claim":"Connected CDC14A to APC regulation by showing it dephosphorylates hCdh1 to selectively activate APC(Cdh1), defining a route by which it antagonizes mitotic CDK output.","evidence":"in vitro phosphatase assay and APC activity reconstitution with immunofluorescence","pmids":["11598127"],"confidence":"High","gaps":["In vivo timing of APC(Cdh1) activation by CDC14A not resolved","selectivity over APC(Cdc20) mechanism not detailed"]},{"year":2002,"claim":"Defined CDC14A subcellular behavior and centrosome function, showing NES-dependent cytoplasmic localization to interphase centrosomes is required for centrosome separation and faithful division.","evidence":"siRNA knockdown, conditional overexpression, NES and phosphatase-dead mutants, live imaging, and in vitro CDK-substrate assays in human cells","pmids":["11901424","12134069"],"confidence":"High","gaps":["Direct centrosomal substrate driving separation not identified","how NES export is regulated through the cycle unclear"]},{"year":2004,"claim":"Provided the structural and enzymological basis for CDC14 substrate selectivity and catalysis, explaining its preference for proline-directed phospho-sites.","evidence":"X-ray crystallography of yeast Cdc14, kinetic/pH-dependence and active-site mutagenesis including the human CDC14A substrate hCdh1; antibody injection in Xenopus embryos confirming a division requirement","pmids":["12853468","15128740","15251038"],"confidence":"High","gaps":["Structure is of the yeast ortholog, not human CDC14A","in vivo catalytic mechanism for individual cellular substrates not dissected"]},{"year":2005,"claim":"Demonstrated functional conservation and a Cdc25-directed activity, linking CDC14A to mitotic-entry control via heterologous complementation.","evidence":"fission yeast complementation, co-IP, and in vitro/in vivo dephosphorylation of S. pombe Cdc25","pmids":["15911625"],"confidence":"Medium","gaps":["Heterologous system; human Cdc25 relevance addressed only later","single lab"]},{"year":2007,"claim":"Expanded the substrate repertoire beyond cell-cycle regulators to ERK3 and the Rab5-GAP RN-tre, showing CDC14A reverses cell-cycle-dependent CDK phosphorylation on diverse targets.","evidence":"yeast two-hybrid, GST pull-down, substrate-trapping co-IP, and in vitro/in vivo phosphatase assays","pmids":["18235225","17371873"],"confidence":"Medium","gaps":["Cellular phenotypes downstream of RN-tre/ERK3 dephosphorylation incompletely defined","substrate-trapping evidence from single lab"]},{"year":2010,"claim":"Distinguished CDC14A's roles in DNA repair versus checkpoint signaling and quantified its effect on the G2/M transition, while extending substrates to the actin cytoskeleton.","evidence":"gene knockouts in three vertebrate cell lines with γ-H2AX/comet assays; overexpression/knockdown cell-cycle analysis with in vitro Cdc25B dephosphorylation; native-locus phosphatase-dead knock-in with migration/adhesion assays and KIBRA rescue; in vitro RNA Pol II CTD assay","pmids":["20479464","20956543","26747605","20236090","22020438"],"confidence":"High","gaps":["Direct DSB-repair substrate of CDC14A not identified","CTD phosphatase activity rests on a single in vitro assay","mechanism linking actin substrates to migration phenotype incomplete"]},{"year":2012,"claim":"Refined the G2/M control circuit by showing CDC14A stabilizes Wee1 and dephosphorylates KIBRA at defined CDK sites, tying it to mitotic-entry and mitotic-exit regulation.","evidence":"co-IP, in vitro phosphatase assays with site mutagenesis, siRNA depletion, and stability/cell-cycle assays","pmids":["23051732","22784093"],"confidence":"Medium","gaps":["Quantitative contribution of Wee1 stabilization to mitotic timing not established","single-lab site mapping"]},{"year":2015,"claim":"Established functional redundancy with CDC14B in DSB repair across HR and NHEJ, clarifying why single-gene phenotypes can be subtle.","evidence":"knockout MEFs, siRNA, and IR-induced HR/NHEJ reporter assays","pmids":["26283732"],"confidence":"Medium","gaps":["Direct CDC14A repair substrate not defined","Cdh1 link to repair only partially characterized"]},{"year":2017,"claim":"Identified eplin as a physiological CDC14A substrate at ERK sites, mechanistically linking CDC14A to maintenance of cadherin-based cell-cell adhesion.","evidence":"phosphoproteomics, BioID, in vitro/in vivo dephosphorylation, and phosphatase-dead knock-in cell lines","pmids":["28465438"],"confidence":"High","gaps":["In vivo tissue context of eplin regulation not addressed","single lab"]},{"year":2018,"claim":"Defined CDC14A's ciliary function and its physiological essentiality, establishing it as a phosphatase required for cilium-length control, hearing, and male fertility through phosphatase-dependent mechanisms.","evidence":"phosphatase-dead knock-in RPE1 cells with phosphoproteomics (drebrin Ser142, Arp2); CRISPR phosphatase-dead/truncating mouse and zebrafish models with histology and ciliary localization; human genetics and zebrafish morpholino for deafness","pmids":["30467237","29293958","27259055"],"confidence":"High","gaps":["Full set of ciliary substrates not enumerated","kinocilium-length phenotype differs between morphant and germ-line mutant models","molecular cause of postnatal hair-cell degeneration unresolved"]},{"year":null,"claim":"How CDC14A's many substrate dephosphorylation events are spatially and temporally coordinated to produce its distinct roles in division, migration, ciliogenesis, DNA repair, and sensory/reproductive tissue maintenance remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking centrosomal, cytoskeletal, and ciliary functions","regulation of CDC14A activity/localization across the cell cycle and across tissues not defined","direct DSB-repair substrate unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,5,7,8,13,14,21,22,23]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,22,23]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,2,8]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,1,18]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,7]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[8,9,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,16]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2,13,14]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,9,10]}],"complexes":[],"partners":["ERK3","KIBRA","WEE1","CDC25B","RN-TRE","P53","HCDH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UNH5","full_name":"Dual specificity protein phosphatase CDC14A","aliases":["CDC14 cell division cycle 14 homolog A"],"length_aa":594,"mass_kda":66.6,"function":"Dual-specificity phosphatase. Required for centrosome separation and productive cytokinesis during cell division. Dephosphorylates SIRT2 around early anaphase. May dephosphorylate the APC subunit FZR1/CDH1, thereby promoting APC-FZR1 dependent degradation of mitotic cyclins and subsequent exit from mitosis. 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response to replication stress in fission yeast.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18385517","citation_count":28,"is_preprint":false},{"pmid":"28465438","id":"PMC_28465438","title":"Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28465438","citation_count":27,"is_preprint":false},{"pmid":"18481975","id":"PMC_18481975","title":"The role of Cdc14 phosphatases in the control of cell division.","date":"2008","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/18481975","citation_count":27,"is_preprint":false},{"pmid":"29868497","id":"PMC_29868497","title":"The Aspergillus flavus Phosphatase CDC14 Regulates Development, Aflatoxin Biosynthesis and Pathogenicity.","date":"2018","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29868497","citation_count":27,"is_preprint":false},{"pmid":"15251038","id":"PMC_15251038","title":"Xenopus Cdc14 alpha/beta are localized to the nucleolus and centrosome and are required for embryonic cell division.","date":"2004","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15251038","citation_count":27,"is_preprint":false},{"pmid":"19270517","id":"PMC_19270517","title":"The CDC14A phosphatase regulates oocyte maturation in mouse.","date":"2009","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19270517","citation_count":26,"is_preprint":false},{"pmid":"15128740","id":"PMC_15128740","title":"Kinetic and mechanistic studies of a cell cycle protein phosphatase Cdc14.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15128740","citation_count":26,"is_preprint":false},{"pmid":"17292885","id":"PMC_17292885","title":"Regulation of multiple cell cycle events by Cdc14 homologues in vertebrates.","date":"2007","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/17292885","citation_count":26,"is_preprint":false},{"pmid":"20236090","id":"PMC_20236090","title":"C-terminal domain phosphorylation of ERK3 controlled by Cdk1 and Cdc14 regulates its stability in mitosis.","date":"2010","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/20236090","citation_count":26,"is_preprint":false},{"pmid":"18923139","id":"PMC_18923139","title":"Putting the brake on FEAR: Tof2 promotes the biphasic release of Cdc14 phosphatase during mitotic exit.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18923139","citation_count":26,"is_preprint":false},{"pmid":"26283732","id":"PMC_26283732","title":"Cdc14A and Cdc14B Redundantly Regulate DNA Double-Strand Break Repair.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26283732","citation_count":25,"is_preprint":false},{"pmid":"31973188","id":"PMC_31973188","title":"The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31973188","citation_count":25,"is_preprint":false},{"pmid":"23051732","id":"PMC_23051732","title":"Human Cdc14A regulates Wee1 stability by counteracting CDK-mediated phosphorylation.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23051732","citation_count":25,"is_preprint":false},{"pmid":"22872148","id":"PMC_22872148","title":"The Mitotic Exit Network and Cdc14 phosphatase initiate cytokinesis by counteracting CDK phosphorylations and blocking polarised growth.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22872148","citation_count":25,"is_preprint":false},{"pmid":"27852625","id":"PMC_27852625","title":"Stabilization of the metaphase spindle by Cdc14 is required for recombinational DNA repair.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/27852625","citation_count":24,"is_preprint":false},{"pmid":"28663385","id":"PMC_28663385","title":"Re-examining the role of Cdc14 phosphatase in reversal of Cdk phosphorylation during mitotic exit.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28663385","citation_count":24,"is_preprint":false},{"pmid":"17371873","id":"PMC_17371873","title":"Regulation of the Rab5 GTPase-activating protein RN-tre by the dual specificity phosphatase Cdc14A in human cells.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17371873","citation_count":24,"is_preprint":false},{"pmid":"18927509","id":"PMC_18927509","title":"The Polo-like kinase Cdc5 interacts with FEAR network components and Cdc14.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18927509","citation_count":23,"is_preprint":false},{"pmid":"26116076","id":"PMC_26116076","title":"Cdc14 phosphatase: warning, no delay allowed for chromosome segregation!","date":"2015","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26116076","citation_count":22,"is_preprint":false},{"pmid":"18595708","id":"PMC_18595708","title":"A nucleolus-localized activator of Cdc14 phosphatase supports rDNA segregation in yeast mitosis.","date":"2008","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/18595708","citation_count":22,"is_preprint":false},{"pmid":"19570916","id":"PMC_19570916","title":"The molecular function of the yeast polo-like kinase Cdc5 in Cdc14 release during early anaphase.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19570916","citation_count":21,"is_preprint":false},{"pmid":"26240346","id":"PMC_26240346","title":"Synthetic physical interactions map kinetochore regulators and regions sensitive to constitutive Cdc14 localization.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26240346","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43644,"output_tokens":6371,"usd":0.113249,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15279,"output_tokens":4251,"usd":0.091335,"stage2_stop_reason":"end_turn"},"total_usd":0.204584,"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\": 2002,\n      \"finding\": \"Human CDC14A phosphatase localizes to interphase centrosomes (not mitotic centrosomes), and this localization is independent of microtubules and phosphatase activity but requires active nuclear export via a nuclear export signal (NES). Disrupting the NES relocalizes CDC14A to nucleoli. Conditional overproduction of CDC14A (but not phosphatase-dead or NES-deficient mutants, or CDC14B) causes premature centrosome splitting and supernumerary mitotic spindles. siRNA-mediated knockdown of CDC14A impairs centrosome separation and cytokinesis, causing aberrant chromosome segregation.\",\n      \"method\": \"siRNA knockdown, conditional overexpression, NES mutagenesis, immunofluorescence localization, live-cell imaging\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and cell-biological approaches (siRNA KD, OE, phosphatase-dead and NES mutants), multiple orthogonal methods, replicated by Kaiser et al. same year\",\n      \"pmids\": [\"11901424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human CDC14A is selective for CDK substrates in vitro. CDC14A dynamically localizes to interphase (but not mitotic) centrosomes, whereas CDC14B localizes to the interphase nucleolus. Overexpression of CDC14A causes loss of pericentrin and γ-tubulin from centrosomes, mitotic spindle defects, chromosome segregation errors, and failure to complete cytokinesis.\",\n      \"method\": \"In vitro phosphatase assay with CDK substrates, immunofluorescence, overexpression in human cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro substrate specificity assay combined with cell-biological localization and overexpression phenotype; independently corroborated by Mailand et al. 2002\",\n      \"pmids\": [\"12134069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human CDC14A (hCdc14a) dephosphorylates hCdh1, reversing cyclin B-Cdc2-mediated phosphorylation that prevents hCdh1 from activating the APC. hCdc14a activates APC(Cdh1) but does not affect APC(Cdc20) activity. hCdc14a localizes to centrosomes in HeLa cells.\",\n      \"method\": \"In vitro phosphatase assay, APC activity reconstitution, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of dephosphorylation and APC activation, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"11598127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human CDC14A and CDC14B interact with tumor suppressor p53 both in vitro and in vivo; this interaction requires the N-termini of the hCdc14 proteins and the C-terminus of p53. Both phosphatases specifically dephosphorylate p53 at the p34(Cdc2)/Clb phosphorylation site Ser315.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, in vitro phosphatase assay with p53\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vitro and in vivo binding plus in vitro dephosphorylation, single lab\",\n      \"pmids\": [\"10644693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human CDC14A binds directly to the atypical MAPK ERK3 via ERK3's unique C-terminal domain. CDC14A can remove CDK-mediated phosphorylation from ERK3 in vitro. CDC14A forms a stable complex with ERK3 in human cells independently of its phosphatase activity, mediated by CDC14A's C-terminal regulatory domain. CDC14A upregulation redistributes the ERK3 substrate MK5 from nucleus to cytoplasm and stabilizes ERK3-cyclin D3 complex formation.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, in vitro phosphatase assay, subcellular localization imaging\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by pulldown and Co-IP, in vitro phosphatase activity shown, single lab\",\n      \"pmids\": [\"18235225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RN-tre, a Rab5 GTPase-activating protein, is identified as a substrate of human CDC14A. A substrate-trapping mutant (CDC14A C278S) stably associates with RN-tre in human cells. RN-tre undergoes cell cycle-dependent phosphorylation peaking at mitosis, which CDC14A reverses in vitro and in vivo. RN-tre is a direct CDK substrate and CDC14A dephosphorylates proline-directed CDK phosphorylation sites. RN-tre phosphorylation modulates its catalytic activity.\",\n      \"method\": \"Substrate-trapping Co-IP, in vitro phosphatase assay, tungstate competition, cell cycle phosphorylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate trapping plus in vitro and in vivo dephosphorylation demonstrated, single lab\",\n      \"pmids\": [\"17371873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human CDC14A associates with the actin cytoskeleton of human cells. Ablation of CDC14A phosphatase activity (phosphatase-dead knock-in) diminishes stress fibers, increases cell migration speed, and reduces cell adhesion. CDC14A colocalizes with its substrate KIBRA at the cell leading edge, and KIBRA overexpression rescues CDC14A phosphatase-dead phenotypes.\",\n      \"method\": \"Phosphatase-dead knock-in at native locus, immunofluorescence, cell migration assays, adhesion assays, co-localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — native locus PD mutation in two independent cell lines, multiple orthogonal functional assays, substrate rescue experiment\",\n      \"pmids\": [\"26747605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human CDC14A dephosphorylates eplin (epithelial protein lost in neoplasm) at ERK-phosphorylated sites Ser362 and Ser604, counteracting EGF-induced actin cytoskeleton rearrangements. CDC14A phosphatase-dead (PD) cells and eplin knockout cells both show reduced E-cadherin and α/β-catenin at cell-cell adhesions.\",\n      \"method\": \"Phospho-proteome profiling, proximity-dependent biotin identification (BioID), in vitro and in vivo dephosphorylation assays, phosphatase-dead knock-in cell lines\",\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 — phosphoproteomics combined with BioID substrate identification and in vitro/in vivo dephosphorylation validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28465438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human CDC14A regulates primary cilia length by dephosphorylating the actin-binding protein drebrin at CDK5-phosphorylated Ser142, and by regulating recruitment of the actin organizer Arp2 to centrosomes. CDC14A phosphatase-dead RPE1 cells have longer cilia than wild-type, while CDC14A overexpression reduces cilia formation. CDC14A also regulates endocytosis and targeting of myosin Va vesicles to the basal body during ciliogenesis.\",\n      \"method\": \"Phosphatase-dead knock-in, phospho-proteome analysis, immunofluorescence, cilia length measurement, overexpression\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-proteomics substrate identification with phosphatase-dead cells, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30467237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDC14A phosphatase activity is essential in vivo for hearing and male fertility in mammals. CRISPR/Cas9 phosphatase-dead (p.C278S) mouse Cdc14a mutations cause deafness and male infertility. CDC14A protein localizes to inner ear hair cell kinocilia, basal bodies, and stereocilia. Auditory hair cells develop normally but degenerate postnatally in mutants. In males, degeneration of seminiferous tubules and spermiation defects lead to low sperm count and abnormal sperm motility/morphology.\",\n      \"method\": \"CRISPR/Cas9 phosphatase-dead and truncating knock-in mouse models, zebrafish mutants, immunofluorescence localization, histology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphatase-dead knock-in (not just null) in mouse and zebrafish, multiple alleles, human genetic validation, orthogonal species\",\n      \"pmids\": [\"29293958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Biallelic loss-of-function mutations in CDC14A (nonsense alleles) cause severe-to-profound sensorineural deafness in humans. CDC14A protein is strongly expressed in kinocilia of inner ear hair cells in mouse. Morpholino knockdown of cdc14a in zebrafish reduces kinocilium length in inner ear hair cells, indicating that CDC14A is required for proper kinocilium growth/maintenance in hair bundles.\",\n      \"method\": \"Human genetic linkage analysis and whole-exome sequencing, mouse immunofluorescence, zebrafish morpholino knockdown and kinocilium length measurement\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with specific ciliary phenotype readout plus human genetics, single lab; kinocilia length phenotype not fully replicated in germ-line mutants per Imtiaz et al. 2018\",\n      \"pmids\": [\"27259055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Vertebrate cells with CDC14A gene deletion (chicken DT40, human HCT116, human RPE1) are DNA damage checkpoint proficient and arrest normally in G2 after irradiation with normal Chk1/Chk2 activation. However, CDC14A-KO cells show persistent γ-H2AX foci and slower resolution of DNA double-strand breaks, indicating CDC14A is required for efficient DNA repair but not checkpoint signaling.\",\n      \"method\": \"Gene knockout (targeted deletion) in three cell lines, irradiation assay, γ-H2AX foci quantification, comet assay, immunoblot for checkpoint kinase activation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout validated in three independent vertebrate cell lines with multiple orthogonal assays, checkpoint negative result clearly established\",\n      \"pmids\": [\"20479464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CDC14A and CDC14B redundantly regulate DNA double-strand break repair in mammalian cells. CDC14B-KO MEFs show DSB repair defects at late passages when CDC14A levels are also low. Combined loss of both CDC14A and CDC14B impairs both homologous recombination and non-homologous end joining. Cdh1 is a downstream target of Cdc14B in DSB repair.\",\n      \"method\": \"Knockout MEFs, siRNA knockdown, IR-induced DSB repair assays (γ-H2AX, HR and NHEJ reporters), immunoblot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout cells with specific repair pathway readouts, single lab, Cdh1 substrate link is supporting but not fully characterized here\",\n      \"pmids\": [\"26283732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human CDC14A modulates the G2/M transition: increasing CDC14A levels delays mitotic entry by inhibiting Cdk1-cyclin B1 activity, whereas depleting CDC14A accelerates mitotic entry. CDC14A directly binds to and dephosphorylates Cdc25B, inhibiting its catalytic activity. CDC14A also regulates Cdc25A activity at the G2/M transition.\",\n      \"method\": \"Overexpression and siRNA knockdown in human cells, in vitro phosphatase assay with Cdc25B, cell cycle analysis, Cdk1 kinase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro dephosphorylation of Cdc25B plus cellular gain- and loss-of-function with cell cycle readouts, single lab\",\n      \"pmids\": [\"20956543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human CDC14A binds to Wee1 at its amino-terminal domain and dephosphorylates Wee1 at CDK-phosphorylated Ser123 and Ser139, preventing Plk1-mediated phosphorylation and subsequent Wee1 degradation at mitotic entry. CDC14A depletion significantly reduces Wee1 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase assay with recombinant Wee1, siRNA depletion, phospho-site mutagenesis, Wee1 stability assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro dephosphorylation with identified sites, Co-IP, siRNA phenotype, single lab\",\n      \"pmids\": [\"23051732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CDC14A and CDC14B phosphatases associate with KIBRA in human cells and dephosphorylate CDK1-phosphorylated KIBRA in vitro and in cells. CDK1 phosphorylates KIBRA at Ser542 and Ser931. Phospho-regulation of KIBRA by CDK1 and CDC14 is involved in mitotic exit under spindle stress.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase/phosphatase assays, site-directed mutagenesis, inducible expression, cell cycle analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo dephosphorylation with identified sites, Co-IP, single lab\",\n      \"pmids\": [\"22784093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mouse CDC14A concentrates in the nucleus of meiotically incompetent oocytes but disperses throughout meiotically competent oocytes. Between metaphase I and metaphase II, CDC14A co-localizes with the central portion of the meiotic spindle. Antibody microinjection against CDC14A specifically delays exit from meiosis I and generates eggs with chromosome alignment abnormalities and elevated aneuploidy. Overexpression of CDC14A delays meiotic progression after meiosis resumption.\",\n      \"method\": \"Immunofluorescence localization in mouse oocytes, antibody microinjection, overexpression, chromosome spread analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody microinjection loss-of-function with specific meiosis I exit defect, single lab\",\n      \"pmids\": [\"19270517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human CDC14A (like budding yeast Cdc14) can act as a CTD phosphatase for RNA polymerase II, targeting CTD phosphorylation at Ser2 and Ser5, consistent with a conserved role in transcriptional repression.\",\n      \"method\": \"In vitro CTD phosphatase assay with human CDC14A\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro assay, briefly described as conservation evidence in a study primarily focused on yeast Cdc14\",\n      \"pmids\": [\"22020438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Xenopus CDC14A (XCdc14alpha) localizes to the nucleolus in interphase and to mitotic centrosomes. XCdc14beta localizes primarily to centrosomes. Antibody injection against XCdc14alpha/beta into Xenopus embryos at the two-cell stage blocks division of injected blastomeres, demonstrating a requirement for CDC14A/B activity in vertebrate cell division. XCdc14alpha is phosphorylated both meiotically and mitotically.\",\n      \"method\": \"GFP tagging, immunofluorescence, antibody microinjection into Xenopus embryos\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct antibody loss-of-function with cell division arrest phenotype in Xenopus embryos, single lab\",\n      \"pmids\": [\"15251038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ERK3 C-terminal phosphorylation sites (Ser684, Ser688, Thr698, Ser705), all proline-directed, are phosphorylated by cyclin B-Cdk1. CDC14A and CDC14B both bind ERK3 and reverse this C-terminal phosphorylation in mitosis. Alanine substitution of these four sites decreases ERK3 half-life in mitosis, linking CDC14A/B-opposed phosphorylation to ERK3 stabilization.\",\n      \"method\": \"Mass spectrometry site identification, in vitro kinase/phosphatase assays with purified proteins, co-immunoprecipitation, pulse-chase stability assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phosphorylation/dephosphorylation with identified sites, Co-IP binding, stability assay, single lab\",\n      \"pmids\": [\"20236090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human CDC14A rescues flp1-deficient fission yeast strains, demonstrating functional homology. CDC14A interacts in vivo with S. pombe Cdc25 and dephosphorylates Cdc25 both in vitro and in vivo, suggesting CDC14A can inhibit Cdc25 activity.\",\n      \"method\": \"Complementation assay in fission yeast, co-immunoprecipitation, in vitro phosphatase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — heterologous complementation plus in vitro and in vivo dephosphorylation, single lab\",\n      \"pmids\": [\"15911625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of Cdc14 (S. cerevisiae, relevant to the conserved family including CDC14A) reveals two tandem DSP-like domains. The C-terminal domain contains the catalytic PTP motif; the N-terminal domain contributes to substrate specificity but lacks catalytic activity. The active site is at the interface of both domains. The structure reveals a hydrophobic pocket specifying the pSer-Pro motif, explaining selectivity for proline-directed phosphorylation.\",\n      \"method\": \"X-ray crystallography, kinetic analysis, peptide substrate binding\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with kinetic analyses; structural basis for substrate specificity defined; foundational for the whole Cdc14 family including CDC14A\",\n      \"pmids\": [\"12853468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Detailed kinetic and mechanistic analysis of Cdc14 phosphatase (including hCdc14a with substrate hCdh1) reveals: general acid-independent mechanism for substrates with pKa < 7, and general acid-dependent mechanism for substrates with pKa > 7. Asp253 functions as the general acid during phosphoenzyme formation and as the general base during hydrolysis. Asp50, Asp129, Glu168, Glu171, and Asp177 are required for efficient dephosphorylation of hCdh1.\",\n      \"method\": \"Kinetic analysis, mutagenesis of active-site residues, pre-steady-state kinetics, pH-dependence studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous enzymological dissection with mutagenesis, multiple kinetic methods, includes human CDC14A substrate (hCdh1)\",\n      \"pmids\": [\"15128740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cdc14 family phosphatases, including CDC14A homologs, have a strong and conserved preference for phosphoserine over phosphothreonine at proline-directed (CDK) sites. An invariant active-site residue sterically restricts phosphothreonine binding, responsible for phosphoserine selectivity. Optimal substrates additionally possess a basic residue at the +3 position. This selectivity is demonstrated both in vitro with purified proteins and in vivo using serine-to-threonine substitutions.\",\n      \"method\": \"In vitro phosphatase assays with phosphopeptides and phosphoprotein substrates, site-directed mutagenesis of active-site residue and substrate sites, in vivo analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical substrate specificity defined by multiple methods including mutagenesis; shown to be conserved across Cdc14 family\",\n      \"pmids\": [\"22117071\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human CDC14A is a proline-directed dual-specificity phosphatase that selectively dephosphorylates phosphoserine-containing CDK substrates; it localizes to interphase centrosomes (requiring nuclear export via a NES), the cell leading edge (actin cytoskeleton), kinocilia/basal bodies of inner ear hair cells, and the meiotic spindle midzone, where its phosphatase activity is required for centrosome separation, cell migration/adhesion (via dephosphorylation of eplin and KIBRA), primary cilia length regulation (via drebrin and Arp2 at centrosomes), hearing and male fertility in vivo, and efficient DNA double-strand break repair, while also dephosphorylating substrates including hCdh1, p53-Ser315, Cdc25B, Wee1, ERK3, and RN-tre to modulate CDK activity and G2/M entry.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDC14A is a dual-specificity protein phosphatase that selectively reverses CDK-mediated phosphorylation, with a strong intrinsic preference for phosphoserine over phosphothreonine at proline-directed (pSer-Pro) sites favoring a basic residue at +3 [#1, #23]. This selectivity is structurally encoded: the family adopts two tandem DSP-like domains in which the C-terminal domain carries the catalytic PTP motif while the N-terminal domain shapes substrate specificity, creating a hydrophobic pocket that reads the pSer-Pro motif, and active-site residues including Asp253 act as both general acid and general base during catalysis [#21, #22]. In human cells CDC14A localizes to interphase centrosomes through active nuclear export via an NES, and its dosage and activity control centrosome separation, spindle integrity, and cytokinesis [#0, #1]. Beyond mitotic regulation, CDC14A acts on the actin cytoskeleton at the cell leading edge, where its phosphatase activity supports stress fibers, adhesion, and restrains migration through substrates including KIBRA and eplin, the latter dephosphorylated at ERK sites to maintain E-cadherin/catenin-based cell-cell adhesion [#6, #7]. CDC14A also regulates primary cilium length via dephosphorylation of the actin-binding protein drebrin at CDK5-phosphorylated Ser142 and control of Arp2 recruitment to centrosomes [#8]. It modulates the G2/M transition by opposing CDK1-cyclin B1, dephosphorylating and inhibiting Cdc25B and stabilizing Wee1 through dephosphorylation of Ser123/Ser139 [#13, #14]. Through dephosphorylation of hCdh1 at the inhibitory CDK site, CDC14A activates APC(Cdh1) but not APC(Cdc20) [#2]. CDC14A is also required for efficient repair of DNA double-strand breaks, acting redundantly with CDC14B in both homologous recombination and non-homologous end joining without affecting checkpoint signaling [#11, #12]. In vivo, CDC14A phosphatase activity is essential for hearing and male fertility: it localizes to inner ear hair cell kinocilia and basal bodies, and biallelic loss-of-function or phosphatase-dead mutations cause sensorineural deafness in humans and deafness with male infertility in mice [#9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established CDC14A as a phosphatase physically coupled to a key cell-cycle/tumor-suppressor substrate, showing it reverses CDK-type phosphorylation on a defined site.\",\n      \"evidence\": \"in vitro binding, co-IP, and in vitro phosphatase assays mapping p53 Ser315 dephosphorylation\",\n      \"pmids\": [\"10644693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of p53 Ser315 dephosphorylation in cells not established\", \"single-lab in vitro dephosphorylation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected CDC14A to APC regulation by showing it dephosphorylates hCdh1 to selectively activate APC(Cdh1), defining a route by which it antagonizes mitotic CDK output.\",\n      \"evidence\": \"in vitro phosphatase assay and APC activity reconstitution with immunofluorescence\",\n      \"pmids\": [\"11598127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo timing of APC(Cdh1) activation by CDC14A not resolved\", \"selectivity over APC(Cdc20) mechanism not detailed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined CDC14A subcellular behavior and centrosome function, showing NES-dependent cytoplasmic localization to interphase centrosomes is required for centrosome separation and faithful division.\",\n      \"evidence\": \"siRNA knockdown, conditional overexpression, NES and phosphatase-dead mutants, live imaging, and in vitro CDK-substrate assays in human cells\",\n      \"pmids\": [\"11901424\", \"12134069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct centrosomal substrate driving separation not identified\", \"how NES export is regulated through the cycle unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Provided the structural and enzymological basis for CDC14 substrate selectivity and catalysis, explaining its preference for proline-directed phospho-sites.\",\n      \"evidence\": \"X-ray crystallography of yeast Cdc14, kinetic/pH-dependence and active-site mutagenesis including the human CDC14A substrate hCdh1; antibody injection in Xenopus embryos confirming a division requirement\",\n      \"pmids\": [\"12853468\", \"15128740\", \"15251038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure is of the yeast ortholog, not human CDC14A\", \"in vivo catalytic mechanism for individual cellular substrates not dissected\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated functional conservation and a Cdc25-directed activity, linking CDC14A to mitotic-entry control via heterologous complementation.\",\n      \"evidence\": \"fission yeast complementation, co-IP, and in vitro/in vivo dephosphorylation of S. pombe Cdc25\",\n      \"pmids\": [\"15911625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterologous system; human Cdc25 relevance addressed only later\", \"single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Expanded the substrate repertoire beyond cell-cycle regulators to ERK3 and the Rab5-GAP RN-tre, showing CDC14A reverses cell-cycle-dependent CDK phosphorylation on diverse targets.\",\n      \"evidence\": \"yeast two-hybrid, GST pull-down, substrate-trapping co-IP, and in vitro/in vivo phosphatase assays\",\n      \"pmids\": [\"18235225\", \"17371873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular phenotypes downstream of RN-tre/ERK3 dephosphorylation incompletely defined\", \"substrate-trapping evidence from single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Distinguished CDC14A's roles in DNA repair versus checkpoint signaling and quantified its effect on the G2/M transition, while extending substrates to the actin cytoskeleton.\",\n      \"evidence\": \"gene knockouts in three vertebrate cell lines with γ-H2AX/comet assays; overexpression/knockdown cell-cycle analysis with in vitro Cdc25B dephosphorylation; native-locus phosphatase-dead knock-in with migration/adhesion assays and KIBRA rescue; in vitro RNA Pol II CTD assay\",\n      \"pmids\": [\"20479464\", \"20956543\", \"26747605\", \"20236090\", \"22020438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DSB-repair substrate of CDC14A not identified\", \"CTD phosphatase activity rests on a single in vitro assay\", \"mechanism linking actin substrates to migration phenotype incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Refined the G2/M control circuit by showing CDC14A stabilizes Wee1 and dephosphorylates KIBRA at defined CDK sites, tying it to mitotic-entry and mitotic-exit regulation.\",\n      \"evidence\": \"co-IP, in vitro phosphatase assays with site mutagenesis, siRNA depletion, and stability/cell-cycle assays\",\n      \"pmids\": [\"23051732\", \"22784093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of Wee1 stabilization to mitotic timing not established\", \"single-lab site mapping\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established functional redundancy with CDC14B in DSB repair across HR and NHEJ, clarifying why single-gene phenotypes can be subtle.\",\n      \"evidence\": \"knockout MEFs, siRNA, and IR-induced HR/NHEJ reporter assays\",\n      \"pmids\": [\"26283732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CDC14A repair substrate not defined\", \"Cdh1 link to repair only partially characterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified eplin as a physiological CDC14A substrate at ERK sites, mechanistically linking CDC14A to maintenance of cadherin-based cell-cell adhesion.\",\n      \"evidence\": \"phosphoproteomics, BioID, in vitro/in vivo dephosphorylation, and phosphatase-dead knock-in cell lines\",\n      \"pmids\": [\"28465438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tissue context of eplin regulation not addressed\", \"single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined CDC14A's ciliary function and its physiological essentiality, establishing it as a phosphatase required for cilium-length control, hearing, and male fertility through phosphatase-dependent mechanisms.\",\n      \"evidence\": \"phosphatase-dead knock-in RPE1 cells with phosphoproteomics (drebrin Ser142, Arp2); CRISPR phosphatase-dead/truncating mouse and zebrafish models with histology and ciliary localization; human genetics and zebrafish morpholino for deafness\",\n      \"pmids\": [\"30467237\", \"29293958\", \"27259055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of ciliary substrates not enumerated\", \"kinocilium-length phenotype differs between morphant and germ-line mutant models\", \"molecular cause of postnatal hair-cell degeneration unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDC14A's many substrate dephosphorylation events are spatially and temporally coordinated to produce its distinct roles in division, migration, ciliogenesis, DNA repair, and sensory/reproductive tissue maintenance remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking centrosomal, cytoskeletal, and ciliary functions\", \"regulation of CDC14A activity/localization across the cell cycle and across tissues not defined\", \"direct DSB-repair substrate unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 5, 7, 8, 13, 14, 21, 22, 23]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 22, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 1, 18]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [8, 9, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2, 13, 14]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ERK3\", \"KIBRA\", \"Wee1\", \"Cdc25B\", \"RN-tre\", \"p53\", \"hCdh1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":9,"faith_pct":88.88888888888889}}