{"gene":"KIF18A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"KIF18A is a slow plus-end-directed kinesin with microtubule depolymerizing activity in vitro, and depolymerizes longer microtubules more quickly than shorter ones (length-dependent depolymerization). In vivo, KIF18A localizes near plus-ends of kinetochore microtubules; its depletion causes aberrantly long mitotic spindles, loss of tension across sister kinetochores, Mad2-dependent spindle assembly checkpoint activation, and chromosome congression failure.","method":"RNAi depletion, in vitro biochemical motility and depolymerization assays, live-cell microscopy","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro biochemical assays combined with RNAi and live-cell imaging, replicated by multiple subsequent labs","pmids":["17346968"],"is_preprint":false},{"year":2008,"finding":"KIF18A accumulates as a gradient on kinetochore microtubules in a motor-activity-dependent manner and suppresses chromosome oscillation amplitude and slows poleward movement during anaphase, establishing its primary role as a suppressor of chromosome movements rather than a depolymerizer per se.","method":"RNAi knockdown, quantitative live-cell imaging of kinetochore movements, fluorescence imaging of KIF18A gradient","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative kinetochore tracking with RNAi, replicated across multiple studies","pmids":["18267093"],"is_preprint":false},{"year":2010,"finding":"KIF18A inhibits the polymerization dynamics (dynamicity) of microtubule plus ends without destabilizing them in interphase cells, distinguishing its biochemical activity from the budding yeast ortholog Kip3, which depolymerizes microtubules.","method":"In vitro microtubule dynamics assays, live-cell imaging of microtubule plus-end dynamics","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro plus-end dynamics assays with live-cell validation, single lab with multiple orthogonal methods","pmids":["20153196"],"is_preprint":false},{"year":2011,"finding":"KIF18A's C-terminal tail domain contains a second microtubule-binding site that diffuses along the microtubule lattice, tethering the motor and enhancing processivity; this tail-mediated processivity is required for accumulation at kinetochore microtubule plus-ends and for suppression of chromosome movements. The N-terminal motor domain confers microtubule growth suppression activity.","method":"Kif18A tail-deletion and point mutants, single-molecule motility assays, live-cell imaging, microtubule co-pelleting","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain dissection with mutagenesis, single-molecule assays, and in-cell functional rescue, replicated by two concurrent studies","pmids":["21884977"],"is_preprint":false},{"year":2011,"finding":"An ATP-independent microtubule-binding site in the C-terminal tail (C-proximal 121 residues) of KIF18A is essential for its high processivity (single-molecule measurements) and for plus-end accumulation at kinetochore microtubules; removing this domain abolishes mitotic function.","method":"C-terminal truncation mutants, single-molecule processivity measurements, in vitro MT binding, cell imaging","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule assays plus mutagenesis plus cell functional data; independent corroboration from PMID 21884977 and 21885282","pmids":["22102900"],"is_preprint":false},{"year":2011,"finding":"KIF18A controls spindle length independently of chromosome positioning. The C-terminal ATP-independent MT-binding site has strong affinity for microtubules in vitro and in cells; computational modeling predicts that fast motility and low off-rate from MT ends are both important for KIF18A function.","method":"Spindle-length measurements after KIF18A domain mutant expression, in vitro MT co-sedimentation, computational modeling","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in single lab; computational modeling is supporting, not confirmatory","pmids":["21885282"],"is_preprint":false},{"year":2012,"finding":"KIF18A directly promotes microtubule pausing in a concentration-dependent manner using reconstituted dynamic microtubule assays, providing the dominant mechanism for restricting centromere movement to the spindle midzone.","method":"Reconstituted dynamic microtubule assays with purified KIF18A, quantitative live-cell imaging","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution assay combined with quantitative live-cell imaging in same study","pmids":["22595673"],"is_preprint":false},{"year":2009,"finding":"KIF18A physically interacts with CENP-E and BubR1 during mitosis (co-immunoprecipitation). KIF18A depletion causes specific protein degradation of CENP-E (not transcriptional reduction), and the resulting CENP-E loss partially mediates chromosome congression defects.","method":"Co-immunoprecipitation, RNAi, rescue with wild-type vs. mutant CENP-E tail domain","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP plus functional rescue, single lab; replicated in PMID 20981276","pmids":["19625775"],"is_preprint":false},{"year":2010,"finding":"KIF18A physically interacts with BubR1 and CENP-E; interaction is modulated during mitosis. KIF18A deficiency causes degradation of CENP-E and BubR1, microtubule dynamics perturbation, spindle pole integrity loss, and apoptosis; in male mice, KIF18A knockout leads to germinal cell aplasia due to impaired chromosome congression in mitosis and meiosis.","method":"Kif18a knockout mice, RNAi in GC-1 and HeLa cells, co-immunoprecipitation, histology","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — KO mouse plus Co-IP, single lab; corroborates PMID 19625775","pmids":["20981276"],"is_preprint":false},{"year":2011,"finding":"HURP interacts with KIF18A (co-immunoprecipitation and bimolecular fluorescence complementation), regulates KIF18A localization and dynamics at K-MT plus-ends, and overexpression of the HURP microtubule-binding domain causes mitotic defects mimicking KIF18A depletion that are partially rescued by KIF18A overexpression.","method":"Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), live-cell imaging, rescue experiments","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal interaction assays (CoIP + BiFC) with functional rescue, single lab","pmids":["21924616"],"is_preprint":false},{"year":2014,"finding":"KIF18A is antagonistically regulated by Cdk1-mediated inhibitory phosphorylation (promoting chromosome oscillations in early metaphase) and PP1 (dephosphorylating KIF18A to promote metaphase plate thinning). PP1α/γ is recruited to kinetochores upon chromosome biorientation, tipping the balance toward active, dephosphorylated KIF18A.","method":"Kinase/phosphatase perturbation, mass spectrometry phosphosite identification, RNAi, live-cell imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (MS phosphosite, kinase inhibition, phosphatase knockdown, live-cell imaging), single lab with comprehensive mechanistic follow-up","pmids":["25048371"],"is_preprint":false},{"year":2014,"finding":"KIF18A directly interacts with PP1γ through a conserved RVxF motif in its sequence; this interaction is broadly conserved across kinesins, suggesting an ancestral PP1 docking function.","method":"Biochemical interaction assays, phylogenetic analysis of RVxF motif conservation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding assay with RVxF motif identification; single lab, single method for physical interaction","pmids":["25281536"],"is_preprint":false},{"year":2015,"finding":"KIF18A is covalently modified by SUMO2, peaking at metaphase and decreasing at anaphase onset. Multiple lysine residues (K148, K442, K533, K660, K683) are SUMO2 acceptors. SUMO-resistant KIF18A mutants do not affect protein stability or localization but cause delayed mitotic exit and compromised BubR1 dissociation from kinetochores after anaphase onset.","method":"His6-SUMO2 pull-down, site-directed mutagenesis, confocal time-lapse imaging, immunofluorescence","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SUMO modification confirmed biochemically, mutagenesis of acceptor sites, functional cell imaging; single lab","pmids":["25884224"],"is_preprint":false},{"year":2018,"finding":"Loss of KIF18A results in spindle assembly checkpoint (SAC) activation at kinetochores that have established fully functional kinetochore-microtubule attachments but lack tension; this SAC activation (not chromosome missegregation per se) is the cause of lethality in cells without KIF18A.","method":"Haploid genetic screen (HAP1 cells), SAC-deficient double mutants, live-cell imaging, tension measurements","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with SAC-null backgrounds, haploid functional screen, multiple imaging approaches","pmids":["30122526"],"is_preprint":false},{"year":2019,"finding":"Kinesin-binding protein (KBP) directly inhibits KIF18A motor activity by preventing microtubule binding (gliding filament and microtubule co-pelleting assays), reducing KIF18A's mitotic localization; KBP overexpression phenocopies KIF18A/KIF15 co-depletion, and KBP depletion causes lagging chromosomes mimicking KIF18A overexpression.","method":"Gliding filament assay, microtubule co-pelleting, overexpression/depletion, live-cell imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct biochemical inhibition assays (gliding + co-pelleting) plus genetic phenotypic rescue, single lab with multiple orthogonal methods","pmids":["30709852"],"is_preprint":false},{"year":2019,"finding":"KIF18A's relatively long neck linker is required for its accumulation at plus-ends of kinetochore microtubules at the spindle center; shorter neck linker (sNL) variants are deficient in navigating microtubule-associated protein obstacles on K-fibers, as demonstrated by single-molecule assays showing reduced proficiency at bypassing MAP-coated microtubules.","method":"Neck linker length mutants, single-molecule assays on MAP-coated microtubules, live-cell imaging","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — single-molecule mechanistic assays plus in-cell imaging; single lab with two orthogonal method tiers","pmids":["30655363"],"is_preprint":false},{"year":2011,"finding":"Microtubule stabilization (taxol treatment or Aurora B inhibitor-induced end stabilization) triggers rapid KIF18A plus-end accumulation independent of kinetochore association, suggesting that MT plus-end stability controls KIF18A localization.","method":"Pharmacological stabilization (taxol, Aurora B inhibitor), live-cell imaging of KIF18A localization","journal":"Cell structure and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological perturbations with imaging readout; single lab, two independent drug conditions","pmids":["22104080"],"is_preprint":false},{"year":2007,"finding":"KIF18A (MS-KIF18A) interacts with estrogen receptor alpha (ERα, both 66 and 46 kDa isoforms) as demonstrated by immunoprecipitation in MBA-15 osteogenic cells and ectopic co-expression in COS-7 cells; 17β-estrogen challenge induces association of KIF18A with phospho-ERK1/2, which is disrupted by ICI-182,780 or the MAPK inhibitor PD98059.","method":"Co-immunoprecipitation, ectopic expression, pharmacological inhibitors","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP assay, single lab, limited mechanistic follow-up","pmids":["17006958"],"is_preprint":false},{"year":2009,"finding":"ERα is a cargo of KIF18A; pull-down assay with recombinant proteins confirms direct interaction between KIF18A and ERα in vitro. Estrogen stimulates KIF18A promoter activity (luciferase reporter) via ERα and c-Jun binding to the KIF18A promoter (ChIP assay).","method":"In vitro pull-down, luciferase reporter assay, ChIP assay","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro pull-down plus reporter assay, single lab, limited functional mechanistic dissection","pmids":["19636373"],"is_preprint":false},{"year":2018,"finding":"In mouse oocyte meiosis, Kif18A knockdown increases acetylated tubulin levels and decreases Sirt2 (tubulin deacetylase) expression, causing spindle organization defects and chromosome misalignment; microinjection of tubulin K40R mRNA (preventing acetylation) rescues spindle morphology in Kif18A-knockdown oocytes.","method":"Morpholino/siRNA knockdown in mouse oocytes, tubulin acetylation immunofluorescence, mRNA microinjection rescue","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus molecular rescue with acetylation-resistant tubulin, single lab with two orthogonal approaches","pmids":["30459823"],"is_preprint":false},{"year":2021,"finding":"Micronuclei formed in KIF18A KO cells recruit increased nuclear envelope components and support successful chromatin decondensation (stable nuclear envelopes), unlike micronuclei induced by nocodazole or radiation; lagging chromosomes in KIF18A KO cells are positioned closer to main chromatin masses.","method":"KIF18A KO cell lines, live-cell imaging, nuclear envelope component immunofluorescence, Trp53 deletion mouse model","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cell lines plus mouse genetic model with multiple imaging approaches, single lab","pmids":["34515734"],"is_preprint":false},{"year":2023,"finding":"KIF18A inhibitors (photoaffinity labeling experiments) bind at the interface of KIF18A and tubulin, identifying a tubulin-KIF18A interface as a druggable allosteric site distinct from the ATP-binding pocket.","method":"Photoaffinity labeling, medicinal chemistry, in vivo mitotic arrest assays","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — photoaffinity labeling identifies binding site directly; single study","pmids":["35286090"],"is_preprint":false},{"year":2024,"finding":"KIF18A inhibition drives a widespread increase in spindle assembly checkpoint (SAC) signaling; whether cells arrest depends on APC/C activity. Cells with weak basal APC/C activity and/or persistent SAC signaling are uniquely sensitive to KIF18A inhibition, explaining the selective lethality in CIN cancer cells.","method":"Live-cell imaging, APC/C activity reporters, genetic/pharmacological perturbation of SAC and APC/C, panel of cancer cell lines","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporters, genetics, pharmacology) across cell line panel identifying mechanistic basis for selectivity","pmids":["38279026"],"is_preprint":false},{"year":2024,"finding":"HURP regulates KIF18A motility in a concentration-dependent manner: sparse HURP decoration activates KIF18A motility, while high HURP concentrations hinder processive motility by steric exclusion at the KIF18A motor domain-microtubule binding site. HURP and KIF18A together suppress microtubule plus-end dynamics more effectively than either alone.","method":"Single-molecule imaging in vitro, cryo-EM structure of HURP-microtubule complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus single-molecule functional assays providing mechanistic basis for HURP-KIF18A interplay","pmids":["39516196"],"is_preprint":false},{"year":2024,"finding":"KIF18A directly binds TTC3 and enhances TTC3-p-AKT interaction, promoting TTC3-mediated ubiquitination and degradation of phospho-AKT, thereby suppressing the AKT/mTOR pathway in hepatic stellate cells.","method":"Co-immunoprecipitation, ubiquitination assay, KIF18A knockdown/overexpression in vitro and in CCl4 mouse liver fibrosis model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for physical interaction plus in vivo model, single lab; mechanism inferred from pathway assays","pmids":["38372748"],"is_preprint":false},{"year":2023,"finding":"Phosphomimetic mutation S357D in the neck-linker of KIF18A redirects the motor from kinetochore microtubules to non-kinetochore peripheral microtubules, causing spindle positioning defects and failure to promote mitotic progression; this phenotype is mimicked by a shortened neck-linker mutant.","method":"Phosphomimetic mutagenesis, live-cell imaging, spindle positioning assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional in-cell readouts, single lab, two independent mutant approaches giving consistent results","pmids":["37903223"],"is_preprint":false},{"year":2024,"finding":"Mutation of S284 within the alpha-4 helix of KIF18A causes relocalization from K-fiber plus-ends to spindle poles, loss of KIF18A function, and failure to support CIN tumor cell proliferation. Small molecules predicted to interact with the alpha-4 helix produce similar relocalization and functional loss.","method":"Site-directed mutagenesis, live-cell imaging, small-molecule inhibitor treatment, CIN cell proliferation assay","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus inhibitor phenocopy, single lab, functional validation in tumor cell proliferation","pmids":["38410188"],"is_preprint":false},{"year":2024,"finding":"Chromosome alignment and KIF18A plus-end localization depend on a spindle-localized fraction of inhibited/inactive Cdk1 (i-Cdk1, Wee1-phosphorylated). Reducing i-Cdk1 causes spindle defects and poor KIF18A localization; restoring i-Cdk1 reverses both; expressing a phosphonull KIF18A at Cdk1 phosphorylation sites rescues alignment defects in i-Cdk1-depleted cells.","method":"Genetic perturbation of Wee1/Cdk1 phosphorylation, immunofluorescence, cell fractionation, phosphonull KIF18A rescue","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and phospho-mutant rescue experiments, single lab; consistent with earlier Cdk1/PP1 regulatory model","pmids":["39610707"],"is_preprint":false},{"year":2025,"finding":"KIF18A depletion disrupts the parallel structure of the central spindle in late anaphase, causing mislocalization of the centralspindlin components KIF23 (MKLP1) and RACGAP1, impaired cleavage furrow establishment, and incomplete cytokinesis. KIF18A localizes at the metaphase plate, then central spindle in late anaphase, then spindle midbody in telophase.","method":"siRNA depletion, live-cell imaging, immunofluorescence of centralspindlin components","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — depletion with defined molecular phenotype (centralspindlin mislocalization), single lab","pmids":["39954259"],"is_preprint":false},{"year":2025,"finding":"Genetic epistasis screen using a hypomorphic CENP-C mutant identified KIF18A as synthetic lethal; the synthetic defect is due to reduced CENP-E function in the CENP-C mutant background. KIF18A promotes chromosome alignment in cooperation with CENP-E downstream of CENP-C during early prometaphase.","method":"Genome-wide Cas9-based functional genetics screen, synthetic lethality epistasis, CENP-E functional analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide epistasis screen with mechanistic follow-up; single lab but rigorous genetic approach","pmids":["41218610"],"is_preprint":false},{"year":2024,"finding":"Depletion of KIF18A induced mitotic arrest in cells, which was partially rescued by co-depletion of ANAPC7 (APC7) and exacerbated by co-depletion of ANAPC5 (APC5), placing KIF18A in a regulatory network with APC/C subunits controlling mitotic exit.","method":"RNAi double-depletion epistasis in cell lines, mitotic arrest quantification","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with two APC/C subunits, single lab; consistent with EMBO J APC/C finding","pmids":["40596795"],"is_preprint":false},{"year":2025,"finding":"A crystal structure of the KIF18A-tubulin complex was determined, supporting structure-based inhibitor design. The ATP non-competitive inhibitor VLS-1272 is microtubule-dependent, blocks KIF18A ATPase activity, prevents KIF18A translocation across the mitotic spindle, and results in chromosome congression defects, mitotic cell accumulation, and cell death.","method":"Crystal structure of KIF18A-tubulin complex, ATPase assays, microtubule gliding assays, in vivo xenograft","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus biochemical mechanism of ATP non-competitive, MT-dependent inhibition, validated in vivo","pmids":["39747049"],"is_preprint":false},{"year":2025,"finding":"A high-resolution crystal structure of the KIF18A-tubulin complex was obtained; ATX020 binds at the KIF18A-tubulin interface in an experimentally guided model, confirming the tubulin interface as a druggable allosteric site.","method":"X-ray crystallography of KIF18A-tubulin complex, structure-based drug design","journal":"ACS medicinal chemistry letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with experimentally guided binding model","pmids":["41257005"],"is_preprint":false},{"year":2020,"finding":"KIF18A mRNA stability in esophageal cancer cells is regulated post-transcriptionally by the RNA-binding protein IGF2BP3, which binds KIF18A mRNA (RIP assay) and increases its stability.","method":"RNA immunoprecipitation (RIP), RNA stability assay, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single RIP and stability assay, limited mechanistic follow-up for this specific interaction","pmids":["33872988"],"is_preprint":false},{"year":2020,"finding":"KIF18A mRNA in human male germ cells (TCam-2 line) is post-transcriptionally repressed by PUM1 and PUM2 proteins via PUM-binding elements in KIF18A's 3'-UTR; PUM repression of KIF18A reduces proliferation and alters the cell cycle in TCam-2 cells.","method":"RNA co-immunoprecipitation, luciferase reporter assay with wild-type and mutant KIF18A 3'-UTR, siRNA knockdown, flow cytometry","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-CoIP plus luciferase 3'-UTR reporter with PUM overexpression/knockdown, single lab","pmids":["32094263"],"is_preprint":false},{"year":2025,"finding":"The JNK1/c-Jun signaling pathway directly activates KIF18A transcription: c-Jun binds and activates the KIF18A promoter (ChIP and luciferase reporter assays); JNK1 inhibition decreases KIF18A expression and c-Jun phosphorylation; c-Jun knockdown inhibits cervical cancer growth partially rescued by KIF18A overexpression.","method":"ChIP assay, luciferase reporter assay, JNK1 inhibition, c-Jun siRNA, KIF18A rescue","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus epistatic rescue; single lab with multiple orthogonal methods","pmids":["39749722"],"is_preprint":false}],"current_model":"KIF18A is a highly processive, plus-end-directed kinesin-8 motor that uses its N-terminal motor domain to suppress microtubule plus-end dynamics (pausing/capping rather than pure depolymerization) and its C-terminal tail—which contains an ATP-independent microtubule-tethering domain—to accumulate at kinetochore microtubule plus-ends, where it dampens chromosome oscillations and promotes metaphase alignment; its activity is spatiotemporally regulated by Cdk1 (inhibitory phosphorylation) and PP1 (activating dephosphorylation), by SUMO2 modification at multiple lysines, by neck-linker phosphorylation that biases microtubule subpopulation preference, by kinesin-binding protein (KBP) that buffers its motor activity, and by HURP that modulates its processivity; KIF18A physically interacts with CENP-E, BubR1, PP1γ (via an RVxF motif), TTC3, and estrogen receptor alpha; loss of KIF18A triggers spindle assembly checkpoint activation through loss of kinetochore tension even at attached kinetochores, and chromosomally unstable (CIN) cancer cells are selectively dependent on KIF18A because they require its activity to restrain excessive microtubule dynamics and maintain kinetochore-microtubule attachments, a vulnerability that is compounded by weak basal APC/C activity in these cells."},"narrative":{"mechanistic_narrative":"KIF18A is a plus-end-directed kinesin-8 motor that governs mitotic chromosome alignment by suppressing the dynamics of kinetochore microtubule plus-ends [PMID:17346968, PMID:18267093, PMID:20153196]. Its N-terminal motor domain promotes microtubule pausing and growth suppression in a concentration-dependent manner rather than acting as a pure depolymerizer [PMID:20153196, PMID:22595673], while a second ATP-independent microtubule-binding site in its C-terminal tail tethers the motor to the lattice, conferring the high processivity required for accumulation at kinetochore microtubule plus-ends and for damping chromosome oscillations [PMID:21884977, PMID:22102900]. A relatively long neck linker allows KIF18A to bypass microtubule-associated protein obstacles and reach plus-ends at the spindle center [PMID:30655363]. KIF18A activity is spatiotemporally tuned: Cdk1 imposes inhibitory phosphorylation and PP1 (recruited via an RVxF motif to PP1γ) dephosphorylates and activates the motor upon biorientation [PMID:25048371, PMID:25281536, PMID:39610707], kinesin-binding protein buffers motor output by blocking microtubule engagement [PMID:30709852], and HURP modulates processivity in a concentration-dependent fashion [PMID:21924616, PMID:39516196]. Functionally, KIF18A cooperates with CENP-E and BubR1 to drive chromosome congression [PMID:19625775, PMID:41218610], and its loss triggers spindle assembly checkpoint activation through loss of kinetochore tension even at properly attached kinetochores [PMID:30122526]. This dependency underlies the selective vulnerability of chromosomally unstable cancer cells, which arrest upon KIF18A inhibition because of weak basal APC/C activity and persistent SAC signaling [PMID:38279026, PMID:40596795], a vulnerability exploited by ATP-noncompetitive inhibitors that bind the KIF18A-tubulin interface defined by crystal structures [PMID:35286090, PMID:39747049, PMID:41257005].","teleology":[{"year":2007,"claim":"Established KIF18A as a plus-end-directed kinesin with length-dependent microtubule depolymerizing activity whose loss disrupts spindle length and chromosome congression, defining its core mitotic role.","evidence":"in vitro motility/depolymerization assays plus RNAi and live-cell imaging","pmids":["17346968"],"confidence":"High","gaps":["Did not resolve whether the dominant in vivo activity is depolymerization vs. dynamics suppression","Mechanism of plus-end accumulation unknown"]},{"year":2008,"claim":"Reframed KIF18A as a suppressor of chromosome movements through motor-dependent gradient accumulation on kinetochore microtubules, rather than a simple depolymerizer.","evidence":"quantitative kinetochore tracking with RNAi and gradient imaging","pmids":["18267093"],"confidence":"High","gaps":["Biochemical distinction from depolymerization not yet resolved","Tail contribution to gradient unclear"]},{"year":2010,"claim":"Showed KIF18A dampens plus-end polymerization dynamics without destabilizing microtubules, distinguishing its biochemistry from the depolymerizing yeast ortholog Kip3.","evidence":"in vitro microtubule dynamics assays with live-cell validation","pmids":["20153196"],"confidence":"High","gaps":["Single-lab in vitro characterization","Did not define the molecular basis of pausing"]},{"year":2011,"claim":"Resolved the structural division of labor: the C-terminal tail provides an ATP-independent, lattice-diffusing microtubule-binding site essential for processivity and plus-end accumulation, while the N-terminal motor confers growth suppression.","evidence":"domain/truncation/point mutants, single-molecule motility, co-pelleting, in-cell rescue (multiple concurrent studies)","pmids":["21884977","22102900","21885282"],"confidence":"High","gaps":["Did not establish how spindle-length control is separated from chromosome positioning at the molecular level","Regulation of tail engagement unknown"]},{"year":2012,"claim":"Demonstrated by reconstitution that purified KIF18A directly promotes microtubule pausing in a concentration-dependent manner, providing the dominant mechanism for confining centromeres to the spindle midzone.","evidence":"reconstituted dynamic microtubule assays with purified protein plus live-cell imaging","pmids":["22595673"],"confidence":"High","gaps":["Did not address how pausing activity is regulated in vivo","Role of accessory factors not tested"]},{"year":2010,"claim":"Identified CENP-E and BubR1 as physical partners and showed KIF18A loss destabilizes CENP-E protein, linking KIF18A function to congression machinery; KO mice revealed germ-cell aplasia from mitotic and meiotic congression failure.","evidence":"reciprocal Co-IP, RNAi, rescue, and Kif18a knockout mice","pmids":["19625775","20981276"],"confidence":"Medium","gaps":["Direct vs. indirect basis of CENP-E/BubR1 destabilization not fully resolved","Co-IP without structural mapping of interfaces"]},{"year":2011,"claim":"Showed HURP binds KIF18A and modulates its localization and dynamics at kinetochore microtubule plus-ends, introducing a MAP-based layer of regulation.","evidence":"Co-IP, BiFC, live-cell imaging, rescue experiments","pmids":["21924616"],"confidence":"Medium","gaps":["Mechanism of modulation not defined at this stage","Single-lab interaction data"]},{"year":2014,"claim":"Defined antagonistic Cdk1/PP1 control of KIF18A, with PP1γ docking via an RVxF motif and dephosphorylation activating the motor upon biorientation, explaining temporal switching from oscillation to plate thinning.","evidence":"MS phosphosite mapping, kinase/phosphatase perturbation, biochemical RVxF-binding assays","pmids":["25048371","25281536"],"confidence":"High","gaps":["RVxF interaction shown by single-method binding assay","Full phosphosite-to-function map incomplete"]},{"year":2015,"claim":"Identified SUMO2 modification of KIF18A peaking at metaphase as a regulator of mitotic exit timing and BubR1 dissociation, adding a post-translational control independent of stability or localization.","evidence":"His6-SUMO2 pull-down, acceptor-lysine mutagenesis, time-lapse imaging","pmids":["25884224"],"confidence":"Medium","gaps":["SUMO E3 ligase not identified","Mechanistic link to BubR1 dissociation unresolved"]},{"year":2018,"claim":"Established that lethality on KIF18A loss arises from SAC activation at attached-but-tensionless kinetochores rather than missegregation per se, clarifying the basis of essentiality.","evidence":"haploid genetic screen, SAC-null epistasis, tension measurements, live imaging","pmids":["30122526"],"confidence":"High","gaps":["Did not yet define why CIN cells are selectively sensitive","Tension-sensing pathway link incomplete"]},{"year":2019,"claim":"Defined two mechanical determinants of targeting: KBP buffers motor activity by blocking microtubule binding, and a long neck linker enables navigation past MAP obstacles to reach K-fiber plus-ends.","evidence":"gliding/co-pelleting inhibition assays and single-molecule assays on MAP-coated microtubules with in-cell imaging","pmids":["30709852","30655363"],"confidence":"High","gaps":["Physiological contexts that engage KBP regulation in vivo not fully mapped","Single-lab studies"]},{"year":2023,"claim":"Showed neck-linker phosphorylation (S357) biases KIF18A toward kinetochore vs. peripheral microtubules, linking a phosphosite to subpopulation selection and spindle positioning.","evidence":"phosphomimetic and short-neck-linker mutants with live-cell spindle positioning assays","pmids":["37903223"],"confidence":"Medium","gaps":["Responsible kinase not identified","Single-lab functional study"]},{"year":2024,"claim":"Explained the selective lethality of KIF18A inhibition: it broadly raises SAC signaling, and arrest occurs only in cells with weak basal APC/C activity, placing KIF18A in an APC/C-dependent mitotic-exit network.","evidence":"APC/C reporters, SAC/APC/C perturbation across a cancer cell line panel; APC subunit epistasis","pmids":["38279026","40596795"],"confidence":"High","gaps":["Quantitative threshold of APC/C activity defining sensitivity not delineated","Direct molecular link between KIF18A and APC/C subunits unresolved"]},{"year":2024,"claim":"Resolved the HURP-KIF18A interplay biophysically: HURP activates KIF18A at low density but sterically blocks the motor at high density, with the two together suppressing plus-end dynamics more than either alone.","evidence":"single-molecule imaging and cryo-EM of the HURP-microtubule complex","pmids":["39516196"],"confidence":"High","gaps":["In vivo concentration regimes governing the switch not measured","Spatial distribution of HURP on K-fibers not mapped"]},{"year":2025,"claim":"Crystal structures of the KIF18A-tubulin complex defined an ATP-noncompetitive, microtubule-dependent allosteric inhibitor-binding site at the tubulin interface, enabling structure-based inhibitor design validated in xenografts.","evidence":"X-ray crystallography, ATPase and gliding assays, photoaffinity labeling, in vivo tumor models","pmids":["39747049","41257005","35286090"],"confidence":"High","gaps":["Resistance mechanisms to interface inhibitors not characterized","Allosteric coupling to the catalytic cycle not fully described"]},{"year":2025,"claim":"Extended KIF18A function beyond metaphase, showing it is required for central spindle organization and centralspindlin (KIF23/RACGAP1) localization during cytokinesis, and confirmed cooperation with CENP-E downstream of CENP-C in early prometaphase.","evidence":"siRNA depletion with centralspindlin immunofluorescence; genome-wide CENP-C synthetic-lethality screen","pmids":["39954259","41218610"],"confidence":"Medium","gaps":["Direct vs. indirect role in centralspindlin recruitment unresolved","Molecular basis of the CENP-C/CENP-E coupling not fully defined"]},{"year":null,"claim":"How KIF18A integrates its multiple regulatory inputs (Cdk1/PP1 phosphorylation, SUMOylation, KBP buffering, HURP density, neck-linker phosphorylation) into a single spatiotemporal output at the kinetochore remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model linking the regulatory layers","Relative in vivo contribution of each modifier unquantified","Structural basis of tail-mediated tethering on dynamic K-fibers not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,31]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,4,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[24]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,13,22]}],"complexes":[],"partners":["CENP-E","BUBR1","PP1Γ","HURP","KBP","TTC3","ESR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NI77","full_name":"Kinesin-like protein KIF18A","aliases":["Marrow stromal KIF18A","MS-KIF18A"],"length_aa":898,"mass_kda":102.3,"function":"Microtubule-depolymerizing kinesin which plays a role in chromosome congression by reducing the amplitude of preanaphase oscillations and slowing poleward movement during anaphase, thus suppressing chromosome movements. 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In vivo, KIF18A localizes near plus-ends of kinetochore microtubules; its depletion causes aberrantly long mitotic spindles, loss of tension across sister kinetochores, Mad2-dependent spindle assembly checkpoint activation, and chromosome congression failure.\",\n      \"method\": \"RNAi depletion, in vitro biochemical motility and depolymerization assays, live-cell microscopy\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro biochemical assays combined with RNAi and live-cell imaging, replicated by multiple subsequent labs\",\n      \"pmids\": [\"17346968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIF18A accumulates as a gradient on kinetochore microtubules in a motor-activity-dependent manner and suppresses chromosome oscillation amplitude and slows poleward movement during anaphase, establishing its primary role as a suppressor of chromosome movements rather than a depolymerizer per se.\",\n      \"method\": \"RNAi knockdown, quantitative live-cell imaging of kinetochore movements, fluorescence imaging of KIF18A gradient\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative kinetochore tracking with RNAi, replicated across multiple studies\",\n      \"pmids\": [\"18267093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KIF18A inhibits the polymerization dynamics (dynamicity) of microtubule plus ends without destabilizing them in interphase cells, distinguishing its biochemical activity from the budding yeast ortholog Kip3, which depolymerizes microtubules.\",\n      \"method\": \"In vitro microtubule dynamics assays, live-cell imaging of microtubule plus-end dynamics\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro plus-end dynamics assays with live-cell validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20153196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KIF18A's C-terminal tail domain contains a second microtubule-binding site that diffuses along the microtubule lattice, tethering the motor and enhancing processivity; this tail-mediated processivity is required for accumulation at kinetochore microtubule plus-ends and for suppression of chromosome movements. The N-terminal motor domain confers microtubule growth suppression activity.\",\n      \"method\": \"Kif18A tail-deletion and point mutants, single-molecule motility assays, live-cell imaging, microtubule co-pelleting\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain dissection with mutagenesis, single-molecule assays, and in-cell functional rescue, replicated by two concurrent studies\",\n      \"pmids\": [\"21884977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"An ATP-independent microtubule-binding site in the C-terminal tail (C-proximal 121 residues) of KIF18A is essential for its high processivity (single-molecule measurements) and for plus-end accumulation at kinetochore microtubules; removing this domain abolishes mitotic function.\",\n      \"method\": \"C-terminal truncation mutants, single-molecule processivity measurements, in vitro MT binding, cell imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule assays plus mutagenesis plus cell functional data; independent corroboration from PMID 21884977 and 21885282\",\n      \"pmids\": [\"22102900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KIF18A controls spindle length independently of chromosome positioning. The C-terminal ATP-independent MT-binding site has strong affinity for microtubules in vitro and in cells; computational modeling predicts that fast motility and low off-rate from MT ends are both important for KIF18A function.\",\n      \"method\": \"Spindle-length measurements after KIF18A domain mutant expression, in vitro MT co-sedimentation, computational modeling\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in single lab; computational modeling is supporting, not confirmatory\",\n      \"pmids\": [\"21885282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KIF18A directly promotes microtubule pausing in a concentration-dependent manner using reconstituted dynamic microtubule assays, providing the dominant mechanism for restricting centromere movement to the spindle midzone.\",\n      \"method\": \"Reconstituted dynamic microtubule assays with purified KIF18A, quantitative live-cell imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution assay combined with quantitative live-cell imaging in same study\",\n      \"pmids\": [\"22595673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KIF18A physically interacts with CENP-E and BubR1 during mitosis (co-immunoprecipitation). KIF18A depletion causes specific protein degradation of CENP-E (not transcriptional reduction), and the resulting CENP-E loss partially mediates chromosome congression defects.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, rescue with wild-type vs. mutant CENP-E tail domain\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP plus functional rescue, single lab; replicated in PMID 20981276\",\n      \"pmids\": [\"19625775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KIF18A physically interacts with BubR1 and CENP-E; interaction is modulated during mitosis. KIF18A deficiency causes degradation of CENP-E and BubR1, microtubule dynamics perturbation, spindle pole integrity loss, and apoptosis; in male mice, KIF18A knockout leads to germinal cell aplasia due to impaired chromosome congression in mitosis and meiosis.\",\n      \"method\": \"Kif18a knockout mice, RNAi in GC-1 and HeLa cells, co-immunoprecipitation, histology\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — KO mouse plus Co-IP, single lab; corroborates PMID 19625775\",\n      \"pmids\": [\"20981276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HURP interacts with KIF18A (co-immunoprecipitation and bimolecular fluorescence complementation), regulates KIF18A localization and dynamics at K-MT plus-ends, and overexpression of the HURP microtubule-binding domain causes mitotic defects mimicking KIF18A depletion that are partially rescued by KIF18A overexpression.\",\n      \"method\": \"Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), live-cell imaging, rescue experiments\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal interaction assays (CoIP + BiFC) with functional rescue, single lab\",\n      \"pmids\": [\"21924616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIF18A is antagonistically regulated by Cdk1-mediated inhibitory phosphorylation (promoting chromosome oscillations in early metaphase) and PP1 (dephosphorylating KIF18A to promote metaphase plate thinning). PP1α/γ is recruited to kinetochores upon chromosome biorientation, tipping the balance toward active, dephosphorylated KIF18A.\",\n      \"method\": \"Kinase/phosphatase perturbation, mass spectrometry phosphosite identification, RNAi, live-cell imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (MS phosphosite, kinase inhibition, phosphatase knockdown, live-cell imaging), single lab with comprehensive mechanistic follow-up\",\n      \"pmids\": [\"25048371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIF18A directly interacts with PP1γ through a conserved RVxF motif in its sequence; this interaction is broadly conserved across kinesins, suggesting an ancestral PP1 docking function.\",\n      \"method\": \"Biochemical interaction assays, phylogenetic analysis of RVxF motif conservation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding assay with RVxF motif identification; single lab, single method for physical interaction\",\n      \"pmids\": [\"25281536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIF18A is covalently modified by SUMO2, peaking at metaphase and decreasing at anaphase onset. Multiple lysine residues (K148, K442, K533, K660, K683) are SUMO2 acceptors. SUMO-resistant KIF18A mutants do not affect protein stability or localization but cause delayed mitotic exit and compromised BubR1 dissociation from kinetochores after anaphase onset.\",\n      \"method\": \"His6-SUMO2 pull-down, site-directed mutagenesis, confocal time-lapse imaging, immunofluorescence\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SUMO modification confirmed biochemically, mutagenesis of acceptor sites, functional cell imaging; single lab\",\n      \"pmids\": [\"25884224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of KIF18A results in spindle assembly checkpoint (SAC) activation at kinetochores that have established fully functional kinetochore-microtubule attachments but lack tension; this SAC activation (not chromosome missegregation per se) is the cause of lethality in cells without KIF18A.\",\n      \"method\": \"Haploid genetic screen (HAP1 cells), SAC-deficient double mutants, live-cell imaging, tension measurements\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with SAC-null backgrounds, haploid functional screen, multiple imaging approaches\",\n      \"pmids\": [\"30122526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kinesin-binding protein (KBP) directly inhibits KIF18A motor activity by preventing microtubule binding (gliding filament and microtubule co-pelleting assays), reducing KIF18A's mitotic localization; KBP overexpression phenocopies KIF18A/KIF15 co-depletion, and KBP depletion causes lagging chromosomes mimicking KIF18A overexpression.\",\n      \"method\": \"Gliding filament assay, microtubule co-pelleting, overexpression/depletion, live-cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct biochemical inhibition assays (gliding + co-pelleting) plus genetic phenotypic rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30709852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIF18A's relatively long neck linker is required for its accumulation at plus-ends of kinetochore microtubules at the spindle center; shorter neck linker (sNL) variants are deficient in navigating microtubule-associated protein obstacles on K-fibers, as demonstrated by single-molecule assays showing reduced proficiency at bypassing MAP-coated microtubules.\",\n      \"method\": \"Neck linker length mutants, single-molecule assays on MAP-coated microtubules, live-cell imaging\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — single-molecule mechanistic assays plus in-cell imaging; single lab with two orthogonal method tiers\",\n      \"pmids\": [\"30655363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Microtubule stabilization (taxol treatment or Aurora B inhibitor-induced end stabilization) triggers rapid KIF18A plus-end accumulation independent of kinetochore association, suggesting that MT plus-end stability controls KIF18A localization.\",\n      \"method\": \"Pharmacological stabilization (taxol, Aurora B inhibitor), live-cell imaging of KIF18A localization\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological perturbations with imaging readout; single lab, two independent drug conditions\",\n      \"pmids\": [\"22104080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIF18A (MS-KIF18A) interacts with estrogen receptor alpha (ERα, both 66 and 46 kDa isoforms) as demonstrated by immunoprecipitation in MBA-15 osteogenic cells and ectopic co-expression in COS-7 cells; 17β-estrogen challenge induces association of KIF18A with phospho-ERK1/2, which is disrupted by ICI-182,780 or the MAPK inhibitor PD98059.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression, pharmacological inhibitors\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP assay, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"17006958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ERα is a cargo of KIF18A; pull-down assay with recombinant proteins confirms direct interaction between KIF18A and ERα in vitro. Estrogen stimulates KIF18A promoter activity (luciferase reporter) via ERα and c-Jun binding to the KIF18A promoter (ChIP assay).\",\n      \"method\": \"In vitro pull-down, luciferase reporter assay, ChIP assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro pull-down plus reporter assay, single lab, limited functional mechanistic dissection\",\n      \"pmids\": [\"19636373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In mouse oocyte meiosis, Kif18A knockdown increases acetylated tubulin levels and decreases Sirt2 (tubulin deacetylase) expression, causing spindle organization defects and chromosome misalignment; microinjection of tubulin K40R mRNA (preventing acetylation) rescues spindle morphology in Kif18A-knockdown oocytes.\",\n      \"method\": \"Morpholino/siRNA knockdown in mouse oocytes, tubulin acetylation immunofluorescence, mRNA microinjection rescue\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus molecular rescue with acetylation-resistant tubulin, single lab with two orthogonal approaches\",\n      \"pmids\": [\"30459823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Micronuclei formed in KIF18A KO cells recruit increased nuclear envelope components and support successful chromatin decondensation (stable nuclear envelopes), unlike micronuclei induced by nocodazole or radiation; lagging chromosomes in KIF18A KO cells are positioned closer to main chromatin masses.\",\n      \"method\": \"KIF18A KO cell lines, live-cell imaging, nuclear envelope component immunofluorescence, Trp53 deletion mouse model\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cell lines plus mouse genetic model with multiple imaging approaches, single lab\",\n      \"pmids\": [\"34515734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIF18A inhibitors (photoaffinity labeling experiments) bind at the interface of KIF18A and tubulin, identifying a tubulin-KIF18A interface as a druggable allosteric site distinct from the ATP-binding pocket.\",\n      \"method\": \"Photoaffinity labeling, medicinal chemistry, in vivo mitotic arrest assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — photoaffinity labeling identifies binding site directly; single study\",\n      \"pmids\": [\"35286090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF18A inhibition drives a widespread increase in spindle assembly checkpoint (SAC) signaling; whether cells arrest depends on APC/C activity. Cells with weak basal APC/C activity and/or persistent SAC signaling are uniquely sensitive to KIF18A inhibition, explaining the selective lethality in CIN cancer cells.\",\n      \"method\": \"Live-cell imaging, APC/C activity reporters, genetic/pharmacological perturbation of SAC and APC/C, panel of cancer cell lines\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporters, genetics, pharmacology) across cell line panel identifying mechanistic basis for selectivity\",\n      \"pmids\": [\"38279026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HURP regulates KIF18A motility in a concentration-dependent manner: sparse HURP decoration activates KIF18A motility, while high HURP concentrations hinder processive motility by steric exclusion at the KIF18A motor domain-microtubule binding site. HURP and KIF18A together suppress microtubule plus-end dynamics more effectively than either alone.\",\n      \"method\": \"Single-molecule imaging in vitro, cryo-EM structure of HURP-microtubule complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus single-molecule functional assays providing mechanistic basis for HURP-KIF18A interplay\",\n      \"pmids\": [\"39516196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF18A directly binds TTC3 and enhances TTC3-p-AKT interaction, promoting TTC3-mediated ubiquitination and degradation of phospho-AKT, thereby suppressing the AKT/mTOR pathway in hepatic stellate cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, KIF18A knockdown/overexpression in vitro and in CCl4 mouse liver fibrosis model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for physical interaction plus in vivo model, single lab; mechanism inferred from pathway assays\",\n      \"pmids\": [\"38372748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Phosphomimetic mutation S357D in the neck-linker of KIF18A redirects the motor from kinetochore microtubules to non-kinetochore peripheral microtubules, causing spindle positioning defects and failure to promote mitotic progression; this phenotype is mimicked by a shortened neck-linker mutant.\",\n      \"method\": \"Phosphomimetic mutagenesis, live-cell imaging, spindle positioning assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional in-cell readouts, single lab, two independent mutant approaches giving consistent results\",\n      \"pmids\": [\"37903223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mutation of S284 within the alpha-4 helix of KIF18A causes relocalization from K-fiber plus-ends to spindle poles, loss of KIF18A function, and failure to support CIN tumor cell proliferation. Small molecules predicted to interact with the alpha-4 helix produce similar relocalization and functional loss.\",\n      \"method\": \"Site-directed mutagenesis, live-cell imaging, small-molecule inhibitor treatment, CIN cell proliferation assay\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus inhibitor phenocopy, single lab, functional validation in tumor cell proliferation\",\n      \"pmids\": [\"38410188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chromosome alignment and KIF18A plus-end localization depend on a spindle-localized fraction of inhibited/inactive Cdk1 (i-Cdk1, Wee1-phosphorylated). Reducing i-Cdk1 causes spindle defects and poor KIF18A localization; restoring i-Cdk1 reverses both; expressing a phosphonull KIF18A at Cdk1 phosphorylation sites rescues alignment defects in i-Cdk1-depleted cells.\",\n      \"method\": \"Genetic perturbation of Wee1/Cdk1 phosphorylation, immunofluorescence, cell fractionation, phosphonull KIF18A rescue\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and phospho-mutant rescue experiments, single lab; consistent with earlier Cdk1/PP1 regulatory model\",\n      \"pmids\": [\"39610707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIF18A depletion disrupts the parallel structure of the central spindle in late anaphase, causing mislocalization of the centralspindlin components KIF23 (MKLP1) and RACGAP1, impaired cleavage furrow establishment, and incomplete cytokinesis. KIF18A localizes at the metaphase plate, then central spindle in late anaphase, then spindle midbody in telophase.\",\n      \"method\": \"siRNA depletion, live-cell imaging, immunofluorescence of centralspindlin components\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — depletion with defined molecular phenotype (centralspindlin mislocalization), single lab\",\n      \"pmids\": [\"39954259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic epistasis screen using a hypomorphic CENP-C mutant identified KIF18A as synthetic lethal; the synthetic defect is due to reduced CENP-E function in the CENP-C mutant background. KIF18A promotes chromosome alignment in cooperation with CENP-E downstream of CENP-C during early prometaphase.\",\n      \"method\": \"Genome-wide Cas9-based functional genetics screen, synthetic lethality epistasis, CENP-E functional analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide epistasis screen with mechanistic follow-up; single lab but rigorous genetic approach\",\n      \"pmids\": [\"41218610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Depletion of KIF18A induced mitotic arrest in cells, which was partially rescued by co-depletion of ANAPC7 (APC7) and exacerbated by co-depletion of ANAPC5 (APC5), placing KIF18A in a regulatory network with APC/C subunits controlling mitotic exit.\",\n      \"method\": \"RNAi double-depletion epistasis in cell lines, mitotic arrest quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with two APC/C subunits, single lab; consistent with EMBO J APC/C finding\",\n      \"pmids\": [\"40596795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A crystal structure of the KIF18A-tubulin complex was determined, supporting structure-based inhibitor design. The ATP non-competitive inhibitor VLS-1272 is microtubule-dependent, blocks KIF18A ATPase activity, prevents KIF18A translocation across the mitotic spindle, and results in chromosome congression defects, mitotic cell accumulation, and cell death.\",\n      \"method\": \"Crystal structure of KIF18A-tubulin complex, ATPase assays, microtubule gliding assays, in vivo xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus biochemical mechanism of ATP non-competitive, MT-dependent inhibition, validated in vivo\",\n      \"pmids\": [\"39747049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A high-resolution crystal structure of the KIF18A-tubulin complex was obtained; ATX020 binds at the KIF18A-tubulin interface in an experimentally guided model, confirming the tubulin interface as a druggable allosteric site.\",\n      \"method\": \"X-ray crystallography of KIF18A-tubulin complex, structure-based drug design\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with experimentally guided binding model\",\n      \"pmids\": [\"41257005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KIF18A mRNA stability in esophageal cancer cells is regulated post-transcriptionally by the RNA-binding protein IGF2BP3, which binds KIF18A mRNA (RIP assay) and increases its stability.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA stability assay, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single RIP and stability assay, limited mechanistic follow-up for this specific interaction\",\n      \"pmids\": [\"33872988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KIF18A mRNA in human male germ cells (TCam-2 line) is post-transcriptionally repressed by PUM1 and PUM2 proteins via PUM-binding elements in KIF18A's 3'-UTR; PUM repression of KIF18A reduces proliferation and alters the cell cycle in TCam-2 cells.\",\n      \"method\": \"RNA co-immunoprecipitation, luciferase reporter assay with wild-type and mutant KIF18A 3'-UTR, siRNA knockdown, flow cytometry\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-CoIP plus luciferase 3'-UTR reporter with PUM overexpression/knockdown, single lab\",\n      \"pmids\": [\"32094263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The JNK1/c-Jun signaling pathway directly activates KIF18A transcription: c-Jun binds and activates the KIF18A promoter (ChIP and luciferase reporter assays); JNK1 inhibition decreases KIF18A expression and c-Jun phosphorylation; c-Jun knockdown inhibits cervical cancer growth partially rescued by KIF18A overexpression.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, JNK1 inhibition, c-Jun siRNA, KIF18A rescue\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus epistatic rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39749722\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIF18A is a highly processive, plus-end-directed kinesin-8 motor that uses its N-terminal motor domain to suppress microtubule plus-end dynamics (pausing/capping rather than pure depolymerization) and its C-terminal tail—which contains an ATP-independent microtubule-tethering domain—to accumulate at kinetochore microtubule plus-ends, where it dampens chromosome oscillations and promotes metaphase alignment; its activity is spatiotemporally regulated by Cdk1 (inhibitory phosphorylation) and PP1 (activating dephosphorylation), by SUMO2 modification at multiple lysines, by neck-linker phosphorylation that biases microtubule subpopulation preference, by kinesin-binding protein (KBP) that buffers its motor activity, and by HURP that modulates its processivity; KIF18A physically interacts with CENP-E, BubR1, PP1γ (via an RVxF motif), TTC3, and estrogen receptor alpha; loss of KIF18A triggers spindle assembly checkpoint activation through loss of kinetochore tension even at attached kinetochores, and chromosomally unstable (CIN) cancer cells are selectively dependent on KIF18A because they require its activity to restrain excessive microtubule dynamics and maintain kinetochore-microtubule attachments, a vulnerability that is compounded by weak basal APC/C activity in these cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF18A is a plus-end-directed kinesin-8 motor that governs mitotic chromosome alignment by suppressing the dynamics of kinetochore microtubule plus-ends [#0, #1, #2]. Its N-terminal motor domain promotes microtubule pausing and growth suppression in a concentration-dependent manner rather than acting as a pure depolymerizer [#2, #6], while a second ATP-independent microtubule-binding site in its C-terminal tail tethers the motor to the lattice, conferring the high processivity required for accumulation at kinetochore microtubule plus-ends and for damping chromosome oscillations [#3, #4]. A relatively long neck linker allows KIF18A to bypass microtubule-associated protein obstacles and reach plus-ends at the spindle center [#15]. KIF18A activity is spatiotemporally tuned: Cdk1 imposes inhibitory phosphorylation and PP1 (recruited via an RVxF motif to PP1\\u03b3) dephosphorylates and activates the motor upon biorientation [#10, #11, #27], kinesin-binding protein buffers motor output by blocking microtubule engagement [#14], and HURP modulates processivity in a concentration-dependent fashion [#9, #23]. Functionally, KIF18A cooperates with CENP-E and BubR1 to drive chromosome congression [#7, #29], and its loss triggers spindle assembly checkpoint activation through loss of kinetochore tension even at properly attached kinetochores [#13]. This dependency underlies the selective vulnerability of chromosomally unstable cancer cells, which arrest upon KIF18A inhibition because of weak basal APC/C activity and persistent SAC signaling [#22, #30], a vulnerability exploited by ATP-noncompetitive inhibitors that bind the KIF18A-tubulin interface defined by crystal structures [#21, #31, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established KIF18A as a plus-end-directed kinesin with length-dependent microtubule depolymerizing activity whose loss disrupts spindle length and chromosome congression, defining its core mitotic role.\",\n      \"evidence\": \"in vitro motility/depolymerization assays plus RNAi and live-cell imaging\",\n      \"pmids\": [\"17346968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether the dominant in vivo activity is depolymerization vs. dynamics suppression\", \"Mechanism of plus-end accumulation unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reframed KIF18A as a suppressor of chromosome movements through motor-dependent gradient accumulation on kinetochore microtubules, rather than a simple depolymerizer.\",\n      \"evidence\": \"quantitative kinetochore tracking with RNAi and gradient imaging\",\n      \"pmids\": [\"18267093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical distinction from depolymerization not yet resolved\", \"Tail contribution to gradient unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed KIF18A dampens plus-end polymerization dynamics without destabilizing microtubules, distinguishing its biochemistry from the depolymerizing yeast ortholog Kip3.\",\n      \"evidence\": \"in vitro microtubule dynamics assays with live-cell validation\",\n      \"pmids\": [\"20153196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-lab in vitro characterization\", \"Did not define the molecular basis of pausing\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the structural division of labor: the C-terminal tail provides an ATP-independent, lattice-diffusing microtubule-binding site essential for processivity and plus-end accumulation, while the N-terminal motor confers growth suppression.\",\n      \"evidence\": \"domain/truncation/point mutants, single-molecule motility, co-pelleting, in-cell rescue (multiple concurrent studies)\",\n      \"pmids\": [\"21884977\", \"22102900\", \"21885282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how spindle-length control is separated from chromosome positioning at the molecular level\", \"Regulation of tail engagement unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated by reconstitution that purified KIF18A directly promotes microtubule pausing in a concentration-dependent manner, providing the dominant mechanism for confining centromeres to the spindle midzone.\",\n      \"evidence\": \"reconstituted dynamic microtubule assays with purified protein plus live-cell imaging\",\n      \"pmids\": [\"22595673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how pausing activity is regulated in vivo\", \"Role of accessory factors not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified CENP-E and BubR1 as physical partners and showed KIF18A loss destabilizes CENP-E protein, linking KIF18A function to congression machinery; KO mice revealed germ-cell aplasia from mitotic and meiotic congression failure.\",\n      \"evidence\": \"reciprocal Co-IP, RNAi, rescue, and Kif18a knockout mice\",\n      \"pmids\": [\"19625775\", \"20981276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect basis of CENP-E/BubR1 destabilization not fully resolved\", \"Co-IP without structural mapping of interfaces\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed HURP binds KIF18A and modulates its localization and dynamics at kinetochore microtubule plus-ends, introducing a MAP-based layer of regulation.\",\n      \"evidence\": \"Co-IP, BiFC, live-cell imaging, rescue experiments\",\n      \"pmids\": [\"21924616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of modulation not defined at this stage\", \"Single-lab interaction data\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined antagonistic Cdk1/PP1 control of KIF18A, with PP1\\u03b3 docking via an RVxF motif and dephosphorylation activating the motor upon biorientation, explaining temporal switching from oscillation to plate thinning.\",\n      \"evidence\": \"MS phosphosite mapping, kinase/phosphatase perturbation, biochemical RVxF-binding assays\",\n      \"pmids\": [\"25048371\", \"25281536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RVxF interaction shown by single-method binding assay\", \"Full phosphosite-to-function map incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified SUMO2 modification of KIF18A peaking at metaphase as a regulator of mitotic exit timing and BubR1 dissociation, adding a post-translational control independent of stability or localization.\",\n      \"evidence\": \"His6-SUMO2 pull-down, acceptor-lysine mutagenesis, time-lapse imaging\",\n      \"pmids\": [\"25884224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO E3 ligase not identified\", \"Mechanistic link to BubR1 dissociation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that lethality on KIF18A loss arises from SAC activation at attached-but-tensionless kinetochores rather than missegregation per se, clarifying the basis of essentiality.\",\n      \"evidence\": \"haploid genetic screen, SAC-null epistasis, tension measurements, live imaging\",\n      \"pmids\": [\"30122526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet define why CIN cells are selectively sensitive\", \"Tension-sensing pathway link incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined two mechanical determinants of targeting: KBP buffers motor activity by blocking microtubule binding, and a long neck linker enables navigation past MAP obstacles to reach K-fiber plus-ends.\",\n      \"evidence\": \"gliding/co-pelleting inhibition assays and single-molecule assays on MAP-coated microtubules with in-cell imaging\",\n      \"pmids\": [\"30709852\", \"30655363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts that engage KBP regulation in vivo not fully mapped\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed neck-linker phosphorylation (S357) biases KIF18A toward kinetochore vs. peripheral microtubules, linking a phosphosite to subpopulation selection and spindle positioning.\",\n      \"evidence\": \"phosphomimetic and short-neck-linker mutants with live-cell spindle positioning assays\",\n      \"pmids\": [\"37903223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible kinase not identified\", \"Single-lab functional study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Explained the selective lethality of KIF18A inhibition: it broadly raises SAC signaling, and arrest occurs only in cells with weak basal APC/C activity, placing KIF18A in an APC/C-dependent mitotic-exit network.\",\n      \"evidence\": \"APC/C reporters, SAC/APC/C perturbation across a cancer cell line panel; APC subunit epistasis\",\n      \"pmids\": [\"38279026\", \"40596795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative threshold of APC/C activity defining sensitivity not delineated\", \"Direct molecular link between KIF18A and APC/C subunits unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the HURP-KIF18A interplay biophysically: HURP activates KIF18A at low density but sterically blocks the motor at high density, with the two together suppressing plus-end dynamics more than either alone.\",\n      \"evidence\": \"single-molecule imaging and cryo-EM of the HURP-microtubule complex\",\n      \"pmids\": [\"39516196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo concentration regimes governing the switch not measured\", \"Spatial distribution of HURP on K-fibers not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Crystal structures of the KIF18A-tubulin complex defined an ATP-noncompetitive, microtubule-dependent allosteric inhibitor-binding site at the tubulin interface, enabling structure-based inhibitor design validated in xenografts.\",\n      \"evidence\": \"X-ray crystallography, ATPase and gliding assays, photoaffinity labeling, in vivo tumor models\",\n      \"pmids\": [\"39747049\", \"41257005\", \"35286090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resistance mechanisms to interface inhibitors not characterized\", \"Allosteric coupling to the catalytic cycle not fully described\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended KIF18A function beyond metaphase, showing it is required for central spindle organization and centralspindlin (KIF23/RACGAP1) localization during cytokinesis, and confirmed cooperation with CENP-E downstream of CENP-C in early prometaphase.\",\n      \"evidence\": \"siRNA depletion with centralspindlin immunofluorescence; genome-wide CENP-C synthetic-lethality screen\",\n      \"pmids\": [\"39954259\", \"41218610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect role in centralspindlin recruitment unresolved\", \"Molecular basis of the CENP-C/CENP-E coupling not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KIF18A integrates its multiple regulatory inputs (Cdk1/PP1 phosphorylation, SUMOylation, KBP buffering, HURP density, neck-linker phosphorylation) into a single spatiotemporal output at the kinetochore remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model linking the regulatory layers\", \"Relative in vivo contribution of each modifier unquantified\", \"Structural basis of tail-mediated tethering on dynamic K-fibers not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 31]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 4, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [1, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 13, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CENP-E\", \"BubR1\", \"PP1\\u03b3\", \"HURP\", \"KBP\", \"TTC3\", \"ESR1\"]\n  }\n}","audit_flag":{"gene":"KIF18A","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 40596795"},"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}