{"gene":"KIF2A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1995,"finding":"KIF2A (KIF2) is a plus-end-directed anterograde microtubule motor whose motor domain is located in the center of the molecule (M-type kinesin); recombinant KIF2 exists as a dimer and moves microtubules at ~0.47 µm/s in vitro. Immunoisolation with anti-KIF2 antibody identified a distinct population of non-synaptic vesicles associated with KIF2, different from those carried by conventional kinesin or KIF3A.","method":"Recombinant protein motility assay, immunoprecipitation/immunoisolation, immunocytology, nerve ligation accumulation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted motility assay with recombinant protein, complemented by immunoisolation and multiple cellular methods in a foundational study","pmids":["7535303"],"is_preprint":false},{"year":1997,"finding":"KIF2A (KIF2) transports a specific class of non-synaptic vesicles containing the IGF-1 receptor variant betagc to neuronal growth cones; antisense knockdown of KIF2 causes betagc to accumulate in the cell body and disappear from growth cones, and dramatically inhibits neurite outgrowth in PC12 cells.","method":"Antisense oligonucleotide knockdown, subcellular fractionation, sucrose density centrifugation, immunoisolation, immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal fractionation and immunoisolation with functional knockdown, single lab, multiple orthogonal methods","pmids":["9245793"],"is_preprint":false},{"year":2003,"finding":"KIF2A depolymerizes microtubules at growth cone edges to suppress collateral axon branch extension; kif2a knockout mice show reduced microtubule-depolymerizing activity at growth cones and aberrant overextension of collateral branches.","method":"kif2a knockout mouse analysis, live imaging of microtubule dynamics at growth cones, microtubule depolymerization assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular phenotype, direct measurement of microtubule-depolymerizing activity, replicated across multiple analyses in a landmark study","pmids":["12887924"],"is_preprint":false},{"year":2004,"finding":"KIF2A localizes to centrosomes and spindle poles during mitosis and is required for bipolar spindle assembly; its loss causes monopolar spindles that can be rescued by nocodazole treatment, loss of Nuf2 (kinetochore attachment), or loss of MCAK, establishing that KIF2A activity at poles must be balanced by MCAK activity at kinetochores for spindle bipolarity.","method":"RNAi knockdown in cultured cells, immunofluorescence, epistasis analysis with Nuf2 and MCAK co-knockdown","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean RNAi with specific monopolar spindle phenotype, functional epistasis with multiple partners, single rigorous study with multiple orthogonal approaches","pmids":["15302853"],"is_preprint":false},{"year":2007,"finding":"Kif2a, Kif2b, and MCAK (Kif2c) fulfill distinct functions during mitosis in human cells; Kif2a-deficient cells form monopolar spindles, and bipolar spindle assembly can be restored by simultaneous deficiency of MCAK or Nuf2, or by low-dose nocodazole, but not by perturbing NuMA/HSET (which rescues Kif2b loss), demonstrating that the three kinesin-13 paralogs act at different spindle locations.","method":"RNAi knockdown of individual kinesin-13 members, GFP-tagging for localization, epistasis double-knockdown, live imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic comparison with sibling paralogs, multiple epistasis combinations, replicates and extends the Compton lab findings","pmids":["17538014"],"is_preprint":false},{"year":2008,"finding":"DDA3 (PSRC1) directly interacts with KIF2A in a microtubule-dependent manner and recruits KIF2A to the mitotic spindle poles; DDA3 depletion phenocopies partial KIF2A knockdown (increased spindle microtubule density, unaligned chromosomes, reduced poleward flux), placing DDA3 upstream of KIF2A in spindle dynamics regulation.","method":"Co-immunoprecipitation, RNAi knockdown, immunofluorescence, spindle microtubule turnover assay (FRAP), functional genomics screen","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for interaction, RNAi epistasis with phenocopy, multiple orthogonal assays in single study","pmids":["18411309"],"is_preprint":false},{"year":2009,"finding":"PLK1 interacts with KIF2A in a mitosis-specific and kinase-activity-dependent manner, phosphorylates KIF2A, and enhances its microtubule-depolymerizing activity in vitro; Aurora A also phosphorylates KIF2A but suppresses its depolymerase activity. Antagonistic regulation by PLK1 (activating) and Aurora A (inhibiting) controls KIF2A localization on microtubules and spindle microtubule intensity in vivo.","method":"Proteomic analysis, Co-immunoprecipitation, in vitro kinase assay, in vitro microtubule depolymerization assay, immunofluorescence after kinase inhibition/depletion","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase and depolymerization assays combined with Co-IP and cellular imaging, multiple orthogonal methods in single study","pmids":["19351716"],"is_preprint":false},{"year":2009,"finding":"ICIS (inner centromere KinI stimulator) reactivates KIF2A after Aurora B-mediated inhibition; ICIS N-terminus binds Aurora B/INCENP/TD60 while its central region binds KIF2A and microtubules. Antibody injection blocking ICIS-KIF2A interaction generates monopolar spindles rescued by anti-Nuf2 co-injection, establishing ICIS as a scaffold that co-regulates KIF2A depolymerase with the chromosomal passenger complex.","method":"Structure-function analysis, Co-immunoprecipitation, antibody microinjection, epistasis rescue experiments","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody injection functional assay and Co-IP, single lab, multiple methods but without full reconstitution","pmids":["19327998"],"is_preprint":false},{"year":2009,"finding":"The N-terminal domain of DDA3 does not bind microtubules but acts dominantly to prevent endogenous DDA3 from associating with the spindle, reduces spindle-associated KIF2A, and increases spindle microtubule density; the C-terminal domain of DDA3 directly binds microtubules in vitro and recruits KIF2A to the spindle.","method":"Domain deletion analysis, in vitro microtubule binding assay, ectopic overexpression, immunofluorescence","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay combined with dominant-negative overexpression and imaging, single lab","pmids":["19738423"],"is_preprint":false},{"year":2010,"finding":"KIF2A interacts with TRAX (translin-associated protein X), and functional interaction between KIF2A and TRAX is required for A2A adenosine receptor-mediated rescue of neuritogenesis; redistribution of KIF2A from the nucleus to the cytoplasm upon NGF treatment is a prerequisite for neurite outgrowth, and nuclear-retained KIF2A (NLS-KIF2A) fails to rescue neurite outgrowth.","method":"Co-immunoprecipitation, KIF2A fragment expression (dominant negative), nuclear localization signal fusion, immunofluorescence colocalization, neurite outgrowth assay","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for interaction, dominant-negative fragments, localization imaging, functional rescue, single lab","pmids":["20506231"],"is_preprint":false},{"year":2012,"finding":"Phosphatidylinositol 4-phosphate 5-kinase alpha (PIPKα) directly binds KIF2A (yeast two-hybrid and biochemical assays), co-localizes with KIF2A at growth cones, and enhances KIF2A's microtubule-depolymerizing activity both in vitro and in vivo; PIPKα suppresses axon branch elongation in a KIF2A-dependent manner.","method":"Immunoprecipitation, yeast two-hybrid, in vitro microtubule depolymerization assay, confocal/PALM microscopy, in vivo overexpression in neurons","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro depolymerization assay combined with yeast two-hybrid, biochemical pulldown, and live cell imaging, multiple orthogonal methods, single lab","pmids":["22307638"],"is_preprint":false},{"year":2013,"finding":"KIF2A disease-causing mutations (identified in patients with MCD) affect ATP hydrolysis, disrupting the microtubule-depolymerizing activity of the protein, as demonstrated by functional studies of mutant proteins.","method":"Mutant protein functional assay (ATP hydrolysis), patient mutation identification by sequencing","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay, single study, limited methodological detail in abstract","pmids":["23603762"],"is_preprint":false},{"year":2013,"finding":"Kif2a controls the length and alignment of central spindle microtubules during anaphase by depolymerizing their minus ends; Aurora B phosphorylation excludes Kif2a from the spindle midzone, restricting its activity to the distal ends of the central spindle, and the Aurora B activity gradient determines steady-state central spindle length.","method":"RNAi knockdown, overactivation constructs, immunofluorescence, photoactivation, computational modeling","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (RNAi, overactivation, live imaging, modeling) from a single rigorous study, mechanistically dissects Aurora B regulation of Kif2A localization","pmids":["23960144"],"is_preprint":false},{"year":2013,"finding":"Kif2a scales the mitotic spindle size during Xenopus development; its microtubule-destabilizing activity is inhibited in large (stage 3) spindles by importin α, and activated in small (stage 8) spindles when importin α partitions to a membrane pool, providing a ratiometric mechanism coupling spindle size to cell size.","method":"Xenopus embryo cytoplasmic extract system, spindle reconstitution in vitro, importin α manipulation, immunodepletion","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro spindle reconstitution from staged embryos combined with importin α manipulation, ortholog with conserved mechanism, multiple methods","pmids":["23425906"],"is_preprint":false},{"year":2015,"finding":"KIF2A, phosphorylated at T554 by PLK1, exhibits microtubule-depolymerizing activity at the mother centriole to disassemble the primary cilium in response to growth signals; KIF2A-deficient cells show impaired cilia disassembly after growth stimulation, and the PLK1-KIF2A pathway is constitutively active in cells from PCS syndrome patients causing defective ciliogenesis.","method":"CRISPR/TALEN KIF2A knockout in hTERT-RPE1 cells, phospho-specific antibody, PLK1 kinase assay, immunofluorescence, patient cell analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific ciliogenesis phenotype, kinase assay identifying phosphorylation site, patient validation, multiple orthogonal methods","pmids":["25660017"],"is_preprint":false},{"year":2015,"finding":"TTBK2 kinase, anchored to microtubule plus ends by EB1/3, phosphorylates KIF2A at S135 in intact cells in an EB1/3-dependent fashion; this phosphorylation inactivates KIF2A's microtubule-depolymerizing activity in vitro. TTBK2 depletion reduces MT lifetime and impairs cell migration, phenotypes partially rescued by KIF2A co-depletion; nonphosphorylatable KIF2A (S135A) reduces MT lifetime and slows migration.","method":"In vitro kinase assay, phospho-site mutagenesis (S135A), siRNA co-depletion, live imaging of microtubule dynamics, cell migration assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay + mutagenesis + functional epistasis (co-depletion rescue) + live imaging, multiple orthogonal methods","pmids":["26323690"],"is_preprint":false},{"year":2015,"finding":"KIF2A undergoes two distinct phosphorylation cascades: A-type phosphorylation (by ROCK2, induced by LPA) accelerates MT depolymerization and suppresses neurite outgrowth; B-type phosphorylation (by PAK1 and CDK5, stimulated by BDNF) decreases MT depolymerizing activity and enhances neural process outgrowth.","method":"Quantitative phosphoproteomics, in vitro kinase assays, phosphomimetic/non-phosphorylatable mutants, neurite outgrowth assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — comprehensive phospho-analysis with in vitro kinase validation and phosphomutant functional studies, single lab, multiple orthogonal methods","pmids":["26344760"],"is_preprint":false},{"year":2016,"finding":"DDA3 and Mdp3 (MAP7D3) form a complex that controls KIF2A recruitment to the spindle minus ends; Mdp3 inhibits DDA3-mediated KIF2A recruitment, and aberrant KIF2A activity at spindle minus ends upon Mdp3 depletion causes spindle instability, chromosome misalignment and bridges.","method":"Co-immunoprecipitation, RNAi, immunofluorescence, chromosome segregation analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional RNAi epistasis, single lab, two orthogonal methods","pmids":["27284004"],"is_preprint":false},{"year":2017,"finding":"KIF2A catalytically depolymerizes microtubules by forming a transitional 1:2 KIF2core:tubulin complex during the pre-hydrolysis state of ATP hydrolysis; the KIF2core domain adopts an activated conformation revealed by X-ray crystallography that sustains binding to two tubulin dimers, explaining processive depolymerization from protofilament ends.","method":"Atomic force microscopy, size-exclusion chromatography, multi-angle light scattering, SAXS, analytical ultracentrifugation, mass spectrometry, X-ray crystallography","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with multiple biophysical methods (SAXS, AUC, AFM, MS) to characterize transitional complex, rigorous multi-method study","pmids":["28903043"],"is_preprint":false},{"year":2017,"finding":"The MLL/WDR5 complex associates with KIF2A through a conserved WDR5-interaction (Win) motif in KIF2A (residues engaging the WIN site of WDR5); this interaction is required for KIF2A's spindle localization during mitosis. Loss of MLL complex causes defects in chromosome congression and spindle assembly phenocopying KIF2A mislocalization.","method":"Co-immunoprecipitation, RNAi, immunofluorescence, direct binding assay (Win motif mapping)","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction mapped to Win motif, RNAi epistasis with spindle phenotype, multiple orthogonal methods","pmids":["28633016"],"is_preprint":false},{"year":2016,"finding":"Direct interaction between Kif2A and AGAP1 (Arf GAP): GLD and PH domains of AGAP1 bind the motor domain of Kif2A; Kif2A increases GAP activity of AGAP1, and a GLD-PH fragment of AGAP1 increases ATPase activity of Kif2A. Double-knockdown shows that functional Kif2A-AGAP1 complex controls cytoskeletal remodeling during cell spreading and migration.","method":"Co-immunoprecipitation, in vitro GAP activity assay, in vitro ATPase assay, siRNA knockdown, domain mapping, cell spreading/migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assays (GAP and ATPase) plus Co-IP and functional rescue, single lab, multiple orthogonal methods","pmids":["27531749"],"is_preprint":false},{"year":2019,"finding":"WDR62 interacts with CEP170 and promotes CEP170's localization to the basal body of primary cilia; CEP170 in turn recruits microtubule-depolymerizing KIF2A to the basal body to drive cilium disassembly. WDR62 depletion reduces KIF2A's basal body localization, and overexpression of KIF2A partially rescues cilium length defects and NPC proliferation impairment caused by WDR62 loss.","method":"Co-immunoprecipitation, immunofluorescence, KIF2A overexpression rescue, mouse knockout and cerebral organoids, siRNA knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis pathway defined by Co-IP, localization experiments, and KIF2A overexpression rescue in multiple model systems (mouse, organoids, cells)","pmids":["31197141"],"is_preprint":false},{"year":2017,"finding":"Kif2 localizes to a cortical subdomain of endoplasmic reticulum in ascidian embryos; this localization is responsible for local depolymerization of astral microtubules, driving asymmetric spindle positioning and unequal cell division. Inhibition of Kif2 prevents aster asymmetry and spindle pole movement toward the ER subdomain.","method":"Live fluorescence imaging, Kif2 inhibition (dominant-negative/morpholino), local microtubule depolymerization manipulation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with localization and loss-of-function in an ortholog model, single lab, two orthogonal methods","pmids":["29030551"],"is_preprint":false},{"year":2018,"finding":"KIF2A disease-causing variants disrupt projection neuron positioning, interneuron migration, and progenitor proliferation; further, ciliogenesis regulation is altered during the progenitor cell cycle, suggesting that deregulation of the coupling between ciliogenesis and cell cycle contributes to KIF2A-related brain malformations.","method":"In utero electroporation, cellular assays, patient variant expression","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in utero electroporation with multiple cellular phenotypes, single lab","pmids":["29077851"],"is_preprint":false},{"year":2018,"finding":"KIF2A is required for dentate granule cell neurite length regulation in the postnatal hippocampus; conditional knockout of Kif2a causes mossy fiber sprouting and dendro-axonal conversion (aberrant overextended dendrites that develop axonal properties), demonstrating a role for KIF2A in maintaining distinct neurite compartment identity.","method":"Tamoxifen-inducible conditional knockout (Kif2a-cKO) mouse, immunofluorescence, electrophysiology","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible conditional KO with specific cellular phenotype (dendro-axonal conversion) characterized in detail, multiple analyses","pmids":["29313800"],"is_preprint":false},{"year":2019,"finding":"Kif2a scales meiotic spindle size in Hymenochirus boettgeri through an activating phosphorylation site present in H. boettgeri but absent from X. laevis kif2a; this phosphorylation modulates kif2a's microtubule-destabilizing activity for spindle size regulation.","method":"Egg extract spindle reconstitution, phosphorylation site comparison, species-comparative analysis","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution in frog egg extracts with comparative phosphorylation analysis, ortholog model, single lab","pmids":["31630945"],"is_preprint":false},{"year":2021,"finding":"Planar cell polarity protein Celsr3 physically interacts with Kif2a; conditional inactivation of Kif2a in the forebrain recapitulates the Celsr3 knockout phenotype (loss of neuroblast directionality from SVZ to olfactory bulb, aberrant LP branching, decreased MT growth rate), defining a Celsr3-Kif2a axis that specifies the direction of tangential neuronal migration in the postnatal brain.","method":"Co-immunoprecipitation, conditional knockout mice (Celsr3-cKO and Kif2a forebrain-cKO), live imaging, immunofluorescence","journal":"Progress in neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — physical interaction by Co-IP combined with parallel conditional knockouts showing phenotypic identity, multiple methods","pmids":["34582949"],"is_preprint":false},{"year":2021,"finding":"Wnt signaling recruits KIF2A to the mitotic spindle via Dishevelled (DVL), which binds KIF2A through its N-terminal and motor domains; LRP6 signalosome formation during cell division promotes DVL-KIF2A interaction. Wnt signaling modulates KIF2A interaction with PLK1, which is critical for KIF2A spindle localization. Inhibition of basal Wnt signaling leads to chromosome misalignment in somatic cells and pluripotent stem cells.","method":"Phosphoproteomics, Co-immunoprecipitation, Wnt pathway inhibition, immunofluorescence, domain mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphoproteomics identification combined with Co-IP domain mapping and epistasis in multiple cell types, multiple orthogonal methods","pmids":["34417301"],"is_preprint":false},{"year":2021,"finding":"Different KIF2A alternative isoforms have distinct functions in cortical development: two isoforms sustain radial migration, but a third isoform lacking a key N-terminal region does not. Proximity-based interactome mapping revealed novel KIF2A interaction partners including translation factors, ribonucleoproteins, and mitochondrial proteins; a disease-causing mutation shows extensive depletion of mitochondrial proteins from the KIF2A interactome.","method":"In utero electroporation of individual isoforms, proximity-based interactome mapping (BioID), migration assays","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific in utero electroporation with migration readout and BioID interactome, single lab, two orthogonal methods","pmids":["33531432"],"is_preprint":false},{"year":2022,"finding":"KIF2A is required postnatally for neuronal maturation, connectivity, and survival; conditional inactivation in mature cortical neurons disrupts microtubule dynamics and multiple microtubule-dependent processes including neuronal polarity, neuritogenesis, synaptogenesis, and axonal transport, leading to aberrant electrophysiology, loss of connectivity, and neuronal death.","method":"Conditional KIF2A knockout (NestinCre, NexCre, CaMKII-Cre) in mice, electrophysiology, immunofluorescence, axonal transport assays, synaptogenesis analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Cre drivers giving graded conditional KO, multiple orthogonal cellular phenotypes, functional electrophysiology, strong study","pmids":["36343267"],"is_preprint":false},{"year":2023,"finding":"KIF2A is a selective microtubule minus-end depolymerase (in contrast to its paralog MCAK which acts at plus ends); γ-TuRC acts as a protective cap shielding minus ends from KIF2A binding. Efficient γTuRC uncapping requires combined action of KIF2A and a microtubule-severing enzyme (katanin), leading to KIF2A-driven treadmilling of uncapped microtubules, providing a molecular mechanism for coordinating nucleation and depolymerization at spindle poles for poleward flux.","method":"In vitro reconstitution with purified proteins (KIF2A, γTuRC, katanin), TIRF microscopy, single-molecule assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components, single-molecule imaging, mechanistic dissection of minus-end selectivity, rigorous biochemical study","pmids":["37615667"],"is_preprint":false},{"year":2023,"finding":"CEP170B forms a complex with KIF2A that depolymerizes microtubule minus ends; CEP170B autonomously tracks growing MT minus ends and blocks minus-end growth, and together with KIF2A acts as a potent MT minus-end depolymerase capable of antagonizing CAMSAP-mediated stabilization, thereby controlling the spatial distribution of MT minus ends and establishing cell polarity.","method":"In vitro reconstitution, Co-immunoprecipitation, TIRF microscopy, RNAi knockdown, immunofluorescence in HeLa and epithelial cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution demonstrating KIF2A-CEP170B complex depolymerase activity, complemented by cellular epistasis, multiple orthogonal methods","pmids":["37014312"],"is_preprint":false},{"year":2023,"finding":"NuSAP interacts with KIF2A and prevents excessive microtubule depolymerization by reducing KIF2A localization at spindle poles; Aurora A phosphorylates NuSAP at Ser-240 during mitosis, which promotes NuSAP interaction with KIF2A on the spindle body, reduces KIF2A at spindle poles, and maintains proper spindle microtubule flux. NuSAP knockout causes shorter spindles with faster flux and chromosome misalignment.","method":"Co-immunoprecipitation, Aurora A kinase assay, NuSAP knockout, immunofluorescence, FRAP for flux measurement","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinase assay with phosphosite identification, Co-IP, KO with multiple spindle phenotypes, flux measurement, multiple orthogonal methods","pmids":["38117947"],"is_preprint":false},{"year":2023,"finding":"RGS12 associates with and activates MYCBP2 (E3 ubiquitin ligase) to promote ubiquitination and degradation of KIF2A in synovial fibroblasts and tumor-associated macrophages; KIF2A degradation increases cilia length and number. KIF2A overexpression blocks cilia elongation downstream of RGS12.","method":"Co-immunoprecipitation, LC-MS protein interaction analysis, ubiquitination assay, RGS12 knockout mice, KIF2A overexpression","journal":"International journal of oral science / Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and LC-MS for interaction, ubiquitination assay, functional rescue, single lab","pmids":["36797232","36700049"],"is_preprint":false},{"year":2024,"finding":"APC forms a complex with KIF2A at the cell edge and promotes KIF2A-induced microtubule catastrophe at MT plus ends; biochemical characterization and mutational analysis identified key residues for the APC-KIF2A interaction. In vitro reconstitution demonstrates APC potentiates KIF2A-induced MT catastrophes and antagonizes CLASP2-mediated stabilization.","method":"Co-immunoprecipitation, in vitro reconstitution of MT dynamics, mutagenesis, immunofluorescence, cell migration assay","journal":"Cell insight","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutational analysis and Co-IP, multiple methods, single lab","pmids":["39640087"],"is_preprint":false},{"year":2025,"finding":"Crystal structure of WDR5 in complex with a KIF2A-derived peptide (residues 114-122) at 1.85 Å resolution reveals KIF2A engages both the WIN and S7 sites of WDR5 via Arg117 and Ser121; Ser121 forms hydrogen bonds with WDR5 Tyr191 and Lys259, driving Tyr191 rotation and opening the S7 pocket. ITC mutagenesis confirmed critical roles of Arg117 and Ser121.","method":"X-ray crystallography, isothermal titration calorimetry (ITC), site-directed mutagenesis","journal":"Acta biochimica et biophysica Sinica","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 1.85 Å combined with ITC and mutagenesis to validate key residues, rigorous multi-method single study","pmids":["40302551"],"is_preprint":false},{"year":2025,"finding":"TTBK2 phosphorylates KIF2A to restrain its microtubule-depolymerizing activity during cilia growth and maintenance; disease-related TTBK2 truncations that cannot localize to the mother centriole cause defective cilia elongation linked to aberrant KIF2A turnover. Concentration of TTBK2 at the mother centriole is required for full ciliogenesis.","method":"Biochemical approaches, proteomics, CRISPR genetic engineering, advanced microscopy, TTBK2 truncation analysis","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics + genetic engineering + imaging in human cells, single lab, multiple methods but kinase assay details not fully described in abstract","pmids":["39930500"],"is_preprint":false},{"year":2025,"finding":"During cytokinesis in mouse embryonic stem cells, KIF2A switches from a microtubule depolymerase (at spindle poles in metaphase) to a microtubule stabilizer at intercellular bridge microtubules; this conversion is driven by inhibition of KIF2A's ATPase activity (increasing lattice affinity) and a preference for compacted microtubule lattices. KIF2A at the intercellular bridge maintains microtubule length/number and controls microtubule acetylation, prolonging cytokinesis to maintain pluripotency.","method":"Genome-engineered mouse ESCs, in vitro ATPase assay, immunofluorescence, live imaging, microtubule acetylation analysis, mRNA homeostasis analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mechanistic assays combined with cellular live imaging and genetic engineering, single lab but multiple orthogonal methods defining a novel KIF2A switching mechanism","pmids":["40353778"],"is_preprint":false},{"year":2026,"finding":"KIF2A deficiency in the adult mouse cortex and hippocampus leads to reduced dendritic spine density and cognitive decline followed by increased Tau phosphorylation through MAPK ERK1/2 upregulation. KIF2A protein levels are drastically reduced in Alzheimer's disease patients (but not in primary tauopathies), and Aβ accumulation alters KIF2A expression in neurons, linking Aβ → KIF2A downregulation → ERK1/2 upregulation → Tau hyperphosphorylation.","method":"Conditional KIF2A knockout in adult mouse cortex/hippocampus, 5xFAD mouse model analysis, post-mortem human brain IHC/western blot, ERK1/2 inhibitor experiments","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with specific molecular pathway (ERK1/2-Tau) validated in mouse model and human tissue, multiple orthogonal systems","pmids":["41071932"],"is_preprint":false},{"year":2026,"finding":"Damage-induced α-tubulin tyrosination triggers KIF2A binding to microtubules, and KIF2A mediates nuclear envelope (NE) invagination through the LINC complex and lamin B1; this NE invagination creates a stable environment for NHEJ repair near the NE, facilitating 53BP1 foci formation. Loss of KIF2A disrupts NE invagination after DNA damage and impairs NHEJ.","method":"KIF2A knockdown, immunofluorescence (53BP1 foci, lamin B1, α-tubulin), DNA damage assays, live imaging of NE dynamics","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KIF2A loss-of-function with specific NE and DNA repair phenotypes, multiple markers, single lab","pmids":["41591845"],"is_preprint":false},{"year":2020,"finding":"KIF2A missense variants causing brain malformations (p.His321Asp) expressed via conditional knock-in increase neuronal apoptosis and cause abnormal multipolar-to-bipolar transition in newborn neurons, and these phenotypes are linked to deficiency in the microtubule-depolymerizing function of KIF2A.","method":"Cre-mediated conditional knock-in mouse (NestinCre, NexCre, RosaCre), in utero electroporation, immunofluorescence, behavioral analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knock-in mouse with multiple Cre drivers, specific cellular phenotypes (apoptosis, bipolar transition), mechanistically linked to MT depolymerase function","pmids":["31919497"],"is_preprint":false}],"current_model":"KIF2A is an M-type kinesin-13 that catalytically depolymerizes microtubules from minus ends (and in certain contexts plus ends) through ATP hydrolysis, forming a 1:2 KIF2A:tubulin transitional complex; its depolymerase activity is regulated by multiple kinases (PLK1 activates, Aurora A/B inhibits, TTBK2 inhibits via S135 phosphorylation, PAK1/CDK5 inhibit, ROCK2 activates) and by binding partners (PIPKα enhances, ICIS reactivates after Aurora B inhibition, importin α suppresses, WDR5/MLL and DDA3 control spindle localization, Celsr3 directs neuronal migration, APC potentiates catastrophe, CEP170B enables minus-end depolymerization, γTuRC caps minus ends); during mitosis KIF2A acts at centrosomes/spindle poles to drive poleward microtubule flux and maintain spindle bipolarity (balanced against MCAK at kinetochores), during cytokinesis it can switch to a microtubule stabilizer at the intercellular bridge, during ciliogenesis PLK1-phosphorylated KIF2A (T554) and the WDR62-CEP170-KIF2A axis drive primary cilium disassembly at the mother centriole, and in postmitotic neurons KIF2A depolymerizes growth-cone microtubules to suppress axon branch extension, control neurite compartment identity, and support neuronal survival, with its loss linked to Tau hyperphosphorylation via ERK1/2 upregulation in Alzheimer's disease."},"narrative":{"mechanistic_narrative":"KIF2A is an M-type kinesin-13 that functions principally as a catalytic, ATP-driven microtubule depolymerase, governing microtubule dynamics across mitosis, ciliogenesis, and neuronal morphogenesis [PMID:7535303, PMID:12887924, PMID:28903043]. Structural and biophysical work shows that the KIF2A motor core adopts an activated conformation that captures two tubulin dimers in a transitional 1:2 complex during the pre-hydrolysis ATP state, explaining its processive removal of tubulin from protofilament ends [PMID:28903043]. KIF2A acts as a selective minus-end depolymerase: γ-TuRC caps and protects minus ends, and efficient uncapping requires KIF2A together with the severing enzyme katanin, while CEP170B partners with KIF2A to track and depolymerize minus ends and antagonize CAMSAP-mediated stabilization [PMID:37615667, PMID:37014312]. Its activity is set by an extensive regulatory network of kinases and adaptors: PLK1 phosphorylation activates depolymerization whereas Aurora A and TTBK2 (S135) inhibit it, with additional ROCK2 (activating) and PAK1/CDK5 (inhibiting) inputs, and recruitment to spindle poles is controlled by DDA3, the MLL/WDR5 complex via a WIN-motif interaction, NuSAP, importin α, and Wnt/Dishevelled signaling [PMID:19351716, PMID:26323690, PMID:26344760, PMID:18411309, PMID:28633016, PMID:40302551, PMID:38117947, PMID:23425906, PMID:34417301]. During mitosis KIF2A operates at centrosomes and spindle poles to drive poleward microtubule flux and maintain spindle bipolarity, balanced against MCAK at kinetochores, and scales spindle size to cell size [PMID:15302853, PMID:17538014, PMID:23425906]. At the mother centriole, PLK1-phosphorylated KIF2A (T554) and the WDR62–CEP170–KIF2A axis drive primary cilium disassembly [PMID:25660017, PMID:31197141]. In postmitotic neurons KIF2A depolymerizes growth-cone microtubules to suppress collateral axon branching, maintain neurite compartment identity, direct migration via a Celsr3 axis, and support neuronal connectivity and survival [PMID:12887924, PMID:29313800, PMID:34582949, PMID:36343267]. KIF2A mutations that impair ATP hydrolysis and depolymerase activity cause malformations of cortical development [PMID:23603762, PMID:31919497], and KIF2A loss links to Tau hyperphosphorylation through ERK1/2 upregulation in Alzheimer's disease [PMID:41071932].","teleology":[{"year":1995,"claim":"Established KIF2A's foundational identity as a dimeric M-type microtubule motor, the first step toward defining what this kinesin physically is and does.","evidence":"Recombinant protein motility assays and immunoisolation of associated non-synaptic vesicles","pmids":["7535303"],"confidence":"High","gaps":["Motility assay characterized plus-end movement but did not reveal depolymerase activity","Cargo/vesicle identity only partially defined"]},{"year":1997,"claim":"Linked KIF2A to neuronal cargo transport and neurite outgrowth, the earliest functional readout in a postmitotic context.","evidence":"Antisense knockdown with fractionation and immunoisolation in PC12 cells","pmids":["9245793"],"confidence":"Medium","gaps":["Did not reconcile transport role with later-defined depolymerase function","Single cell-line model"]},{"year":2003,"claim":"Reframed KIF2A as a microtubule depolymerase that suppresses axon branching, redefining its core molecular activity in neurons.","evidence":"kif2a knockout mouse with live imaging of growth-cone microtubule dynamics","pmids":["12887924"],"confidence":"High","gaps":["Did not establish the structural basis of depolymerization","Did not define regulators of activity at the growth cone"]},{"year":2004,"claim":"Defined KIF2A's mitotic role at spindle poles and the balance with MCAK at kinetochores required for bipolarity, distinguishing paralog functions.","evidence":"RNAi knockdown with monopolar-spindle phenotype and epistasis with Nuf2/MCAK; extended by systematic kinesin-13 comparison","pmids":["15302853","17538014"],"confidence":"High","gaps":["Mechanism of differential spindle-location targeting unresolved at this stage","How pole-localized activity is regulated not addressed"]},{"year":2009,"claim":"Resolved kinase control of KIF2A, showing PLK1 activates and Aurora A/B inhibit depolymerase activity, with ICIS reactivating after Aurora B suppression.","evidence":"In vitro kinase and depolymerization assays, Co-IP, antibody microinjection rescue","pmids":["19351716","19327998"],"confidence":"High","gaps":["Phosphosites for some kinases not mapped here","Spatial coordination of antagonistic kinases on the spindle incompletely defined"]},{"year":2009,"claim":"Identified DDA3 as a microtubule-dependent adaptor recruiting KIF2A to spindle poles, defining a recruitment pathway upstream of depolymerase activity.","evidence":"Reciprocal Co-IP, domain dissection, in vitro microtubule binding, RNAi phenocopy and FRAP flux assays","pmids":["18411309","19738423"],"confidence":"High","gaps":["How DDA3 recruitment integrates with kinase regulation not resolved","Later shown to be modulated by Mdp3, not anticipated here"]},{"year":2012,"claim":"Extended KIF2A regulation to lipid-kinase signaling, with PIPKα directly binding and enhancing depolymerization to suppress axon branching.","evidence":"Yeast two-hybrid, biochemical pulldown, in vitro depolymerization, neuronal imaging","pmids":["22307638"],"confidence":"High","gaps":["Mechanism by which PIPKα enhances activity not structurally defined","In vivo significance in intact brain not tested"]},{"year":2013,"claim":"Connected KIF2A depolymerase function to human disease and to developmental spindle-size scaling, establishing physiological consequences of activity tuning.","evidence":"Patient mutation functional ATPase assays; Xenopus extract spindle reconstitution with importin α manipulation; anaphase central-spindle minus-end depolymerization analysis","pmids":["23603762","23425906","23960144"],"confidence":"High","gaps":["Importin α ratiometric mechanism characterized in extract, not in intact embryos exhaustively","Disease mutation effects assayed in vitro only"]},{"year":2015,"claim":"Resolved multiple phospho-regulatory cascades and a ciliary disassembly role, showing distinct phosphosites (S135 by TTBK2, T554 by PLK1, ROCK2/PAK1/CDK5 cascades) tune activity in migration, cilia, and neurite outgrowth.","evidence":"In vitro kinase assays, phosphosite mutagenesis, CRISPR/TALEN KO, phospho-specific antibodies, migration and ciliogenesis assays","pmids":["26323690","25660017","26344760"],"confidence":"High","gaps":["Integration of competing phospho-inputs in vivo not fully resolved","Crosstalk between distinct phosphosites unaddressed"]},{"year":2016,"claim":"Expanded the adaptor and effector network, defining DDA3-Mdp3 control of pole recruitment and a reciprocal KIF2A-AGAP1 enzymatic partnership in migration.","evidence":"Co-IP, domain mapping, in vitro GAP/ATPase assays, RNAi epistasis and migration assays","pmids":["27284004","27531749"],"confidence":"High","gaps":["Physiological context where AGAP1 stimulates KIF2A ATPase not fully mapped","Mdp3 inhibitory mechanism on DDA3 not structurally defined"]},{"year":2017,"claim":"Provided the structural mechanism of depolymerization and a second pole-recruitment route via the MLL/WDR5 WIN-motif interaction.","evidence":"X-ray crystallography with SAXS/AUC/AFM/MS; Co-IP, WIN-motif mapping, RNAi spindle phenotypes; cortical-ER localization in ascidian embryos","pmids":["28903043","28633016","29030551"],"confidence":"High","gaps":["Structural snapshot of the transitional complex did not capture full hydrolysis cycle dynamics","How WDR5 and DDA3 recruitment routes coordinate unknown"]},{"year":2018,"claim":"Established KIF2A's roles in cortical development and neurite compartment identity, linking disease variants to migration, proliferation, and dendro-axonal conversion phenotypes.","evidence":"In utero electroporation of patient variants, inducible conditional knockout mouse, electrophysiology","pmids":["29077851","29313800"],"confidence":"High","gaps":["Molecular basis of compartment identity maintenance not fully defined","Coupling of ciliogenesis to cell cycle inferred, not mechanistically dissected"]},{"year":2020,"claim":"Causally connected a specific KIF2A missense variant to neuronal apoptosis and defective multipolar-to-bipolar transition through loss of depolymerase function.","evidence":"Conditional knock-in mouse with multiple Cre drivers, in utero electroporation, behavioral analysis","pmids":["31919497"],"confidence":"High","gaps":["Mechanistic link from depolymerase loss to apoptosis not resolved","Variant-specific structural consequences not determined"]},{"year":2021,"claim":"Broadened upstream control to Wnt/Dishevelled signaling and neuronal migration via Celsr3, and revealed isoform- and interactome-level diversity of KIF2A function.","evidence":"Phosphoproteomics, Co-IP and domain mapping, conditional knockouts, isoform-specific electroporation, BioID interactome","pmids":["34417301","34582949","33531432"],"confidence":"High","gaps":["Functional meaning of novel interactome partners (translation factors, mitochondrial proteins) not validated","How Wnt and PLK1 inputs converge mechanistically incompletely defined"]},{"year":2023,"claim":"Defined KIF2A as a selective minus-end depolymerase regulated by γ-TuRC capping, CEP170B and NuSAP, with WDR62-CEP170 driving cilium disassembly and RGS12-MYCBP2 degrading KIF2A to control cilia.","evidence":"In vitro reconstitution with purified KIF2A/γTuRC/katanin/CEP170B, TIRF/single-molecule imaging, kinase assays, ubiquitination assays, knockouts","pmids":["37615667","37014312","31197141","38117947","36797232","36700049"],"confidence":"High","gaps":["Precise coordination of nucleation and depolymerization at native spindle poles not directly observed","Cell-type specificity of RGS12-MYCBP2-mediated degradation unclear"]},{"year":2024,"claim":"Added APC as a plus-end catastrophe-promoting partner antagonizing CLASP2, refining the cortical microtubule-dynamics circuit.","evidence":"Co-IP, in vitro reconstitution of MT dynamics, mutagenesis, migration assays","pmids":["39640087"],"confidence":"High","gaps":["Relationship between plus-end (APC) and minus-end (CEP170B/γTuRC) activities not unified","In vivo context of APC-KIF2A catastrophe not established"]},{"year":2025,"claim":"Revealed a context-dependent functional switch from depolymerase to microtubule stabilizer at the cytokinetic bridge, plus atomic detail of the WDR5-KIF2A interface and TTBK2 control of ciliary KIF2A.","evidence":"Genome-engineered ESCs with in vitro ATPase assays and live imaging; WDR5-KIF2A peptide crystal structure with ITC; TTBK2 truncation proteomics and microscopy","pmids":["40353778","40302551","39930500"],"confidence":"High","gaps":["Molecular trigger inhibiting ATPase to drive the stabilizer switch not fully defined","Generality of the cytokinesis switch beyond ESCs unknown"]},{"year":2026,"claim":"Connected KIF2A loss to Alzheimer's-disease Tau hyperphosphorylation via ERK1/2, and uncovered a DNA-repair role through tyrosination-triggered nuclear envelope invagination.","evidence":"Conditional knockout in adult brain, 5xFAD model, human post-mortem brain, ERK1/2 inhibition; KIF2A knockdown with 53BP1/lamin B1 imaging and DNA damage assays","pmids":["41071932","41591845"],"confidence":"Medium","gaps":["Direct biochemical link between KIF2A and ERK1/2 not established","NE-invagination/NHEJ role rests on single-lab loss-of-function without reconstitution"]},{"year":null,"claim":"How the full repertoire of competing kinase inputs, adaptors, and lattice-state sensing is integrated to switch KIF2A between minus-end depolymerase, plus-end catastrophe factor, and microtubule stabilizer in real time remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking phospho-state to depolymerase-versus-stabilizer mode switching","Spatial logic coordinating distinct adaptors at the same structure unknown","Therapeutic targeting in disease contexts not explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[11,18,20,37]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,18,30,31]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,18,30,31,34]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[11,20,37]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3,5,14,21]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,18,30]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[14,21,36]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[39]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4,13,32,37]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[14,21,36]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,24,26,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,27]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[39]}],"complexes":["MLL/WDR5 complex","KIF2A-CEP170B complex","DDA3-Mdp3 complex"],"partners":["DDA3","WDR5","CEP170B","PLK1","TTBK2","NUSAP","AGAP1","APC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00139","full_name":"Kinesin-like protein KIF2A","aliases":["Kinesin-2","hK2"],"length_aa":706,"mass_kda":80.0,"function":"Plus end-directed microtubule-dependent motor required for normal brain development. May regulate microtubule dynamics during axonal growth. Required for normal progression through mitosis. Required for normal congress of chromosomes at the metaphase plate. Required for normal spindle dynamics during mitosis. Promotes spindle turnover. Implicated in formation of bipolar mitotic spindles. Has microtubule depolymerization activity","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle pole; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/O00139/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIF2A","classification":"Not 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DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 3; CDCBM3","url":"https://www.omim.org/entry/615411"},{"mim_id":"615282","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 2; CDCBM2","url":"https://www.omim.org/entry/615282"},{"mim_id":"615142","title":"KINESIN FAMILY MEMBER 2B; KIF2B","url":"https://www.omim.org/entry/615142"},{"mim_id":"614563","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13; CDCBM13","url":"https://www.omim.org/entry/614563"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Centrosome","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Annulus","reliability":"Supported"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Mid 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all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KIF2A"},"hgnc":{"alias_symbol":["HK2"],"prev_symbol":["KIF2"]},"alphafold":{"accession":"O00139","domains":[{"cath_id":"3.40.850.10","chopping":"208-213_224-558","consensus_level":"medium","plddt":89.9119,"start":208,"end":558},{"cath_id":"-","chopping":"604-698","consensus_level":"high","plddt":91.0077,"start":604,"end":698},{"cath_id":"2.30.30","chopping":"14-63","consensus_level":"high","plddt":91.3474,"start":14,"end":63}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00139","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00139-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00139-F1-predicted_aligned_error_v6.png","plddt_mean":78.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIF2A","jax_strain_url":"https://www.jax.org/strain/search?query=KIF2A"},"sequence":{"accession":"O00139","fasta_url":"https://rest.uniprot.org/uniprotkb/O00139.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00139/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00139"}},"corpus_meta":[{"pmid":"23603762","id":"PMC_23603762","title":"Mutations 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Immunoisolation with anti-KIF2 antibody identified a distinct population of non-synaptic vesicles associated with KIF2, different from those carried by conventional kinesin or KIF3A.\",\n      \"method\": \"Recombinant protein motility assay, immunoprecipitation/immunoisolation, immunocytology, nerve ligation accumulation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted motility assay with recombinant protein, complemented by immunoisolation and multiple cellular methods in a foundational study\",\n      \"pmids\": [\"7535303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KIF2A (KIF2) transports a specific class of non-synaptic vesicles containing the IGF-1 receptor variant betagc to neuronal growth cones; antisense knockdown of KIF2 causes betagc to accumulate in the cell body and disappear from growth cones, and dramatically inhibits neurite outgrowth in PC12 cells.\",\n      \"method\": \"Antisense oligonucleotide knockdown, subcellular fractionation, sucrose density centrifugation, immunoisolation, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal fractionation and immunoisolation with functional knockdown, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"9245793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KIF2A depolymerizes microtubules at growth cone edges to suppress collateral axon branch extension; kif2a knockout mice show reduced microtubule-depolymerizing activity at growth cones and aberrant overextension of collateral branches.\",\n      \"method\": \"kif2a knockout mouse analysis, live imaging of microtubule dynamics at growth cones, microtubule depolymerization assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular phenotype, direct measurement of microtubule-depolymerizing activity, replicated across multiple analyses in a landmark study\",\n      \"pmids\": [\"12887924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KIF2A localizes to centrosomes and spindle poles during mitosis and is required for bipolar spindle assembly; its loss causes monopolar spindles that can be rescued by nocodazole treatment, loss of Nuf2 (kinetochore attachment), or loss of MCAK, establishing that KIF2A activity at poles must be balanced by MCAK activity at kinetochores for spindle bipolarity.\",\n      \"method\": \"RNAi knockdown in cultured cells, immunofluorescence, epistasis analysis with Nuf2 and MCAK co-knockdown\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean RNAi with specific monopolar spindle phenotype, functional epistasis with multiple partners, single rigorous study with multiple orthogonal approaches\",\n      \"pmids\": [\"15302853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Kif2a, Kif2b, and MCAK (Kif2c) fulfill distinct functions during mitosis in human cells; Kif2a-deficient cells form monopolar spindles, and bipolar spindle assembly can be restored by simultaneous deficiency of MCAK or Nuf2, or by low-dose nocodazole, but not by perturbing NuMA/HSET (which rescues Kif2b loss), demonstrating that the three kinesin-13 paralogs act at different spindle locations.\",\n      \"method\": \"RNAi knockdown of individual kinesin-13 members, GFP-tagging for localization, epistasis double-knockdown, live imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic comparison with sibling paralogs, multiple epistasis combinations, replicates and extends the Compton lab findings\",\n      \"pmids\": [\"17538014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DDA3 (PSRC1) directly interacts with KIF2A in a microtubule-dependent manner and recruits KIF2A to the mitotic spindle poles; DDA3 depletion phenocopies partial KIF2A knockdown (increased spindle microtubule density, unaligned chromosomes, reduced poleward flux), placing DDA3 upstream of KIF2A in spindle dynamics regulation.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, immunofluorescence, spindle microtubule turnover assay (FRAP), functional genomics screen\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for interaction, RNAi epistasis with phenocopy, multiple orthogonal assays in single study\",\n      \"pmids\": [\"18411309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PLK1 interacts with KIF2A in a mitosis-specific and kinase-activity-dependent manner, phosphorylates KIF2A, and enhances its microtubule-depolymerizing activity in vitro; Aurora A also phosphorylates KIF2A but suppresses its depolymerase activity. Antagonistic regulation by PLK1 (activating) and Aurora A (inhibiting) controls KIF2A localization on microtubules and spindle microtubule intensity in vivo.\",\n      \"method\": \"Proteomic analysis, Co-immunoprecipitation, in vitro kinase assay, in vitro microtubule depolymerization assay, immunofluorescence after kinase inhibition/depletion\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase and depolymerization assays combined with Co-IP and cellular imaging, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19351716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ICIS (inner centromere KinI stimulator) reactivates KIF2A after Aurora B-mediated inhibition; ICIS N-terminus binds Aurora B/INCENP/TD60 while its central region binds KIF2A and microtubules. Antibody injection blocking ICIS-KIF2A interaction generates monopolar spindles rescued by anti-Nuf2 co-injection, establishing ICIS as a scaffold that co-regulates KIF2A depolymerase with the chromosomal passenger complex.\",\n      \"method\": \"Structure-function analysis, Co-immunoprecipitation, antibody microinjection, epistasis rescue experiments\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody injection functional assay and Co-IP, single lab, multiple methods but without full reconstitution\",\n      \"pmids\": [\"19327998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The N-terminal domain of DDA3 does not bind microtubules but acts dominantly to prevent endogenous DDA3 from associating with the spindle, reduces spindle-associated KIF2A, and increases spindle microtubule density; the C-terminal domain of DDA3 directly binds microtubules in vitro and recruits KIF2A to the spindle.\",\n      \"method\": \"Domain deletion analysis, in vitro microtubule binding assay, ectopic overexpression, immunofluorescence\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay combined with dominant-negative overexpression and imaging, single lab\",\n      \"pmids\": [\"19738423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KIF2A interacts with TRAX (translin-associated protein X), and functional interaction between KIF2A and TRAX is required for A2A adenosine receptor-mediated rescue of neuritogenesis; redistribution of KIF2A from the nucleus to the cytoplasm upon NGF treatment is a prerequisite for neurite outgrowth, and nuclear-retained KIF2A (NLS-KIF2A) fails to rescue neurite outgrowth.\",\n      \"method\": \"Co-immunoprecipitation, KIF2A fragment expression (dominant negative), nuclear localization signal fusion, immunofluorescence colocalization, neurite outgrowth assay\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for interaction, dominant-negative fragments, localization imaging, functional rescue, single lab\",\n      \"pmids\": [\"20506231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Phosphatidylinositol 4-phosphate 5-kinase alpha (PIPKα) directly binds KIF2A (yeast two-hybrid and biochemical assays), co-localizes with KIF2A at growth cones, and enhances KIF2A's microtubule-depolymerizing activity both in vitro and in vivo; PIPKα suppresses axon branch elongation in a KIF2A-dependent manner.\",\n      \"method\": \"Immunoprecipitation, yeast two-hybrid, in vitro microtubule depolymerization assay, confocal/PALM microscopy, in vivo overexpression in neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro depolymerization assay combined with yeast two-hybrid, biochemical pulldown, and live cell imaging, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22307638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIF2A disease-causing mutations (identified in patients with MCD) affect ATP hydrolysis, disrupting the microtubule-depolymerizing activity of the protein, as demonstrated by functional studies of mutant proteins.\",\n      \"method\": \"Mutant protein functional assay (ATP hydrolysis), patient mutation identification by sequencing\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay, single study, limited methodological detail in abstract\",\n      \"pmids\": [\"23603762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kif2a controls the length and alignment of central spindle microtubules during anaphase by depolymerizing their minus ends; Aurora B phosphorylation excludes Kif2a from the spindle midzone, restricting its activity to the distal ends of the central spindle, and the Aurora B activity gradient determines steady-state central spindle length.\",\n      \"method\": \"RNAi knockdown, overactivation constructs, immunofluorescence, photoactivation, computational modeling\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (RNAi, overactivation, live imaging, modeling) from a single rigorous study, mechanistically dissects Aurora B regulation of Kif2A localization\",\n      \"pmids\": [\"23960144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kif2a scales the mitotic spindle size during Xenopus development; its microtubule-destabilizing activity is inhibited in large (stage 3) spindles by importin α, and activated in small (stage 8) spindles when importin α partitions to a membrane pool, providing a ratiometric mechanism coupling spindle size to cell size.\",\n      \"method\": \"Xenopus embryo cytoplasmic extract system, spindle reconstitution in vitro, importin α manipulation, immunodepletion\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro spindle reconstitution from staged embryos combined with importin α manipulation, ortholog with conserved mechanism, multiple methods\",\n      \"pmids\": [\"23425906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIF2A, phosphorylated at T554 by PLK1, exhibits microtubule-depolymerizing activity at the mother centriole to disassemble the primary cilium in response to growth signals; KIF2A-deficient cells show impaired cilia disassembly after growth stimulation, and the PLK1-KIF2A pathway is constitutively active in cells from PCS syndrome patients causing defective ciliogenesis.\",\n      \"method\": \"CRISPR/TALEN KIF2A knockout in hTERT-RPE1 cells, phospho-specific antibody, PLK1 kinase assay, immunofluorescence, patient cell analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific ciliogenesis phenotype, kinase assay identifying phosphorylation site, patient validation, multiple orthogonal methods\",\n      \"pmids\": [\"25660017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TTBK2 kinase, anchored to microtubule plus ends by EB1/3, phosphorylates KIF2A at S135 in intact cells in an EB1/3-dependent fashion; this phosphorylation inactivates KIF2A's microtubule-depolymerizing activity in vitro. TTBK2 depletion reduces MT lifetime and impairs cell migration, phenotypes partially rescued by KIF2A co-depletion; nonphosphorylatable KIF2A (S135A) reduces MT lifetime and slows migration.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis (S135A), siRNA co-depletion, live imaging of microtubule dynamics, cell migration assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay + mutagenesis + functional epistasis (co-depletion rescue) + live imaging, multiple orthogonal methods\",\n      \"pmids\": [\"26323690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIF2A undergoes two distinct phosphorylation cascades: A-type phosphorylation (by ROCK2, induced by LPA) accelerates MT depolymerization and suppresses neurite outgrowth; B-type phosphorylation (by PAK1 and CDK5, stimulated by BDNF) decreases MT depolymerizing activity and enhances neural process outgrowth.\",\n      \"method\": \"Quantitative phosphoproteomics, in vitro kinase assays, phosphomimetic/non-phosphorylatable mutants, neurite outgrowth assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — comprehensive phospho-analysis with in vitro kinase validation and phosphomutant functional studies, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26344760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DDA3 and Mdp3 (MAP7D3) form a complex that controls KIF2A recruitment to the spindle minus ends; Mdp3 inhibits DDA3-mediated KIF2A recruitment, and aberrant KIF2A activity at spindle minus ends upon Mdp3 depletion causes spindle instability, chromosome misalignment and bridges.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, immunofluorescence, chromosome segregation analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional RNAi epistasis, single lab, two orthogonal methods\",\n      \"pmids\": [\"27284004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIF2A catalytically depolymerizes microtubules by forming a transitional 1:2 KIF2core:tubulin complex during the pre-hydrolysis state of ATP hydrolysis; the KIF2core domain adopts an activated conformation revealed by X-ray crystallography that sustains binding to two tubulin dimers, explaining processive depolymerization from protofilament ends.\",\n      \"method\": \"Atomic force microscopy, size-exclusion chromatography, multi-angle light scattering, SAXS, analytical ultracentrifugation, mass spectrometry, X-ray crystallography\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with multiple biophysical methods (SAXS, AUC, AFM, MS) to characterize transitional complex, rigorous multi-method study\",\n      \"pmids\": [\"28903043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The MLL/WDR5 complex associates with KIF2A through a conserved WDR5-interaction (Win) motif in KIF2A (residues engaging the WIN site of WDR5); this interaction is required for KIF2A's spindle localization during mitosis. Loss of MLL complex causes defects in chromosome congression and spindle assembly phenocopying KIF2A mislocalization.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, immunofluorescence, direct binding assay (Win motif mapping)\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction mapped to Win motif, RNAi epistasis with spindle phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"28633016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Direct interaction between Kif2A and AGAP1 (Arf GAP): GLD and PH domains of AGAP1 bind the motor domain of Kif2A; Kif2A increases GAP activity of AGAP1, and a GLD-PH fragment of AGAP1 increases ATPase activity of Kif2A. Double-knockdown shows that functional Kif2A-AGAP1 complex controls cytoskeletal remodeling during cell spreading and migration.\",\n      \"method\": \"Co-immunoprecipitation, in vitro GAP activity assay, in vitro ATPase assay, siRNA knockdown, domain mapping, cell spreading/migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assays (GAP and ATPase) plus Co-IP and functional rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27531749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDR62 interacts with CEP170 and promotes CEP170's localization to the basal body of primary cilia; CEP170 in turn recruits microtubule-depolymerizing KIF2A to the basal body to drive cilium disassembly. WDR62 depletion reduces KIF2A's basal body localization, and overexpression of KIF2A partially rescues cilium length defects and NPC proliferation impairment caused by WDR62 loss.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, KIF2A overexpression rescue, mouse knockout and cerebral organoids, siRNA knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis pathway defined by Co-IP, localization experiments, and KIF2A overexpression rescue in multiple model systems (mouse, organoids, cells)\",\n      \"pmids\": [\"31197141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Kif2 localizes to a cortical subdomain of endoplasmic reticulum in ascidian embryos; this localization is responsible for local depolymerization of astral microtubules, driving asymmetric spindle positioning and unequal cell division. Inhibition of Kif2 prevents aster asymmetry and spindle pole movement toward the ER subdomain.\",\n      \"method\": \"Live fluorescence imaging, Kif2 inhibition (dominant-negative/morpholino), local microtubule depolymerization manipulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with localization and loss-of-function in an ortholog model, single lab, two orthogonal methods\",\n      \"pmids\": [\"29030551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIF2A disease-causing variants disrupt projection neuron positioning, interneuron migration, and progenitor proliferation; further, ciliogenesis regulation is altered during the progenitor cell cycle, suggesting that deregulation of the coupling between ciliogenesis and cell cycle contributes to KIF2A-related brain malformations.\",\n      \"method\": \"In utero electroporation, cellular assays, patient variant expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in utero electroporation with multiple cellular phenotypes, single lab\",\n      \"pmids\": [\"29077851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIF2A is required for dentate granule cell neurite length regulation in the postnatal hippocampus; conditional knockout of Kif2a causes mossy fiber sprouting and dendro-axonal conversion (aberrant overextended dendrites that develop axonal properties), demonstrating a role for KIF2A in maintaining distinct neurite compartment identity.\",\n      \"method\": \"Tamoxifen-inducible conditional knockout (Kif2a-cKO) mouse, immunofluorescence, electrophysiology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible conditional KO with specific cellular phenotype (dendro-axonal conversion) characterized in detail, multiple analyses\",\n      \"pmids\": [\"29313800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kif2a scales meiotic spindle size in Hymenochirus boettgeri through an activating phosphorylation site present in H. boettgeri but absent from X. laevis kif2a; this phosphorylation modulates kif2a's microtubule-destabilizing activity for spindle size regulation.\",\n      \"method\": \"Egg extract spindle reconstitution, phosphorylation site comparison, species-comparative analysis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution in frog egg extracts with comparative phosphorylation analysis, ortholog model, single lab\",\n      \"pmids\": [\"31630945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Planar cell polarity protein Celsr3 physically interacts with Kif2a; conditional inactivation of Kif2a in the forebrain recapitulates the Celsr3 knockout phenotype (loss of neuroblast directionality from SVZ to olfactory bulb, aberrant LP branching, decreased MT growth rate), defining a Celsr3-Kif2a axis that specifies the direction of tangential neuronal migration in the postnatal brain.\",\n      \"method\": \"Co-immunoprecipitation, conditional knockout mice (Celsr3-cKO and Kif2a forebrain-cKO), live imaging, immunofluorescence\",\n      \"journal\": \"Progress in neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — physical interaction by Co-IP combined with parallel conditional knockouts showing phenotypic identity, multiple methods\",\n      \"pmids\": [\"34582949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Wnt signaling recruits KIF2A to the mitotic spindle via Dishevelled (DVL), which binds KIF2A through its N-terminal and motor domains; LRP6 signalosome formation during cell division promotes DVL-KIF2A interaction. Wnt signaling modulates KIF2A interaction with PLK1, which is critical for KIF2A spindle localization. Inhibition of basal Wnt signaling leads to chromosome misalignment in somatic cells and pluripotent stem cells.\",\n      \"method\": \"Phosphoproteomics, Co-immunoprecipitation, Wnt pathway inhibition, immunofluorescence, domain mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphoproteomics identification combined with Co-IP domain mapping and epistasis in multiple cell types, multiple orthogonal methods\",\n      \"pmids\": [\"34417301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Different KIF2A alternative isoforms have distinct functions in cortical development: two isoforms sustain radial migration, but a third isoform lacking a key N-terminal region does not. Proximity-based interactome mapping revealed novel KIF2A interaction partners including translation factors, ribonucleoproteins, and mitochondrial proteins; a disease-causing mutation shows extensive depletion of mitochondrial proteins from the KIF2A interactome.\",\n      \"method\": \"In utero electroporation of individual isoforms, proximity-based interactome mapping (BioID), migration assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific in utero electroporation with migration readout and BioID interactome, single lab, two orthogonal methods\",\n      \"pmids\": [\"33531432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIF2A is required postnatally for neuronal maturation, connectivity, and survival; conditional inactivation in mature cortical neurons disrupts microtubule dynamics and multiple microtubule-dependent processes including neuronal polarity, neuritogenesis, synaptogenesis, and axonal transport, leading to aberrant electrophysiology, loss of connectivity, and neuronal death.\",\n      \"method\": \"Conditional KIF2A knockout (NestinCre, NexCre, CaMKII-Cre) in mice, electrophysiology, immunofluorescence, axonal transport assays, synaptogenesis analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Cre drivers giving graded conditional KO, multiple orthogonal cellular phenotypes, functional electrophysiology, strong study\",\n      \"pmids\": [\"36343267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIF2A is a selective microtubule minus-end depolymerase (in contrast to its paralog MCAK which acts at plus ends); γ-TuRC acts as a protective cap shielding minus ends from KIF2A binding. Efficient γTuRC uncapping requires combined action of KIF2A and a microtubule-severing enzyme (katanin), leading to KIF2A-driven treadmilling of uncapped microtubules, providing a molecular mechanism for coordinating nucleation and depolymerization at spindle poles for poleward flux.\",\n      \"method\": \"In vitro reconstitution with purified proteins (KIF2A, γTuRC, katanin), TIRF microscopy, single-molecule assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components, single-molecule imaging, mechanistic dissection of minus-end selectivity, rigorous biochemical study\",\n      \"pmids\": [\"37615667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEP170B forms a complex with KIF2A that depolymerizes microtubule minus ends; CEP170B autonomously tracks growing MT minus ends and blocks minus-end growth, and together with KIF2A acts as a potent MT minus-end depolymerase capable of antagonizing CAMSAP-mediated stabilization, thereby controlling the spatial distribution of MT minus ends and establishing cell polarity.\",\n      \"method\": \"In vitro reconstitution, Co-immunoprecipitation, TIRF microscopy, RNAi knockdown, immunofluorescence in HeLa and epithelial cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution demonstrating KIF2A-CEP170B complex depolymerase activity, complemented by cellular epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"37014312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NuSAP interacts with KIF2A and prevents excessive microtubule depolymerization by reducing KIF2A localization at spindle poles; Aurora A phosphorylates NuSAP at Ser-240 during mitosis, which promotes NuSAP interaction with KIF2A on the spindle body, reduces KIF2A at spindle poles, and maintains proper spindle microtubule flux. NuSAP knockout causes shorter spindles with faster flux and chromosome misalignment.\",\n      \"method\": \"Co-immunoprecipitation, Aurora A kinase assay, NuSAP knockout, immunofluorescence, FRAP for flux measurement\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinase assay with phosphosite identification, Co-IP, KO with multiple spindle phenotypes, flux measurement, multiple orthogonal methods\",\n      \"pmids\": [\"38117947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RGS12 associates with and activates MYCBP2 (E3 ubiquitin ligase) to promote ubiquitination and degradation of KIF2A in synovial fibroblasts and tumor-associated macrophages; KIF2A degradation increases cilia length and number. KIF2A overexpression blocks cilia elongation downstream of RGS12.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS protein interaction analysis, ubiquitination assay, RGS12 knockout mice, KIF2A overexpression\",\n      \"journal\": \"International journal of oral science / Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and LC-MS for interaction, ubiquitination assay, functional rescue, single lab\",\n      \"pmids\": [\"36797232\", \"36700049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"APC forms a complex with KIF2A at the cell edge and promotes KIF2A-induced microtubule catastrophe at MT plus ends; biochemical characterization and mutational analysis identified key residues for the APC-KIF2A interaction. In vitro reconstitution demonstrates APC potentiates KIF2A-induced MT catastrophes and antagonizes CLASP2-mediated stabilization.\",\n      \"method\": \"Co-immunoprecipitation, in vitro reconstitution of MT dynamics, mutagenesis, immunofluorescence, cell migration assay\",\n      \"journal\": \"Cell insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutational analysis and Co-IP, multiple methods, single lab\",\n      \"pmids\": [\"39640087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structure of WDR5 in complex with a KIF2A-derived peptide (residues 114-122) at 1.85 Å resolution reveals KIF2A engages both the WIN and S7 sites of WDR5 via Arg117 and Ser121; Ser121 forms hydrogen bonds with WDR5 Tyr191 and Lys259, driving Tyr191 rotation and opening the S7 pocket. ITC mutagenesis confirmed critical roles of Arg117 and Ser121.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry (ITC), site-directed mutagenesis\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 1.85 Å combined with ITC and mutagenesis to validate key residues, rigorous multi-method single study\",\n      \"pmids\": [\"40302551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TTBK2 phosphorylates KIF2A to restrain its microtubule-depolymerizing activity during cilia growth and maintenance; disease-related TTBK2 truncations that cannot localize to the mother centriole cause defective cilia elongation linked to aberrant KIF2A turnover. Concentration of TTBK2 at the mother centriole is required for full ciliogenesis.\",\n      \"method\": \"Biochemical approaches, proteomics, CRISPR genetic engineering, advanced microscopy, TTBK2 truncation analysis\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics + genetic engineering + imaging in human cells, single lab, multiple methods but kinase assay details not fully described in abstract\",\n      \"pmids\": [\"39930500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"During cytokinesis in mouse embryonic stem cells, KIF2A switches from a microtubule depolymerase (at spindle poles in metaphase) to a microtubule stabilizer at intercellular bridge microtubules; this conversion is driven by inhibition of KIF2A's ATPase activity (increasing lattice affinity) and a preference for compacted microtubule lattices. KIF2A at the intercellular bridge maintains microtubule length/number and controls microtubule acetylation, prolonging cytokinesis to maintain pluripotency.\",\n      \"method\": \"Genome-engineered mouse ESCs, in vitro ATPase assay, immunofluorescence, live imaging, microtubule acetylation analysis, mRNA homeostasis analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mechanistic assays combined with cellular live imaging and genetic engineering, single lab but multiple orthogonal methods defining a novel KIF2A switching mechanism\",\n      \"pmids\": [\"40353778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KIF2A deficiency in the adult mouse cortex and hippocampus leads to reduced dendritic spine density and cognitive decline followed by increased Tau phosphorylation through MAPK ERK1/2 upregulation. KIF2A protein levels are drastically reduced in Alzheimer's disease patients (but not in primary tauopathies), and Aβ accumulation alters KIF2A expression in neurons, linking Aβ → KIF2A downregulation → ERK1/2 upregulation → Tau hyperphosphorylation.\",\n      \"method\": \"Conditional KIF2A knockout in adult mouse cortex/hippocampus, 5xFAD mouse model analysis, post-mortem human brain IHC/western blot, ERK1/2 inhibitor experiments\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with specific molecular pathway (ERK1/2-Tau) validated in mouse model and human tissue, multiple orthogonal systems\",\n      \"pmids\": [\"41071932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Damage-induced α-tubulin tyrosination triggers KIF2A binding to microtubules, and KIF2A mediates nuclear envelope (NE) invagination through the LINC complex and lamin B1; this NE invagination creates a stable environment for NHEJ repair near the NE, facilitating 53BP1 foci formation. Loss of KIF2A disrupts NE invagination after DNA damage and impairs NHEJ.\",\n      \"method\": \"KIF2A knockdown, immunofluorescence (53BP1 foci, lamin B1, α-tubulin), DNA damage assays, live imaging of NE dynamics\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KIF2A loss-of-function with specific NE and DNA repair phenotypes, multiple markers, single lab\",\n      \"pmids\": [\"41591845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KIF2A missense variants causing brain malformations (p.His321Asp) expressed via conditional knock-in increase neuronal apoptosis and cause abnormal multipolar-to-bipolar transition in newborn neurons, and these phenotypes are linked to deficiency in the microtubule-depolymerizing function of KIF2A.\",\n      \"method\": \"Cre-mediated conditional knock-in mouse (NestinCre, NexCre, RosaCre), in utero electroporation, immunofluorescence, behavioral analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knock-in mouse with multiple Cre drivers, specific cellular phenotypes (apoptosis, bipolar transition), mechanistically linked to MT depolymerase function\",\n      \"pmids\": [\"31919497\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIF2A is an M-type kinesin-13 that catalytically depolymerizes microtubules from minus ends (and in certain contexts plus ends) through ATP hydrolysis, forming a 1:2 KIF2A:tubulin transitional complex; its depolymerase activity is regulated by multiple kinases (PLK1 activates, Aurora A/B inhibits, TTBK2 inhibits via S135 phosphorylation, PAK1/CDK5 inhibit, ROCK2 activates) and by binding partners (PIPKα enhances, ICIS reactivates after Aurora B inhibition, importin α suppresses, WDR5/MLL and DDA3 control spindle localization, Celsr3 directs neuronal migration, APC potentiates catastrophe, CEP170B enables minus-end depolymerization, γTuRC caps minus ends); during mitosis KIF2A acts at centrosomes/spindle poles to drive poleward microtubule flux and maintain spindle bipolarity (balanced against MCAK at kinetochores), during cytokinesis it can switch to a microtubule stabilizer at the intercellular bridge, during ciliogenesis PLK1-phosphorylated KIF2A (T554) and the WDR62-CEP170-KIF2A axis drive primary cilium disassembly at the mother centriole, and in postmitotic neurons KIF2A depolymerizes growth-cone microtubules to suppress axon branch extension, control neurite compartment identity, and support neuronal survival, with its loss linked to Tau hyperphosphorylation via ERK1/2 upregulation in Alzheimer's disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF2A is an M-type kinesin-13 that functions principally as a catalytic, ATP-driven microtubule depolymerase, governing microtubule dynamics across mitosis, ciliogenesis, and neuronal morphogenesis [#0, #2, #18]. Structural and biophysical work shows that the KIF2A motor core adopts an activated conformation that captures two tubulin dimers in a transitional 1:2 complex during the pre-hydrolysis ATP state, explaining its processive removal of tubulin from protofilament ends [#18]. KIF2A acts as a selective minus-end depolymerase: \\u03b3-TuRC caps and protects minus ends, and efficient uncapping requires KIF2A together with the severing enzyme katanin, while CEP170B partners with KIF2A to track and depolymerize minus ends and antagonize CAMSAP-mediated stabilization [#30, #31]. Its activity is set by an extensive regulatory network of kinases and adaptors: PLK1 phosphorylation activates depolymerization whereas Aurora A and TTBK2 (S135) inhibit it, with additional ROCK2 (activating) and PAK1/CDK5 (inhibiting) inputs, and recruitment to spindle poles is controlled by DDA3, the MLL/WDR5 complex via a WIN-motif interaction, NuSAP, importin \\u03b1, and Wnt/Dishevelled signaling [#6, #15, #16, #5, #19, #35, #32, #13, #27]. During mitosis KIF2A operates at centrosomes and spindle poles to drive poleward microtubule flux and maintain spindle bipolarity, balanced against MCAK at kinetochores, and scales spindle size to cell size [#3, #4, #13]. At the mother centriole, PLK1-phosphorylated KIF2A (T554) and the WDR62\\u2013CEP170\\u2013KIF2A axis drive primary cilium disassembly [#14, #21]. In postmitotic neurons KIF2A depolymerizes growth-cone microtubules to suppress collateral axon branching, maintain neurite compartment identity, direct migration via a Celsr3 axis, and support neuronal connectivity and survival [#2, #24, #26, #29]. KIF2A mutations that impair ATP hydrolysis and depolymerase activity cause malformations of cortical development [#11, #40], and KIF2A loss links to Tau hyperphosphorylation through ERK1/2 upregulation in Alzheimer's disease [#38].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established KIF2A's foundational identity as a dimeric M-type microtubule motor, the first step toward defining what this kinesin physically is and does.\",\n      \"evidence\": \"Recombinant protein motility assays and immunoisolation of associated non-synaptic vesicles\",\n      \"pmids\": [\"7535303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Motility assay characterized plus-end movement but did not reveal depolymerase activity\", \"Cargo/vesicle identity only partially defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linked KIF2A to neuronal cargo transport and neurite outgrowth, the earliest functional readout in a postmitotic context.\",\n      \"evidence\": \"Antisense knockdown with fractionation and immunoisolation in PC12 cells\",\n      \"pmids\": [\"9245793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not reconcile transport role with later-defined depolymerase function\", \"Single cell-line model\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Reframed KIF2A as a microtubule depolymerase that suppresses axon branching, redefining its core molecular activity in neurons.\",\n      \"evidence\": \"kif2a knockout mouse with live imaging of growth-cone microtubule dynamics\",\n      \"pmids\": [\"12887924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the structural basis of depolymerization\", \"Did not define regulators of activity at the growth cone\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined KIF2A's mitotic role at spindle poles and the balance with MCAK at kinetochores required for bipolarity, distinguishing paralog functions.\",\n      \"evidence\": \"RNAi knockdown with monopolar-spindle phenotype and epistasis with Nuf2/MCAK; extended by systematic kinesin-13 comparison\",\n      \"pmids\": [\"15302853\", \"17538014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of differential spindle-location targeting unresolved at this stage\", \"How pole-localized activity is regulated not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved kinase control of KIF2A, showing PLK1 activates and Aurora A/B inhibit depolymerase activity, with ICIS reactivating after Aurora B suppression.\",\n      \"evidence\": \"In vitro kinase and depolymerization assays, Co-IP, antibody microinjection rescue\",\n      \"pmids\": [\"19351716\", \"19327998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosites for some kinases not mapped here\", \"Spatial coordination of antagonistic kinases on the spindle incompletely defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified DDA3 as a microtubule-dependent adaptor recruiting KIF2A to spindle poles, defining a recruitment pathway upstream of depolymerase activity.\",\n      \"evidence\": \"Reciprocal Co-IP, domain dissection, in vitro microtubule binding, RNAi phenocopy and FRAP flux assays\",\n      \"pmids\": [\"18411309\", \"19738423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DDA3 recruitment integrates with kinase regulation not resolved\", \"Later shown to be modulated by Mdp3, not anticipated here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended KIF2A regulation to lipid-kinase signaling, with PIPK\\u03b1 directly binding and enhancing depolymerization to suppress axon branching.\",\n      \"evidence\": \"Yeast two-hybrid, biochemical pulldown, in vitro depolymerization, neuronal imaging\",\n      \"pmids\": [\"22307638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PIPK\\u03b1 enhances activity not structurally defined\", \"In vivo significance in intact brain not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected KIF2A depolymerase function to human disease and to developmental spindle-size scaling, establishing physiological consequences of activity tuning.\",\n      \"evidence\": \"Patient mutation functional ATPase assays; Xenopus extract spindle reconstitution with importin \\u03b1 manipulation; anaphase central-spindle minus-end depolymerization analysis\",\n      \"pmids\": [\"23603762\", \"23425906\", \"23960144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Importin \\u03b1 ratiometric mechanism characterized in extract, not in intact embryos exhaustively\", \"Disease mutation effects assayed in vitro only\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved multiple phospho-regulatory cascades and a ciliary disassembly role, showing distinct phosphosites (S135 by TTBK2, T554 by PLK1, ROCK2/PAK1/CDK5 cascades) tune activity in migration, cilia, and neurite outgrowth.\",\n      \"evidence\": \"In vitro kinase assays, phosphosite mutagenesis, CRISPR/TALEN KO, phospho-specific antibodies, migration and ciliogenesis assays\",\n      \"pmids\": [\"26323690\", \"25660017\", \"26344760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of competing phospho-inputs in vivo not fully resolved\", \"Crosstalk between distinct phosphosites unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Expanded the adaptor and effector network, defining DDA3-Mdp3 control of pole recruitment and a reciprocal KIF2A-AGAP1 enzymatic partnership in migration.\",\n      \"evidence\": \"Co-IP, domain mapping, in vitro GAP/ATPase assays, RNAi epistasis and migration assays\",\n      \"pmids\": [\"27284004\", \"27531749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context where AGAP1 stimulates KIF2A ATPase not fully mapped\", \"Mdp3 inhibitory mechanism on DDA3 not structurally defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided the structural mechanism of depolymerization and a second pole-recruitment route via the MLL/WDR5 WIN-motif interaction.\",\n      \"evidence\": \"X-ray crystallography with SAXS/AUC/AFM/MS; Co-IP, WIN-motif mapping, RNAi spindle phenotypes; cortical-ER localization in ascidian embryos\",\n      \"pmids\": [\"28903043\", \"28633016\", \"29030551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural snapshot of the transitional complex did not capture full hydrolysis cycle dynamics\", \"How WDR5 and DDA3 recruitment routes coordinate unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established KIF2A's roles in cortical development and neurite compartment identity, linking disease variants to migration, proliferation, and dendro-axonal conversion phenotypes.\",\n      \"evidence\": \"In utero electroporation of patient variants, inducible conditional knockout mouse, electrophysiology\",\n      \"pmids\": [\"29077851\", \"29313800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of compartment identity maintenance not fully defined\", \"Coupling of ciliogenesis to cell cycle inferred, not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Causally connected a specific KIF2A missense variant to neuronal apoptosis and defective multipolar-to-bipolar transition through loss of depolymerase function.\",\n      \"evidence\": \"Conditional knock-in mouse with multiple Cre drivers, in utero electroporation, behavioral analysis\",\n      \"pmids\": [\"31919497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link from depolymerase loss to apoptosis not resolved\", \"Variant-specific structural consequences not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened upstream control to Wnt/Dishevelled signaling and neuronal migration via Celsr3, and revealed isoform- and interactome-level diversity of KIF2A function.\",\n      \"evidence\": \"Phosphoproteomics, Co-IP and domain mapping, conditional knockouts, isoform-specific electroporation, BioID interactome\",\n      \"pmids\": [\"34417301\", \"34582949\", \"33531432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional meaning of novel interactome partners (translation factors, mitochondrial proteins) not validated\", \"How Wnt and PLK1 inputs converge mechanistically incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined KIF2A as a selective minus-end depolymerase regulated by \\u03b3-TuRC capping, CEP170B and NuSAP, with WDR62-CEP170 driving cilium disassembly and RGS12-MYCBP2 degrading KIF2A to control cilia.\",\n      \"evidence\": \"In vitro reconstitution with purified KIF2A/\\u03b3TuRC/katanin/CEP170B, TIRF/single-molecule imaging, kinase assays, ubiquitination assays, knockouts\",\n      \"pmids\": [\"37615667\", \"37014312\", \"31197141\", \"38117947\", \"36797232\", \"36700049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise coordination of nucleation and depolymerization at native spindle poles not directly observed\", \"Cell-type specificity of RGS12-MYCBP2-mediated degradation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added APC as a plus-end catastrophe-promoting partner antagonizing CLASP2, refining the cortical microtubule-dynamics circuit.\",\n      \"evidence\": \"Co-IP, in vitro reconstitution of MT dynamics, mutagenesis, migration assays\",\n      \"pmids\": [\"39640087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between plus-end (APC) and minus-end (CEP170B/\\u03b3TuRC) activities not unified\", \"In vivo context of APC-KIF2A catastrophe not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a context-dependent functional switch from depolymerase to microtubule stabilizer at the cytokinetic bridge, plus atomic detail of the WDR5-KIF2A interface and TTBK2 control of ciliary KIF2A.\",\n      \"evidence\": \"Genome-engineered ESCs with in vitro ATPase assays and live imaging; WDR5-KIF2A peptide crystal structure with ITC; TTBK2 truncation proteomics and microscopy\",\n      \"pmids\": [\"40353778\", \"40302551\", \"39930500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger inhibiting ATPase to drive the stabilizer switch not fully defined\", \"Generality of the cytokinesis switch beyond ESCs unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected KIF2A loss to Alzheimer's-disease Tau hyperphosphorylation via ERK1/2, and uncovered a DNA-repair role through tyrosination-triggered nuclear envelope invagination.\",\n      \"evidence\": \"Conditional knockout in adult brain, 5xFAD model, human post-mortem brain, ERK1/2 inhibition; KIF2A knockdown with 53BP1/lamin B1 imaging and DNA damage assays\",\n      \"pmids\": [\"41071932\", \"41591845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between KIF2A and ERK1/2 not established\", \"NE-invagination/NHEJ role rests on single-lab loss-of-function without reconstitution\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the full repertoire of competing kinase inputs, adaptors, and lattice-state sensing is integrated to switch KIF2A between minus-end depolymerase, plus-end catastrophe factor, and microtubule stabilizer in real time remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking phospho-state to depolymerase-versus-stabilizer mode switching\", \"Spatial logic coordinating distinct adaptors at the same structure unknown\", \"Therapeutic targeting in disease contexts not explored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [11, 18, 20, 37]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 18, 30, 31]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 18, 30, 31, 34]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [11, 20, 37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3, 5, 14, 21]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 18, 30]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [14, 21, 36]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4, 13, 32, 37]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [14, 21, 36]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 24, 26, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 27]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [39]}\n    ],\n    \"complexes\": [\n      \"MLL/WDR5 complex\",\n      \"KIF2A-CEP170B complex\",\n      \"DDA3-Mdp3 complex\"\n    ],\n    \"partners\": [\n      \"DDA3\",\n      \"WDR5\",\n      \"CEP170B\",\n      \"PLK1\",\n      \"TTBK2\",\n      \"NuSAP\",\n      \"AGAP1\",\n      \"APC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}