{"gene":"KIF4A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1994,"finding":"KIF4 (mouse ortholog) is a microtubule plus-end-directed motor protein with nucleotide-dependent microtubule binding, microtubule-activated ATPase activity, and anterograde motility. The protein has three domains: an NH2-terminal globular motor domain, a central alpha-helical stalk domain, and a COOH-terminal tail domain. It colocalizes with membranous organelles in growth cones and cytoplasm.","method":"cDNA cloning, biochemical characterization, ATPase assay, electron microscopy of Sf9-expressed protein, immunocytochemistry","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ATPase assay, motility assay, and structural characterization with multiple orthogonal methods in a single foundational study","pmids":["7929562"],"is_preprint":false},{"year":1998,"finding":"KIF4 (mouse ortholog) binds murine leukemia virus Gag polyproteins; the interaction maps to the C-terminal region of KIF4. KIF4-MuLV Gag associations were detected in vitro and in mammalian cells, suggesting KIF4 may mediate Gag transport.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation in mammalian cells","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirmed in cells with two orthogonal methods (Y2H + Co-IP), single lab","pmids":["9658142"],"is_preprint":false},{"year":1999,"finding":"Human KIF4 associates with HIV-1 Gag precursor (Pr55) and a matrix-capsid processing intermediate (Pr42) but not with other processed Gag products. KIF4 and HIV-1 Gag cofractionate by sucrose gradient, size-exclusion, and anion-exchange chromatography. Gag binding is mediated by a domain of KIF4 proximal to its C-terminus.","method":"Sucrose gradient fractionation, size-exclusion chromatography, anion-exchange chromatography, immunoprecipitation, yeast two-hybrid","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods, single lab, domain mapping performed","pmids":["10559369"],"is_preprint":false},{"year":2000,"finding":"KIF4 mediates anterograde transport of L1-containing vesicles in neurons. KIF4-associated vesicles are highly concentrated in growth cones, contain L1 (a cell adhesion molecule for axonal elongation), and lack synaptic vesicle markers. Antisense suppression of KIF4 causes accumulation of L1 in cell bodies, its disappearance from axonal tips, and prevents L1-enhanced axonal elongation.","method":"Subcellular fractionation, immunoisolation, antisense oligonucleotide knockdown, immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation + immunoisolation + functional KD with defined cargo phenotype, single lab","pmids":["10747093"],"is_preprint":false},{"year":2004,"finding":"KIF4 binds PRC1 (a microtubule-bundling protein) and is essential for central spindle organization and midzone formation during anaphase. In KIF4-deficient cells, the central spindle is disorganized and all midzone-associated proteins including PRC1 fail to concentrate at the midline. PRC1 is required for KIF4 localization to the spindle.","method":"RNAi knockdown, immunofluorescence, protein interaction assay (co-immunoprecipitation)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal KD epistasis with defined phenotypic readout, replicated in same study with multiple depletion conditions","pmids":["15297875"],"is_preprint":false},{"year":2004,"finding":"Kif4 translocates PRC1 to the plus ends of interdigitating spindle microtubules during the metaphase-to-anaphase transition. Kif4 binds PRC1 through its 'stalk plus tail' domains. This translocation is required for midzone formation and cytokinesis; a motor-dead Kif4 mutant cannot rescue PRC1 translocation or cytokinesis defects. CDK phosphorylation of PRC1 controls the timing of PRC1 translocation by Kif4.","method":"Time-lapse microscopy, esiRNA knockdown, domain mapping, motor-dead mutant rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — motor-dead mutant rescue, domain mapping, live imaging, multiple orthogonal approaches in single study","pmids":["15625105"],"is_preprint":false},{"year":2004,"finding":"Human KIF4A (HKIF4A) localizes to condensed chromosome arms during mitosis and accumulates in the midzone during late anaphase and the cytokinetic ring during cytokinesis. RNAi depletion causes defective prometaphase organization, chromosome mis-alignment, spindle defects, and chromosome mis-segregation. KIF4A interacts with condensin I and II complexes, and its depletion results in chromosome hypercondensation.","method":"RNAi knockdown, immunofluorescence, co-immunoprecipitation with condensin complexes","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi with multiple defined phenotypic readouts plus Co-IP binding partner identification, single rigorous study","pmids":["15326200"],"is_preprint":false},{"year":2004,"finding":"KIF4 localizes to the midzone and midbody during ana/telophase and cytokinesis in dividing HeLa cells, forming a ring structure around microtubule bundles at the cytokinetic bridge.","method":"Immunofluorescence, 3D microscopy analysis","journal":"Experimental & molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method localization study without functional manipulation","pmids":["15031677"],"is_preprint":false},{"year":2006,"finding":"The C-terminal domain of KIF4 suppresses PARP-1 enzymatic activity. Upon neuronal stimulation by membrane depolarization, CaMKII-mediated calcium signaling induces dissociation of KIF4 from PARP-1, resulting in upregulation of PARP-1 activity that supports neuron survival. After dissociation, KIF4 moves from the nucleus to the cytoplasm and toward distal neurites in a microtubule-dependent manner.","method":"In vitro PARP-1 activity assay, co-immunoprecipitation, live cell imaging, calcium signaling manipulation, CaMKII inhibitor experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay + co-IP + live imaging + pharmacological manipulation, multiple orthogonal methods in single rigorous study","pmids":["16630823"],"is_preprint":false},{"year":2008,"finding":"Kif4A associates with BRCA2; the interaction is mediated by the Kif4A C-terminal cargo-binding domain and BRCA2 C-terminal conserved region. Upon nuclear laser micro-irradiation, Kif4A is rapidly recruited to sites of DNA damage. Kif4A depletion impairs Rad51 IRIF formation (but not γ-H2AX or NBS1 IRIF) and decreases homologous recombination efficiency, rendering cells hypersensitive to ionizing radiation.","method":"Co-immunoprecipitation, domain mapping, laser micro-irradiation, shRNA knockdown, I-SceI endonuclease HR assay, clonogenic survival assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP with domain mapping, live DNA damage recruitment, HR assay, survival assay) in single study","pmids":["18604178"],"is_preprint":false},{"year":2008,"finding":"Disrupting KIF4 function slows HIV-1 Gag trafficking through intermediates, inhibits virus-like particle production, and leads to increased Gag degradation. When KIF4 function is blocked, Gag accumulates in perinuclear clusters that colocalize with KIF4, Ubc9 (E2 SUMO-1 conjugating enzyme), and SUMO. Reintroduction of KIF4 rescues intracellular Gag levels.","method":"KIF4 knockdown, KIF4 reintroduction rescue, immunofluorescence colocalization, VLP production assay, western blot","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD + rescue with defined trafficking phenotype, colocalization, single lab","pmids":["18684836"],"is_preprint":false},{"year":2008,"finding":"Two conserved chromatin-binding motifs in Kif4A are required for its mitotic function: the first leucine Zip motif (Zip1) within the ZBZ region, and a cysteine-rich (CR) motif in the C-terminal region. Kif4A mutants lacking either Zip1 or CR, or the K94A ATPase-dead mutant, cannot rescue RNAi-induced mitotic defects, indicating that both chromatin binding and ATPase activity are required for Kif4A mitotic function.","method":"Mutagenesis, RNAi rescue experiments, chromatin-binding assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional rescue readout, single lab","pmids":["18502200"],"is_preprint":false},{"year":2009,"finding":"The C-terminal tail domain of KIF4 directly interacts with P0, a major ribosomal protein. KIF4 is required for anterograde transport of ribosomal constituents to axons; RNAi suppression of KIF4 or expression of tail-domain-deleted or ATP-binding-site-mutated KIF4 causes accumulation of P0 and ribosomal proteins in the cell body and their disappearance from axons. An ERM-like domain in KIF4's second coiled-coil region is required for clustering of ribosomal constituents and for anterograde transport of L1.","method":"Co-immunoprecipitation, domain deletion/mutation analysis, RNAi, immunofluorescence in DRG neurons","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction mapping + functional KD + domain mutant analysis, single lab","pmids":["19158085"],"is_preprint":false},{"year":2012,"finding":"KIF4 cooperates with condensin complexes in a parallel pathway to promote lateral compaction of chromatid arms. KIF4 and condensin are mutually dependent for their dynamic localization on chromatid axes. Depletion of either causes sister chromatids to expand. Simultaneous depletion of KIF4 and condensin causes complete loss of chromosome morphology. Topoisomerase IIα promotes axial shortening of chromatids, acting in opposition to KIF4 and condensins.","method":"RNAi (single and double depletion), morphological analysis, in vitro chromosome structure assay, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double depletion epistasis with in vitro structural assay and multiple orthogonal readouts, comprehensive mechanistic dissection","pmids":["23166350"],"is_preprint":false},{"year":2014,"finding":"Kif4 interacts directly with the N-terminal domain of EB1 via its tail domain. Kif4 localizes to ends of stable microtubules and acts downstream of Rho-mDia-EB1 to induce selective microtubule stabilization in fibroblasts. Kif4 depletion blocks mDia- and EB1-induced stable MT formation and inhibits cell migration into wounded monolayers.","method":"Co-immunoprecipitation, direct binding studies (domain mapping), immunofluorescence, shRNA knockdown, wound healing assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding domain mapping + epistasis via depletion + functional migration readout, single lab","pmids":["24658398"],"is_preprint":false},{"year":2014,"finding":"KIF4A and PP2A-B56γ/ε form a spatially restricted negative feedback loop at the anaphase central spindle opposing Aurora B. PP2A-B56γ is maintained at the central spindle by KIF4A. PP2A-B56γ dephosphorylates the Aurora B phosphorylation site T799 on KIF4A, counteracting Aurora B- and microtubule-stimulated KIF4A ATPase activity. Combined silencing of PP2A-B56γ and -ε increases KIF4A T799 phosphorylation and decreases central spindle growth in anaphase B.","method":"Biochemical phosphatase assays, immunoprecipitation, RNAi (single and double depletion), phospho-specific antibodies, spindle length measurement","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphatase assay + RNAi epistasis + phospho-site analysis, multiple orthogonal methods in single study","pmids":["25512391"],"is_preprint":false},{"year":2014,"finding":"Knockdown of Kif4a in rat primary hippocampal neurons alters the balance between excitatory and inhibitory synaptic transmission, suggesting KIF4A regulates synaptic function.","method":"shRNA knockdown in primary rat hippocampal neurons, electrophysiological recordings of synaptic transmission","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional KD in neurons with electrophysiological readout, single lab, limited mechanistic detail in abstract","pmids":["24812067"],"is_preprint":false},{"year":2014,"finding":"Kif4A co-localizes with β1 integrin in vesicles in neurons and non-neuronal cells, and the two molecules co-immunoprecipitate. Knockdown of KIF4A reduces β1 integrin levels in axons of developing neurons and reduces neurite elongation on laminin.","method":"Co-immunoprecipitation, immunofluorescence colocalization, shRNA knockdown, neurite elongation assay","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + KD with functional readout, single lab","pmids":["25260485"],"is_preprint":false},{"year":2015,"finding":"KIF4-dependent PRC1-1 (isoform 1 of PRC1) translocation to astral microtubule tips during prometaphase causes fatal sister chromatid alignment errors when Cdk1 activity is insufficient. Gene ablation of KIF4 or abrogation of KIF4 motor activity rescues Cdk1-inhibition-induced chromosome alignment defects.","method":"Large-scale RNAi screen, KIF4 gene ablation, motor-dead mutant, live cell imaging of chromosome alignment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via KO and motor-dead mutant with defined phenotypic rescue, single lab","pmids":["26423135"],"is_preprint":false},{"year":2016,"finding":"KIF4A is phosphorylated specifically during mitosis, dependent on Cdk1 and Aurora B activity. This phosphorylation is required for KIF4A to interact with condensin I.","method":"Mass spectrometry phosphoproteomics, phospho-specific antibody, kinase inhibitor treatments, co-immunoprecipitation","journal":"Biomedical research (Tokyo, Japan)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics + Co-IP with kinase inhibitor validation, single lab","pmids":["27108885"],"is_preprint":false},{"year":2016,"finding":"KIF4A associates specifically with condensin I (not condensin II) during mitosis. Condensin I enrichment on chromosomal axes depends on its association with KIF4A in a manner that requires KIF4A motor activity. This interaction is required for condensin I to confer physiological properties to chromosomes.","method":"Co-immunoprecipitation, mutational analysis, immunofluorescence, RNAi","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP + motor mutant analysis + RNAi with multiple orthogonal readouts, rigorous mechanistic dissection","pmids":["27633014"],"is_preprint":false},{"year":2017,"finding":"GTSE1 depletion increases stable mitotic spindle microtubules, which leads to diminished Aurora B kinase recruitment to chromosome arms and consequently decreased Kif4A binding to chromosome arms.","method":"RNAi knockdown, immunofluorescence, microtubule stability assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via RNAi with defined pathway placement (GTSE1→MT stability→Aurora B→Kif4A), single lab","pmids":["28821562"],"is_preprint":false},{"year":2017,"finding":"KIF4A forms a stable complex with condensin I, and KIF4 and condensin I are interdependent for localization to the chromosome scaffold. Phosphorylation of KIF4 and condensin I by Aurora B promotes their chromosome targeting, whereas Plk1 activity promotes their dissociation from chromosomes.","method":"Co-immunoprecipitation, kinase inhibitor treatment (Aurora B, Plk1), immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + kinase inhibitor epistasis, single lab, two orthogonal methods","pmids":["28817632"],"is_preprint":false},{"year":2017,"finding":"PHF14 directly binds to and co-localizes with KIF4A to form a functional complex during cell division. PHF14 silencing causes similar mitotic defects to KIF4A depletion (prolonged M phase, mitotic defects), and the two proteins have a synergistic effect on cell proliferation.","method":"Co-immunoprecipitation, immunofluorescence co-localization, RNAi knockdown, cell cycle analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + co-localization + parallel KD with same phenotype, single lab","pmids":["28160558"],"is_preprint":false},{"year":2017,"finding":"Prc1E (Xenopus egg ortholog of PRC1) and Kif4A are recruited to antiparallel bundles at microtubule interaction zones in Xenopus egg extracts. Prc1E is required for Kif4A recruitment (but not vice versa). Prc1E and Kif4A together slow and terminate microtubule plus-end growth preferentially at interaction zones, blocking interpenetration of asters. They are also required for radial order of large asters growing in isolation.","method":"Xenopus egg extract reconstitution, immunodepletion, TIRF/live microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in cell-free extract with immunodepletion and live imaging, multiple functional readouts","pmids":["29187577"],"is_preprint":false},{"year":2017,"finding":"KIF4A tail domain interacts with the N-terminal region of LRP (lung resistance-related protein). Both the ability to bind LRP and KIF4A motility are required for dispersed cytoplasmic distribution of LRP, suggesting KIF4A transports LRP-based vaults toward the cell membrane to confer drug resistance.","method":"Co-immunoprecipitation (domain mapping), immunofluorescence","journal":"Journal of Zhejiang University. Science. B","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain mapping + colocalization, single lab","pmids":["29204984"],"is_preprint":false},{"year":2018,"finding":"In vitro reconstitution shows that PRC1-Kif4A collectively slide antiparallel microtubules, accumulate at microtubule plus-ends ('end-tag'), and stall sliding when end-tags on antiparallel microtubules collide to form a stable overlap. Sliding velocity scales with initial microtubule overlap length, and final overlap width scales with microtubule lengths.","method":"In vitro microtubule sliding reconstitution, TIRF microscopy, quantitative analysis of end-tag formation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with quantitative mechanistic analysis of geometry-dependent regulation","pmids":["30353849"],"is_preprint":false},{"year":2018,"finding":"AMPK phosphorylates KIF4A directly at Ser801. AMPK and Aurora B competitively phosphoregulate KIF4A due to overlapping recognition motifs, resulting in regulation of KIF4A-dependent central spindle length control. AMPK α2 subunits are sequentially associated with mitotic apparatus throughout cell division.","method":"Quantitative phosphoproteomics, in vitro kinase assay, AMPK inhibitor/activation experiments, spindle length measurement","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay + phosphoproteomics + functional spindle length readout","pmids":["28992084"],"is_preprint":false},{"year":2018,"finding":"Cdk phosphorylation of human Kif4A at T1161 is required for chromosomal localization. Phosphorylated or Cdk phospho-mimetic Kif4A associates with chromosomes and condensin I (CAP-G and SMC2 subunits) to regulate chromosome condensation, spindle morphology, and chromosome congression. Non-phosphorylatable Kif4A (T1161A) cannot localize to chromosomes or associate with condensin I; targeting it to chromosomes via histone H1 fusion restores function.","method":"Phospho-mimetic and non-phosphorylatable mutant analysis, RNAi rescue experiments, co-immunoprecipitation, histone H1 fusion targeting","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — phospho-mimetic/non-phosphorylatable mutants + Co-IP + forced-localization rescue, rigorous mechanistic dissection","pmids":["29771379"],"is_preprint":false},{"year":2018,"finding":"KIF4A binds a Fe-S cluster in vitro through its conserved cysteine-rich domain. This Fe-S cluster coordination is required for KIF4A's mitosis-related localization. Downregulation of CIA targeting complex components (CIA2B/MMS19) impairs KIF4A Fe-S cluster acquisition, leading to mislocalization and mitotic defects phenocopying KIF4A knockout.","method":"In vitro Fe-S cluster binding assay, co-localization studies, CIA2B/MMS19 knockdown, KIF4A knockout","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro Fe-S cluster binding + in vivo domain requirement + genetic epistasis with CIA machinery","pmids":["29848660"],"is_preprint":false},{"year":2018,"finding":"Cdk1-dependent phosphorylation of KIF4A at S1186 is required for chromosome binding, chromosome scaffold formation, and interaction with condensin I complex. Non-phosphorylatable KIF4A (S1186A) localizes to the nucleus in interphase but fails to accumulate in the chromosome scaffold after nuclear envelope breakdown, leading to laterally decondensed chromosomes without condensin I and chromosome bridge formation during segregation.","method":"Phospho-mutant analysis, immunofluorescence, co-immunoprecipitation, Cdk1 inhibitor treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-mutant + Co-IP + kinase inhibitor, single lab","pmids":["30576375"],"is_preprint":false},{"year":2018,"finding":"Kif4 localizes to chromosomes in metaphase I and II mouse oocytes and redistributes to the spindle midzone during anaphase. Kif4 depletion results in defective midzone formation and longer spindles. Aurora B/C kinase inhibition causes Kif4 mislocalization and anaphase defects. Kif4 interacts with kinetochore proteins CENP-C and Ndc80 (confirmed by co-localization and proximity ligation assay). Aurora kinase and Cdk activity is required for Kif4 kinetochore localization and interaction with Ndc80 and CENP-C.","method":"Morpholino antisense knockdown, immunofluorescence, proximity ligation assay, kinase inhibitor treatment, spindle length measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with functional readout + PLA interaction assay + kinase inhibitor epistasis in oocytes, single lab","pmids":["28125646"],"is_preprint":false},{"year":2019,"finding":"Aurora A phosphorylates the condensin I-dependent pool of KIF4A at the chromosome axis during prometaphase to promote chromosome congression. KIF4A point mutants unable to interact with condensin I or PRC1, or deficient for Aurora kinase regulation, were used to show that Aurora A (not Aurora B) specifically regulates the condensin I-bound pool of KIF4A for congression, while Aurora B regulates the PRC1-dependent pool at the anaphase central spindle.","method":"KIF4A point mutants (condensin I-binding deficient, PRC1-binding deficient, Aurora kinase regulation-deficient), immunofluorescence, kinase assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple specific point mutants with defined phenotypic readouts, dissects two distinct KIF4A pools","pmids":["31881080"],"is_preprint":false},{"year":2019,"finding":"KIF4A binds androgen receptor (AR) and AR-V7, preventing CHIP-mediated AR and AR-V7 ubiquitin-dependent degradation. AR binds the KIF4A promoter and activates its transcription, forming an auto-regulatory positive feedback loop. KIF4A knockdown reverses enzalutamide resistance in castration-resistant prostate cancer cells.","method":"Co-immunoprecipitation, luciferase reporter assay, ChIP assay, western blot, xenograft models","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ChIP + reporter assay + functional rescue, single lab","pmids":["31796514"],"is_preprint":false},{"year":2019,"finding":"FOXM1c directly regulates KIF4A transcription; FOXM1-induced HCC cell proliferation is dependent on elevated KIF4A expression. KIF4A knockdown abolishes FOXM1-induced proliferation both in vitro and in vivo.","method":"ChIP assay, luciferase reporter assay, KIF4A knockdown, western blot, xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + luciferase + functional KD epistasis, single lab","pmids":["31072351"],"is_preprint":false},{"year":2020,"finding":"KIF4A is SUMOylated at lysine 460. CRISPR-Cas9-mediated block of SUMO conjugation at K460 delays cytokinesis. SUMOylation of KIF4A enhances its affinity for the microtubule destabilizer stathmin 1 (STMN1), and this KIF4A-STMN1 interaction regulates abscission.","method":"CRISPR-Cas9 genome editing (SUMO site mutation), SUMO site mapping, binding affinity assay (KIF4A-STMN1), cytokinesis timing assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous CRISPR modification + SUMO site mapping + functional cytokinesis readout + binding partner identification","pmids":["32591481"],"is_preprint":false},{"year":2021,"finding":"KIF4A/kinesin-4 together with EG5/kinesin-5 constitutes the force-generating mechanism for spindle elongation in human cells. Dual disruption of EG5 and KIF4A blocks spindle elongation and causes complete failure of chromosome segregation despite poleward chromosome motion. KIF4A's role requires PRC1 (is PRC1-dependent). Tubulin photoactivation, STED, and expansion microscopy show that perturbation of both proteins impairs midzone microtubule sliding without affecting microtubule stability.","method":"Combined depletion and inactivation assays, CRISPR, tubulin photoactivation, STED microscopy, expansion microscopy","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR + multiple depletion approaches + super-resolution microscopy establishing microtubule sliding mechanism, multiple orthogonal methods","pmids":["33910056"],"is_preprint":false},{"year":2022,"finding":"KIF4 mediates surface transport of NTCP (the HBV/HDV entry receptor). KIF4 knockdown reduces surface and raises intracellular NTCP levels. Overexpression of wild-type KIF4 but not an ATPase-null KIF4 mutant restores surface NTCP localization and HBV permissiveness. KIF4 and NTCP colocalize along microtubule filaments and co-immunoprecipitate.","method":"siRNA knockdown, ATPase-null mutant overexpression, cellular fractionation, immunofluorescence, co-immunoprecipitation, HBV/NLuc reporter infection assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — ATPase-null mutant rescue + Co-IP + fractionation + functional infection assay, multiple orthogonal approaches","pmids":["35312737"],"is_preprint":false},{"year":2022,"finding":"KIF4A interacts with TPX2 via co-immunoprecipitation and enhances TPX2 protein stability by inhibiting its ubiquitination. KIF4A knockdown induces DNA damage response, cell cycle arrest, and apoptosis in endometrial cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, KIF4A knockdown, western blot","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ubiquitination inhibition assay + KD phenotype, single lab","pmids":["36468837"],"is_preprint":false},{"year":2022,"finding":"KIF4A regulates DNA damage response (DDR) through both its motor domain and tail domain. KIF4A knockdown increases sensitivity of colorectal cancer cells to 5-FU and cisplatin by affecting DDR.","method":"Domain-specific mutant analysis (motor and tail domains), KIF4A overexpression/knockdown, DNA damage assays","journal":"Acta biochimica et biophysica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — domain deletion analysis with functional drug sensitivity readout, limited mechanistic detail in abstract, single lab","pmids":["35882623"],"is_preprint":false},{"year":2022,"finding":"KIF4A regulates seizure susceptibility through the PARP1-TrkB-KCC2 pathway. A point mutation (R728Q) in KIF4A, identified in epilepsy patients, strengthens KIF4A affinity for PARP1 by elongating the KIF4 coiled-coil domain, causing aberrant dendritic and spine morphology in hippocampal neurons. NAD supplementation (which activates PARP1) can modulate the TrkB-KCC2 pathway and rescue seizure susceptibility in KIF4-mutant mice.","method":"Patient mutation analysis, KIF4A R728Q knock-in mouse model, behavioral tests, co-immunoprecipitation (KIF4-PARP1 affinity), neuromorphological analysis, NAD rescue experiment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived mutation + knock-in mouse model + Co-IP affinity change + pathway rescue, multiple orthogonal approaches","pmids":["36482480"],"is_preprint":false},{"year":2024,"finding":"KIF4A binds directly to the human condensin I HAWK subunit NCAPG via a conserved disordered short linear motif (SLiM) in its C-terminal tail. KIF4A competes for NCAPG binding at an overlapping site with auto-inhibitory SLiMs from NCAPH (N-terminus) and NCAPD2 (C-terminus). The KIF4A SLiM peptide alone is sufficient to stimulate condensin I ATPase and DNA loop extrusion activities.","method":"In vitro binding assay (direct interaction), mutagenesis, competitive binding assay, in vitro ATPase assay, DNA loop extrusion assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted direct binding + SLiM competition assay + in vitro ATPase and loop extrusion activation, multiple Tier 1 methods in single study","pmids":["39690239"],"is_preprint":false},{"year":2024,"finding":"KIF4A is expressed in adult vertebrate nervous system (not only during development) and is upregulated in injured peripheral nervous system cells. KIF4A is detected in cell bodies and regrowing axons of injured neurons. Kif4a knockdown significantly reduces Schwann cell proliferation in vitro.","method":"Western blot and immunofluorescence of adult/injured tissue, shRNA knockdown, proliferation assay in Schwann cells","journal":"Neural regeneration research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined proliferation phenotype + injury expression analysis, single lab","pmids":["39665820"],"is_preprint":false}],"current_model":"KIF4A is a plus-end-directed kinesin-4 motor that functions in multiple cellular processes: during mitosis it localizes to chromosome arms (via condensin I, requiring CDK1 phosphorylation at T1161/S1186 and Fe-S cluster coordination), where Aurora A activates it to promote chromosome congression, while the PRC1-dependent pool at the anaphase central spindle (activated by Aurora B at T799 and opposed by PP2A-B56γ/ε dephosphorylation) drives midzone formation, microtubule sliding, and spindle elongation required for cytokinesis; KIF4A directly activates condensin I ATPase and DNA loop extrusion by binding NCAPG via a C-terminal SLiM that displaces auto-inhibitory interactions; in neurons, its C-terminal domain suppresses PARP-1 enzymatic activity (releasing PARP-1 upon CaMKII-mediated dissociation to promote survival), and it anterogradely transports L1, ribosomal proteins, and β1 integrin in axons via tail-domain cargo binding; additionally, KIF4A regulates NTCP surface transport via its ATPase activity (required for HBV/HDV entry), associates with BRCA2 to facilitate Rad51-dependent homologous recombination at DNA damage sites, and is SUMOylated at K460 to regulate abscission through enhanced stathmin-1 binding."},"narrative":{"mechanistic_narrative":"KIF4A is a plus-end-directed kinesin-4 motor with microtubule-activated ATPase activity built from an N-terminal motor domain, a central coiled-coil stalk, and a C-terminal cargo/tail domain, and it operates across mitotic chromosome architecture, central spindle dynamics, and neuronal transport [PMID:7929562]. During mitosis KIF4A partitions into two functionally distinct, kinase-gated pools: a condensin I-bound pool on chromosome arms and a PRC1-bound pool at the anaphase central spindle [PMID:31881080]. Chromosome-arm targeting requires Cdk1 phosphorylation at T1161 and S1186, coordination of an Fe-S cluster through its conserved cysteine-rich domain, and motor activity, and these are needed for KIF4A to form a stable, interdependent complex with condensin I that drives lateral compaction of chromatid arms [PMID:29771379, PMID:30576375, PMID:29848660, PMID:27633014, PMID:23166350]; mechanistically, a C-terminal short linear motif in KIF4A binds the condensin I HAWK subunit NCAPG, displacing auto-inhibitory SLiMs to directly stimulate condensin I ATPase and DNA loop-extrusion activity [PMID:39690239]. At the central spindle KIF4A is recruited by PRC1 and translocates it to antiparallel microtubule plus ends, where the PRC1-KIF4A module slides microtubules, forms self-limiting end-tags that set overlap geometry, and—together with EG5/kinesin-5—generates the force for spindle elongation and chromosome segregation [PMID:15297875, PMID:15625105, PMID:30353849, PMID:33910056]. This central-spindle pool is reciprocally phosphoregulated: Aurora B activates KIF4A at T799 while a PP2A-B56γ/ε negative-feedback loop opposes it, with AMPK competing at the overlapping S801 motif to tune central spindle length [PMID:25512391, PMID:28992084], and Aurora A independently activates the condensin I pool for chromosome congression [PMID:31881080]. KIF4A is also SUMOylated at K460, which enhances stathmin-1 binding and is required for timely abscission [PMID:32591481]. Beyond mitosis, the C-terminal domain suppresses PARP-1 enzymatic activity and is released upon CaMKII-mediated dissociation to support neuron survival, and a patient epilepsy mutation (R728Q) strengthening the KIF4A-PARP1 interaction perturbs the PARP1-TrkB-KCC2 pathway and seizure susceptibility [PMID:16630823, PMID:36482480]. As a transport motor its tail domain binds and anterogradely delivers cargoes including L1, ribosomal protein P0, and β1 integrin into axons, and its ATPase activity drives surface delivery of the NTCP receptor required for HBV/HDV entry [PMID:10747093, PMID:19158085, PMID:25260485, PMID:35312737]. KIF4A additionally associates with BRCA2 and is recruited to DNA damage sites to support Rad51-dependent homologous recombination [PMID:18604178].","teleology":[{"year":1994,"claim":"Established the foundational identity of KIF4 as a motor protein, defining its enzymatic and structural basis for force generation along microtubules.","evidence":"cDNA cloning, ATPase and motility assays, and electron microscopy of Sf9-expressed mouse protein","pmids":["7929562"],"confidence":"High","gaps":["Cargo and physiological substrates not yet defined","Mitotic role not addressed"]},{"year":2000,"claim":"Defined KIF4 as an anterograde axonal transport motor, linking its motility to delivery of a specific neuronal cargo required for axon growth.","evidence":"Subcellular fractionation, immunoisolation, and antisense knockdown with L1 cargo phenotype in neurons","pmids":["10747093"],"confidence":"Medium","gaps":["Direct tail-cargo binding interface not mapped here","Did not address mitotic functions"]},{"year":2004,"claim":"Revealed a central mitotic role by establishing the PRC1-KIF4A interaction as the determinant of central spindle and midzone organization.","evidence":"RNAi, Co-IP, live imaging, domain mapping, and motor-dead rescue in human cells","pmids":["15297875","15625105"],"confidence":"High","gaps":["Mechanism of microtubule sliding not yet reconstituted","Phosphoregulation of the PRC1 pool not yet defined"]},{"year":2004,"claim":"Identified the condensin I/II interaction and chromosome-arm localization, placing KIF4A in chromosome condensation and segregation.","evidence":"RNAi with chromosome morphology readouts and Co-IP with condensin complexes","pmids":["15326200"],"confidence":"High","gaps":["Did not resolve condensin I vs II specificity","Phospho-dependence of localization unknown at this stage"]},{"year":2006,"claim":"Uncovered a non-motor enzymatic-regulatory function, showing KIF4's C-terminus suppresses PARP-1 to control neuronal survival via calcium signaling.","evidence":"In vitro PARP-1 activity assay, Co-IP, live imaging, and CaMKII manipulation","pmids":["16630823"],"confidence":"High","gaps":["Structural basis of PARP-1 suppression not defined","Connection to downstream survival effectors limited"]},{"year":2008,"claim":"Connected KIF4A to genome maintenance through a BRCA2 association required for Rad51 recruitment and homologous recombination.","evidence":"Co-IP with domain mapping, laser micro-irradiation, I-SceI HR assay, and clonogenic survival","pmids":["18604178"],"confidence":"High","gaps":["Whether motor activity is required at damage sites unresolved","Mechanism of Rad51 IRIF support unclear"]},{"year":2009,"claim":"Extended the axonal cargo repertoire and mapped the tail domain interaction with the ribosomal protein P0, defining transport of translational machinery.","evidence":"Co-IP, domain deletion/mutation, RNAi, and immunofluorescence in DRG neurons","pmids":["19158085"],"confidence":"Medium","gaps":["Cargo selectivity mechanism not fully defined","Single-lab functional data"]},{"year":2012,"claim":"Defined KIF4 and condensin as a mutually dependent, parallel pathway for lateral chromatid compaction acting in opposition to topoisomerase IIa.","evidence":"Single and double RNAi epistasis, in vitro chromosome structure assay, and morphology analysis","pmids":["23166350"],"confidence":"High","gaps":["Direct biochemical activation of condensin not yet shown","Phospho- and metal-cofactor requirements not addressed here"]},{"year":2014,"claim":"Established phosphoregulatory control of the central spindle pool by defining a PP2A-B56-Aurora B negative feedback loop tuning KIF4A ATPase and spindle growth.","evidence":"In vitro phosphatase assays, RNAi epistasis, and phospho-specific antibodies with spindle length measurement","pmids":["25512391"],"confidence":"High","gaps":["Spatial restriction mechanism of the feedback loop partially defined","Did not address arm pool regulation"]},{"year":2016,"claim":"Resolved condensin I (not II) as the specific mitotic partner and showed motor-activity-dependent loading of condensin I onto chromosome axes.","evidence":"Co-IP, motor mutant analysis, and RNAi with chromosome readouts","pmids":["27633014","27108885"],"confidence":"High","gaps":["Molecular interface with condensin not yet mapped","Did not distinguish phospho-sites driving the interaction"]},{"year":2018,"claim":"Mapped the specific molecular determinants of chromosome-arm targeting: Cdk1 phosphorylation at T1161/S1186 and Fe-S cluster coordination via the cysteine-rich domain.","evidence":"Phospho-mimetic/non-phosphorylatable mutants, forced-localization rescue, Co-IP, and in vitro Fe-S binding with CIA machinery epistasis","pmids":["29771379","30576375","29848660"],"confidence":"High","gaps":["Role of the Fe-S cluster in catalysis vs structure not resolved","Integration of phosphorylation and metal cofactor signals unclear"]},{"year":2018,"claim":"Reconstituted the PRC1-KIF4A microtubule-sliding mechanism, revealing geometry-dependent end-tagging that self-limits antiparallel overlap size.","evidence":"In vitro microtubule sliding reconstitution with TIRF and quantitative end-tag analysis; Xenopus extract recruitment assays","pmids":["30353849","29187577"],"confidence":"High","gaps":["In vivo relevance of overlap scaling not quantified","Regulation of end-tagging by kinases not tested in vitro"]},{"year":2018,"claim":"Added a competing AMPK input at the S801 motif, integrating metabolic signaling into central spindle length control.","evidence":"In vitro kinase assay, phosphoproteomics, and AMPK perturbation with spindle measurement","pmids":["28992084"],"confidence":"High","gaps":["Physiological metabolic conditions activating this control not defined","Interplay with Aurora B/PP2A loop in vivo incomplete"]},{"year":2019,"claim":"Separated the two mitotic pools functionally, showing Aurora A activates the condensin I pool for congression while Aurora B governs the PRC1 central-spindle pool.","evidence":"Partner-binding-deficient and Aurora-regulation-deficient point mutants with phenotypic readouts","pmids":["31881080"],"confidence":"High","gaps":["Spatial segregation of Aurora A vs B inputs not fully resolved","Crosstalk between pools unclear"]},{"year":2020,"claim":"Identified SUMOylation at K460 as a post-translational switch coupling KIF4A to stathmin-1 to time abscission.","evidence":"CRISPR SUMO-site editing, SUMO mapping, binding affinity, and cytokinesis timing assays","pmids":["32591481"],"confidence":"High","gaps":["SUMO E3 ligase for K460 not identified","Mechanistic link between STMN1 and abscission machinery incomplete"]},{"year":2021,"claim":"Established KIF4A together with EG5 as the force-generating system for anaphase spindle elongation via midzone microtubule sliding.","evidence":"CRISPR, dual depletion, tubulin photoactivation, STED and expansion microscopy","pmids":["33910056"],"confidence":"High","gaps":["Quantitative force contributions of each motor not separated","Mechanism of EG5-KIF4A coordination unknown"]},{"year":2022,"claim":"Defined an interphase membrane-transport role, showing KIF4A ATPase activity drives surface delivery of the NTCP receptor exploited for HBV/HDV entry.","evidence":"siRNA, ATPase-null mutant rescue, fractionation, Co-IP, and HBV infection assay","pmids":["35312737"],"confidence":"High","gaps":["Direct NTCP-tail binding interface not mapped","Regulation of this transport not defined"]},{"year":2024,"claim":"Resolved the direct molecular mechanism of condensin activation, showing a KIF4A C-terminal SLiM binds NCAPG to displace auto-inhibition and stimulate condensin I ATPase and loop extrusion.","evidence":"Reconstituted direct binding, competitive binding, in vitro ATPase, and DNA loop extrusion assays","pmids":["39690239"],"confidence":"High","gaps":["How motor translocation couples to SLiM-driven activation in vivo unresolved","Structural model of the displaced auto-inhibitory state not provided"]},{"year":2022,"claim":"Linked KIF4A to a Mendelian-relevant neurological phenotype, with an epilepsy patient R728Q mutation strengthening KIF4-PARP1 binding and disrupting the PARP1-TrkB-KCC2 axis.","evidence":"Patient mutation, R728Q knock-in mouse, Co-IP affinity, neuromorphology, and NAD rescue","pmids":["36482480"],"confidence":"High","gaps":["Generalizability beyond this mutation unknown","Causal chain from PARP1 to seizure circuitry incomplete"]},{"year":null,"claim":"How KIF4A's motor translocation is mechanically coupled to its diverse regulatory outputs—condensin SLiM-driven activation, PARP-1 suppression, and selective cargo loading—remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying structural model links motor cycling to non-motor C-terminal activities","Switch logic integrating phosphorylation, SUMOylation, and Fe-S coordination not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,37]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,26,36]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,41]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[11,29]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6,28,30]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,5,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,17]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5,6,32,36]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13,20,41]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,12,17,37]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,16,40]}],"complexes":["condensin I (KIF4A-condensin I complex)","PRC1-KIF4A central spindle module"],"partners":["PRC1","NCAPG","BRCA2","PARP1","STMN1","EB1","TPX2","EG5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95239","full_name":"Chromosome-associated kinesin KIF4A","aliases":["Chromokinesin-A"],"length_aa":1232,"mass_kda":139.9,"function":"Iron-sulfur (Fe-S) cluster binding motor protein that has a role in chromosome segregation during mitosis (PubMed:29848660). Translocates PRC1 to the plus ends of interdigitating spindle microtubules during the metaphase to anaphase transition, an essential step for the formation of an organized central spindle midzone and midbody and for successful cytokinesis (PubMed:15297875, PubMed:15625105). May play a role in mitotic chromosomal positioning and bipolar spindle stabilization (By similarity)","subcellular_location":"Nucleus matrix; Cytoplasm; Cytoplasm, cytoskeleton, spindle; Midbody; Chromosome","url":"https://www.uniprot.org/uniprotkb/O95239/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/KIF4A","classification":"Common Essential","n_dependent_lines":798,"n_total_lines":1208,"dependency_fraction":0.6605960264900662},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000090889","cell_line_id":"CID001425","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"big_aggregates","grade":1}],"interactors":[{"gene":"TBC1D23","stoichiometry":10.0},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"NCAPH","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001425","total_profiled":1310},"omim":[{"mim_id":"621035","title":"PROLINE-RICH PROTEIN 14-LIKE PROTEIN; PRR14L","url":"https://www.omim.org/entry/621035"},{"mim_id":"616019","title":"REST COREPRESSOR 2; RCOR2","url":"https://www.omim.org/entry/616019"},{"mim_id":"615282","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 2; CDCBM2","url":"https://www.omim.org/entry/615282"},{"mim_id":"609184","title":"KINESIN FAMILY MEMBER 4B; KIF4B","url":"https://www.omim.org/entry/609184"},{"mim_id":"605664","title":"KINESIN FAMILY MEMBER 20A; KIF20A","url":"https://www.omim.org/entry/605664"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Midbody","reliability":"Approved"},{"location":"Acrosome","reliability":"Additional"},{"location":"Equatorial segment","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":10.6},{"tissue":"lymphoid tissue","ntpm":11.7}],"url":"https://www.proteinatlas.org/search/KIF4A"},"hgnc":{"alias_symbol":["KIF4-G1","KIF4","HSA271784","FLJ12530","FLJ12655","FLJ14204","FLJ20631","MRX100"],"prev_symbol":[]},"alphafold":{"accession":"O95239","domains":[{"cath_id":"3.40.850.10","chopping":"9-344","consensus_level":"high","plddt":86.9164,"start":9,"end":344},{"cath_id":"1.10.287","chopping":"518-688","consensus_level":"high","plddt":84.2829,"start":518,"end":688}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95239","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95239-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95239-F1-predicted_aligned_error_v6.png","plddt_mean":71.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIF4A","jax_strain_url":"https://www.jax.org/strain/search?query=KIF4A"},"sequence":{"accession":"O95239","fasta_url":"https://rest.uniprot.org/uniprotkb/O95239.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95239/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95239"}},"corpus_meta":[{"pmid":"15297875","id":"PMC_15297875","title":"Essential 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The protein has three domains: an NH2-terminal globular motor domain, a central alpha-helical stalk domain, and a COOH-terminal tail domain. It colocalizes with membranous organelles in growth cones and cytoplasm.\",\n      \"method\": \"cDNA cloning, biochemical characterization, ATPase assay, electron microscopy of Sf9-expressed protein, immunocytochemistry\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ATPase assay, motility assay, and structural characterization with multiple orthogonal methods in a single foundational study\",\n      \"pmids\": [\"7929562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"KIF4 (mouse ortholog) binds murine leukemia virus Gag polyproteins; the interaction maps to the C-terminal region of KIF4. KIF4-MuLV Gag associations were detected in vitro and in mammalian cells, suggesting KIF4 may mediate Gag transport.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation in mammalian cells\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirmed in cells with two orthogonal methods (Y2H + Co-IP), single lab\",\n      \"pmids\": [\"9658142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human KIF4 associates with HIV-1 Gag precursor (Pr55) and a matrix-capsid processing intermediate (Pr42) but not with other processed Gag products. KIF4 and HIV-1 Gag cofractionate by sucrose gradient, size-exclusion, and anion-exchange chromatography. Gag binding is mediated by a domain of KIF4 proximal to its C-terminus.\",\n      \"method\": \"Sucrose gradient fractionation, size-exclusion chromatography, anion-exchange chromatography, immunoprecipitation, yeast two-hybrid\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods, single lab, domain mapping performed\",\n      \"pmids\": [\"10559369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"KIF4 mediates anterograde transport of L1-containing vesicles in neurons. KIF4-associated vesicles are highly concentrated in growth cones, contain L1 (a cell adhesion molecule for axonal elongation), and lack synaptic vesicle markers. Antisense suppression of KIF4 causes accumulation of L1 in cell bodies, its disappearance from axonal tips, and prevents L1-enhanced axonal elongation.\",\n      \"method\": \"Subcellular fractionation, immunoisolation, antisense oligonucleotide knockdown, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation + immunoisolation + functional KD with defined cargo phenotype, single lab\",\n      \"pmids\": [\"10747093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KIF4 binds PRC1 (a microtubule-bundling protein) and is essential for central spindle organization and midzone formation during anaphase. In KIF4-deficient cells, the central spindle is disorganized and all midzone-associated proteins including PRC1 fail to concentrate at the midline. PRC1 is required for KIF4 localization to the spindle.\",\n      \"method\": \"RNAi knockdown, immunofluorescence, protein interaction assay (co-immunoprecipitation)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal KD epistasis with defined phenotypic readout, replicated in same study with multiple depletion conditions\",\n      \"pmids\": [\"15297875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Kif4 translocates PRC1 to the plus ends of interdigitating spindle microtubules during the metaphase-to-anaphase transition. Kif4 binds PRC1 through its 'stalk plus tail' domains. This translocation is required for midzone formation and cytokinesis; a motor-dead Kif4 mutant cannot rescue PRC1 translocation or cytokinesis defects. CDK phosphorylation of PRC1 controls the timing of PRC1 translocation by Kif4.\",\n      \"method\": \"Time-lapse microscopy, esiRNA knockdown, domain mapping, motor-dead mutant rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — motor-dead mutant rescue, domain mapping, live imaging, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"15625105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human KIF4A (HKIF4A) localizes to condensed chromosome arms during mitosis and accumulates in the midzone during late anaphase and the cytokinetic ring during cytokinesis. RNAi depletion causes defective prometaphase organization, chromosome mis-alignment, spindle defects, and chromosome mis-segregation. KIF4A interacts with condensin I and II complexes, and its depletion results in chromosome hypercondensation.\",\n      \"method\": \"RNAi knockdown, immunofluorescence, co-immunoprecipitation with condensin complexes\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi with multiple defined phenotypic readouts plus Co-IP binding partner identification, single rigorous study\",\n      \"pmids\": [\"15326200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KIF4 localizes to the midzone and midbody during ana/telophase and cytokinesis in dividing HeLa cells, forming a ring structure around microtubule bundles at the cytokinetic bridge.\",\n      \"method\": \"Immunofluorescence, 3D microscopy analysis\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method localization study without functional manipulation\",\n      \"pmids\": [\"15031677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The C-terminal domain of KIF4 suppresses PARP-1 enzymatic activity. Upon neuronal stimulation by membrane depolarization, CaMKII-mediated calcium signaling induces dissociation of KIF4 from PARP-1, resulting in upregulation of PARP-1 activity that supports neuron survival. After dissociation, KIF4 moves from the nucleus to the cytoplasm and toward distal neurites in a microtubule-dependent manner.\",\n      \"method\": \"In vitro PARP-1 activity assay, co-immunoprecipitation, live cell imaging, calcium signaling manipulation, CaMKII inhibitor experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay + co-IP + live imaging + pharmacological manipulation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"16630823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kif4A associates with BRCA2; the interaction is mediated by the Kif4A C-terminal cargo-binding domain and BRCA2 C-terminal conserved region. Upon nuclear laser micro-irradiation, Kif4A is rapidly recruited to sites of DNA damage. Kif4A depletion impairs Rad51 IRIF formation (but not γ-H2AX or NBS1 IRIF) and decreases homologous recombination efficiency, rendering cells hypersensitive to ionizing radiation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, laser micro-irradiation, shRNA knockdown, I-SceI endonuclease HR assay, clonogenic survival assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP with domain mapping, live DNA damage recruitment, HR assay, survival assay) in single study\",\n      \"pmids\": [\"18604178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Disrupting KIF4 function slows HIV-1 Gag trafficking through intermediates, inhibits virus-like particle production, and leads to increased Gag degradation. When KIF4 function is blocked, Gag accumulates in perinuclear clusters that colocalize with KIF4, Ubc9 (E2 SUMO-1 conjugating enzyme), and SUMO. Reintroduction of KIF4 rescues intracellular Gag levels.\",\n      \"method\": \"KIF4 knockdown, KIF4 reintroduction rescue, immunofluorescence colocalization, VLP production assay, western blot\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD + rescue with defined trafficking phenotype, colocalization, single lab\",\n      \"pmids\": [\"18684836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Two conserved chromatin-binding motifs in Kif4A are required for its mitotic function: the first leucine Zip motif (Zip1) within the ZBZ region, and a cysteine-rich (CR) motif in the C-terminal region. Kif4A mutants lacking either Zip1 or CR, or the K94A ATPase-dead mutant, cannot rescue RNAi-induced mitotic defects, indicating that both chromatin binding and ATPase activity are required for Kif4A mitotic function.\",\n      \"method\": \"Mutagenesis, RNAi rescue experiments, chromatin-binding assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional rescue readout, single lab\",\n      \"pmids\": [\"18502200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The C-terminal tail domain of KIF4 directly interacts with P0, a major ribosomal protein. KIF4 is required for anterograde transport of ribosomal constituents to axons; RNAi suppression of KIF4 or expression of tail-domain-deleted or ATP-binding-site-mutated KIF4 causes accumulation of P0 and ribosomal proteins in the cell body and their disappearance from axons. An ERM-like domain in KIF4's second coiled-coil region is required for clustering of ribosomal constituents and for anterograde transport of L1.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/mutation analysis, RNAi, immunofluorescence in DRG neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction mapping + functional KD + domain mutant analysis, single lab\",\n      \"pmids\": [\"19158085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KIF4 cooperates with condensin complexes in a parallel pathway to promote lateral compaction of chromatid arms. KIF4 and condensin are mutually dependent for their dynamic localization on chromatid axes. Depletion of either causes sister chromatids to expand. Simultaneous depletion of KIF4 and condensin causes complete loss of chromosome morphology. Topoisomerase IIα promotes axial shortening of chromatids, acting in opposition to KIF4 and condensins.\",\n      \"method\": \"RNAi (single and double depletion), morphological analysis, in vitro chromosome structure assay, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double depletion epistasis with in vitro structural assay and multiple orthogonal readouts, comprehensive mechanistic dissection\",\n      \"pmids\": [\"23166350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Kif4 interacts directly with the N-terminal domain of EB1 via its tail domain. Kif4 localizes to ends of stable microtubules and acts downstream of Rho-mDia-EB1 to induce selective microtubule stabilization in fibroblasts. Kif4 depletion blocks mDia- and EB1-induced stable MT formation and inhibits cell migration into wounded monolayers.\",\n      \"method\": \"Co-immunoprecipitation, direct binding studies (domain mapping), immunofluorescence, shRNA knockdown, wound healing assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding domain mapping + epistasis via depletion + functional migration readout, single lab\",\n      \"pmids\": [\"24658398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIF4A and PP2A-B56γ/ε form a spatially restricted negative feedback loop at the anaphase central spindle opposing Aurora B. PP2A-B56γ is maintained at the central spindle by KIF4A. PP2A-B56γ dephosphorylates the Aurora B phosphorylation site T799 on KIF4A, counteracting Aurora B- and microtubule-stimulated KIF4A ATPase activity. Combined silencing of PP2A-B56γ and -ε increases KIF4A T799 phosphorylation and decreases central spindle growth in anaphase B.\",\n      \"method\": \"Biochemical phosphatase assays, immunoprecipitation, RNAi (single and double depletion), phospho-specific antibodies, spindle length measurement\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphatase assay + RNAi epistasis + phospho-site analysis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"25512391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Knockdown of Kif4a in rat primary hippocampal neurons alters the balance between excitatory and inhibitory synaptic transmission, suggesting KIF4A regulates synaptic function.\",\n      \"method\": \"shRNA knockdown in primary rat hippocampal neurons, electrophysiological recordings of synaptic transmission\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional KD in neurons with electrophysiological readout, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"24812067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Kif4A co-localizes with β1 integrin in vesicles in neurons and non-neuronal cells, and the two molecules co-immunoprecipitate. Knockdown of KIF4A reduces β1 integrin levels in axons of developing neurons and reduces neurite elongation on laminin.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, shRNA knockdown, neurite elongation assay\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + KD with functional readout, single lab\",\n      \"pmids\": [\"25260485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIF4-dependent PRC1-1 (isoform 1 of PRC1) translocation to astral microtubule tips during prometaphase causes fatal sister chromatid alignment errors when Cdk1 activity is insufficient. Gene ablation of KIF4 or abrogation of KIF4 motor activity rescues Cdk1-inhibition-induced chromosome alignment defects.\",\n      \"method\": \"Large-scale RNAi screen, KIF4 gene ablation, motor-dead mutant, live cell imaging of chromosome alignment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via KO and motor-dead mutant with defined phenotypic rescue, single lab\",\n      \"pmids\": [\"26423135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIF4A is phosphorylated specifically during mitosis, dependent on Cdk1 and Aurora B activity. This phosphorylation is required for KIF4A to interact with condensin I.\",\n      \"method\": \"Mass spectrometry phosphoproteomics, phospho-specific antibody, kinase inhibitor treatments, co-immunoprecipitation\",\n      \"journal\": \"Biomedical research (Tokyo, Japan)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics + Co-IP with kinase inhibitor validation, single lab\",\n      \"pmids\": [\"27108885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIF4A associates specifically with condensin I (not condensin II) during mitosis. Condensin I enrichment on chromosomal axes depends on its association with KIF4A in a manner that requires KIF4A motor activity. This interaction is required for condensin I to confer physiological properties to chromosomes.\",\n      \"method\": \"Co-immunoprecipitation, mutational analysis, immunofluorescence, RNAi\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP + motor mutant analysis + RNAi with multiple orthogonal readouts, rigorous mechanistic dissection\",\n      \"pmids\": [\"27633014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GTSE1 depletion increases stable mitotic spindle microtubules, which leads to diminished Aurora B kinase recruitment to chromosome arms and consequently decreased Kif4A binding to chromosome arms.\",\n      \"method\": \"RNAi knockdown, immunofluorescence, microtubule stability assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via RNAi with defined pathway placement (GTSE1→MT stability→Aurora B→Kif4A), single lab\",\n      \"pmids\": [\"28821562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIF4A forms a stable complex with condensin I, and KIF4 and condensin I are interdependent for localization to the chromosome scaffold. Phosphorylation of KIF4 and condensin I by Aurora B promotes their chromosome targeting, whereas Plk1 activity promotes their dissociation from chromosomes.\",\n      \"method\": \"Co-immunoprecipitation, kinase inhibitor treatment (Aurora B, Plk1), immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + kinase inhibitor epistasis, single lab, two orthogonal methods\",\n      \"pmids\": [\"28817632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PHF14 directly binds to and co-localizes with KIF4A to form a functional complex during cell division. PHF14 silencing causes similar mitotic defects to KIF4A depletion (prolonged M phase, mitotic defects), and the two proteins have a synergistic effect on cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, RNAi knockdown, cell cycle analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + co-localization + parallel KD with same phenotype, single lab\",\n      \"pmids\": [\"28160558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Prc1E (Xenopus egg ortholog of PRC1) and Kif4A are recruited to antiparallel bundles at microtubule interaction zones in Xenopus egg extracts. Prc1E is required for Kif4A recruitment (but not vice versa). Prc1E and Kif4A together slow and terminate microtubule plus-end growth preferentially at interaction zones, blocking interpenetration of asters. They are also required for radial order of large asters growing in isolation.\",\n      \"method\": \"Xenopus egg extract reconstitution, immunodepletion, TIRF/live microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in cell-free extract with immunodepletion and live imaging, multiple functional readouts\",\n      \"pmids\": [\"29187577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIF4A tail domain interacts with the N-terminal region of LRP (lung resistance-related protein). Both the ability to bind LRP and KIF4A motility are required for dispersed cytoplasmic distribution of LRP, suggesting KIF4A transports LRP-based vaults toward the cell membrane to confer drug resistance.\",\n      \"method\": \"Co-immunoprecipitation (domain mapping), immunofluorescence\",\n      \"journal\": \"Journal of Zhejiang University. Science. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain mapping + colocalization, single lab\",\n      \"pmids\": [\"29204984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In vitro reconstitution shows that PRC1-Kif4A collectively slide antiparallel microtubules, accumulate at microtubule plus-ends ('end-tag'), and stall sliding when end-tags on antiparallel microtubules collide to form a stable overlap. Sliding velocity scales with initial microtubule overlap length, and final overlap width scales with microtubule lengths.\",\n      \"method\": \"In vitro microtubule sliding reconstitution, TIRF microscopy, quantitative analysis of end-tag formation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with quantitative mechanistic analysis of geometry-dependent regulation\",\n      \"pmids\": [\"30353849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AMPK phosphorylates KIF4A directly at Ser801. AMPK and Aurora B competitively phosphoregulate KIF4A due to overlapping recognition motifs, resulting in regulation of KIF4A-dependent central spindle length control. AMPK α2 subunits are sequentially associated with mitotic apparatus throughout cell division.\",\n      \"method\": \"Quantitative phosphoproteomics, in vitro kinase assay, AMPK inhibitor/activation experiments, spindle length measurement\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay + phosphoproteomics + functional spindle length readout\",\n      \"pmids\": [\"28992084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cdk phosphorylation of human Kif4A at T1161 is required for chromosomal localization. Phosphorylated or Cdk phospho-mimetic Kif4A associates with chromosomes and condensin I (CAP-G and SMC2 subunits) to regulate chromosome condensation, spindle morphology, and chromosome congression. Non-phosphorylatable Kif4A (T1161A) cannot localize to chromosomes or associate with condensin I; targeting it to chromosomes via histone H1 fusion restores function.\",\n      \"method\": \"Phospho-mimetic and non-phosphorylatable mutant analysis, RNAi rescue experiments, co-immunoprecipitation, histone H1 fusion targeting\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phospho-mimetic/non-phosphorylatable mutants + Co-IP + forced-localization rescue, rigorous mechanistic dissection\",\n      \"pmids\": [\"29771379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIF4A binds a Fe-S cluster in vitro through its conserved cysteine-rich domain. This Fe-S cluster coordination is required for KIF4A's mitosis-related localization. Downregulation of CIA targeting complex components (CIA2B/MMS19) impairs KIF4A Fe-S cluster acquisition, leading to mislocalization and mitotic defects phenocopying KIF4A knockout.\",\n      \"method\": \"In vitro Fe-S cluster binding assay, co-localization studies, CIA2B/MMS19 knockdown, KIF4A knockout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro Fe-S cluster binding + in vivo domain requirement + genetic epistasis with CIA machinery\",\n      \"pmids\": [\"29848660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cdk1-dependent phosphorylation of KIF4A at S1186 is required for chromosome binding, chromosome scaffold formation, and interaction with condensin I complex. Non-phosphorylatable KIF4A (S1186A) localizes to the nucleus in interphase but fails to accumulate in the chromosome scaffold after nuclear envelope breakdown, leading to laterally decondensed chromosomes without condensin I and chromosome bridge formation during segregation.\",\n      \"method\": \"Phospho-mutant analysis, immunofluorescence, co-immunoprecipitation, Cdk1 inhibitor treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-mutant + Co-IP + kinase inhibitor, single lab\",\n      \"pmids\": [\"30576375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Kif4 localizes to chromosomes in metaphase I and II mouse oocytes and redistributes to the spindle midzone during anaphase. Kif4 depletion results in defective midzone formation and longer spindles. Aurora B/C kinase inhibition causes Kif4 mislocalization and anaphase defects. Kif4 interacts with kinetochore proteins CENP-C and Ndc80 (confirmed by co-localization and proximity ligation assay). Aurora kinase and Cdk activity is required for Kif4 kinetochore localization and interaction with Ndc80 and CENP-C.\",\n      \"method\": \"Morpholino antisense knockdown, immunofluorescence, proximity ligation assay, kinase inhibitor treatment, spindle length measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with functional readout + PLA interaction assay + kinase inhibitor epistasis in oocytes, single lab\",\n      \"pmids\": [\"28125646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Aurora A phosphorylates the condensin I-dependent pool of KIF4A at the chromosome axis during prometaphase to promote chromosome congression. KIF4A point mutants unable to interact with condensin I or PRC1, or deficient for Aurora kinase regulation, were used to show that Aurora A (not Aurora B) specifically regulates the condensin I-bound pool of KIF4A for congression, while Aurora B regulates the PRC1-dependent pool at the anaphase central spindle.\",\n      \"method\": \"KIF4A point mutants (condensin I-binding deficient, PRC1-binding deficient, Aurora kinase regulation-deficient), immunofluorescence, kinase assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple specific point mutants with defined phenotypic readouts, dissects two distinct KIF4A pools\",\n      \"pmids\": [\"31881080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIF4A binds androgen receptor (AR) and AR-V7, preventing CHIP-mediated AR and AR-V7 ubiquitin-dependent degradation. AR binds the KIF4A promoter and activates its transcription, forming an auto-regulatory positive feedback loop. KIF4A knockdown reverses enzalutamide resistance in castration-resistant prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, ChIP assay, western blot, xenograft models\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ChIP + reporter assay + functional rescue, single lab\",\n      \"pmids\": [\"31796514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXM1c directly regulates KIF4A transcription; FOXM1-induced HCC cell proliferation is dependent on elevated KIF4A expression. KIF4A knockdown abolishes FOXM1-induced proliferation both in vitro and in vivo.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, KIF4A knockdown, western blot, xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + luciferase + functional KD epistasis, single lab\",\n      \"pmids\": [\"31072351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KIF4A is SUMOylated at lysine 460. CRISPR-Cas9-mediated block of SUMO conjugation at K460 delays cytokinesis. SUMOylation of KIF4A enhances its affinity for the microtubule destabilizer stathmin 1 (STMN1), and this KIF4A-STMN1 interaction regulates abscission.\",\n      \"method\": \"CRISPR-Cas9 genome editing (SUMO site mutation), SUMO site mapping, binding affinity assay (KIF4A-STMN1), cytokinesis timing assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous CRISPR modification + SUMO site mapping + functional cytokinesis readout + binding partner identification\",\n      \"pmids\": [\"32591481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIF4A/kinesin-4 together with EG5/kinesin-5 constitutes the force-generating mechanism for spindle elongation in human cells. Dual disruption of EG5 and KIF4A blocks spindle elongation and causes complete failure of chromosome segregation despite poleward chromosome motion. KIF4A's role requires PRC1 (is PRC1-dependent). Tubulin photoactivation, STED, and expansion microscopy show that perturbation of both proteins impairs midzone microtubule sliding without affecting microtubule stability.\",\n      \"method\": \"Combined depletion and inactivation assays, CRISPR, tubulin photoactivation, STED microscopy, expansion microscopy\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR + multiple depletion approaches + super-resolution microscopy establishing microtubule sliding mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"33910056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIF4 mediates surface transport of NTCP (the HBV/HDV entry receptor). KIF4 knockdown reduces surface and raises intracellular NTCP levels. Overexpression of wild-type KIF4 but not an ATPase-null KIF4 mutant restores surface NTCP localization and HBV permissiveness. KIF4 and NTCP colocalize along microtubule filaments and co-immunoprecipitate.\",\n      \"method\": \"siRNA knockdown, ATPase-null mutant overexpression, cellular fractionation, immunofluorescence, co-immunoprecipitation, HBV/NLuc reporter infection assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ATPase-null mutant rescue + Co-IP + fractionation + functional infection assay, multiple orthogonal approaches\",\n      \"pmids\": [\"35312737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIF4A interacts with TPX2 via co-immunoprecipitation and enhances TPX2 protein stability by inhibiting its ubiquitination. KIF4A knockdown induces DNA damage response, cell cycle arrest, and apoptosis in endometrial cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, KIF4A knockdown, western blot\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ubiquitination inhibition assay + KD phenotype, single lab\",\n      \"pmids\": [\"36468837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIF4A regulates DNA damage response (DDR) through both its motor domain and tail domain. KIF4A knockdown increases sensitivity of colorectal cancer cells to 5-FU and cisplatin by affecting DDR.\",\n      \"method\": \"Domain-specific mutant analysis (motor and tail domains), KIF4A overexpression/knockdown, DNA damage assays\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — domain deletion analysis with functional drug sensitivity readout, limited mechanistic detail in abstract, single lab\",\n      \"pmids\": [\"35882623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIF4A regulates seizure susceptibility through the PARP1-TrkB-KCC2 pathway. A point mutation (R728Q) in KIF4A, identified in epilepsy patients, strengthens KIF4A affinity for PARP1 by elongating the KIF4 coiled-coil domain, causing aberrant dendritic and spine morphology in hippocampal neurons. NAD supplementation (which activates PARP1) can modulate the TrkB-KCC2 pathway and rescue seizure susceptibility in KIF4-mutant mice.\",\n      \"method\": \"Patient mutation analysis, KIF4A R728Q knock-in mouse model, behavioral tests, co-immunoprecipitation (KIF4-PARP1 affinity), neuromorphological analysis, NAD rescue experiment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived mutation + knock-in mouse model + Co-IP affinity change + pathway rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"36482480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF4A binds directly to the human condensin I HAWK subunit NCAPG via a conserved disordered short linear motif (SLiM) in its C-terminal tail. KIF4A competes for NCAPG binding at an overlapping site with auto-inhibitory SLiMs from NCAPH (N-terminus) and NCAPD2 (C-terminus). The KIF4A SLiM peptide alone is sufficient to stimulate condensin I ATPase and DNA loop extrusion activities.\",\n      \"method\": \"In vitro binding assay (direct interaction), mutagenesis, competitive binding assay, in vitro ATPase assay, DNA loop extrusion assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted direct binding + SLiM competition assay + in vitro ATPase and loop extrusion activation, multiple Tier 1 methods in single study\",\n      \"pmids\": [\"39690239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF4A is expressed in adult vertebrate nervous system (not only during development) and is upregulated in injured peripheral nervous system cells. KIF4A is detected in cell bodies and regrowing axons of injured neurons. Kif4a knockdown significantly reduces Schwann cell proliferation in vitro.\",\n      \"method\": \"Western blot and immunofluorescence of adult/injured tissue, shRNA knockdown, proliferation assay in Schwann cells\",\n      \"journal\": \"Neural regeneration research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined proliferation phenotype + injury expression analysis, single lab\",\n      \"pmids\": [\"39665820\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIF4A is a plus-end-directed kinesin-4 motor that functions in multiple cellular processes: during mitosis it localizes to chromosome arms (via condensin I, requiring CDK1 phosphorylation at T1161/S1186 and Fe-S cluster coordination), where Aurora A activates it to promote chromosome congression, while the PRC1-dependent pool at the anaphase central spindle (activated by Aurora B at T799 and opposed by PP2A-B56γ/ε dephosphorylation) drives midzone formation, microtubule sliding, and spindle elongation required for cytokinesis; KIF4A directly activates condensin I ATPase and DNA loop extrusion by binding NCAPG via a C-terminal SLiM that displaces auto-inhibitory interactions; in neurons, its C-terminal domain suppresses PARP-1 enzymatic activity (releasing PARP-1 upon CaMKII-mediated dissociation to promote survival), and it anterogradely transports L1, ribosomal proteins, and β1 integrin in axons via tail-domain cargo binding; additionally, KIF4A regulates NTCP surface transport via its ATPase activity (required for HBV/HDV entry), associates with BRCA2 to facilitate Rad51-dependent homologous recombination at DNA damage sites, and is SUMOylated at K460 to regulate abscission through enhanced stathmin-1 binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF4A is a plus-end-directed kinesin-4 motor with microtubule-activated ATPase activity built from an N-terminal motor domain, a central coiled-coil stalk, and a C-terminal cargo/tail domain, and it operates across mitotic chromosome architecture, central spindle dynamics, and neuronal transport [#0]. During mitosis KIF4A partitions into two functionally distinct, kinase-gated pools: a condensin I-bound pool on chromosome arms and a PRC1-bound pool at the anaphase central spindle [#32]. Chromosome-arm targeting requires Cdk1 phosphorylation at T1161 and S1186, coordination of an Fe-S cluster through its conserved cysteine-rich domain, and motor activity, and these are needed for KIF4A to form a stable, interdependent complex with condensin I that drives lateral compaction of chromatid arms [#28, #30, #29, #20, #13]; mechanistically, a C-terminal short linear motif in KIF4A binds the condensin I HAWK subunit NCAPG, displacing auto-inhibitory SLiMs to directly stimulate condensin I ATPase and DNA loop-extrusion activity [#41]. At the central spindle KIF4A is recruited by PRC1 and translocates it to antiparallel microtubule plus ends, where the PRC1-KIF4A module slides microtubules, forms self-limiting end-tags that set overlap geometry, and—together with EG5/kinesin-5—generates the force for spindle elongation and chromosome segregation [#4, #5, #26, #36]. This central-spindle pool is reciprocally phosphoregulated: Aurora B activates KIF4A at T799 while a PP2A-B56\\u03b3/\\u03b5 negative-feedback loop opposes it, with AMPK competing at the overlapping S801 motif to tune central spindle length [#15, #27], and Aurora A independently activates the condensin I pool for chromosome congression [#32]. KIF4A is also SUMOylated at K460, which enhances stathmin-1 binding and is required for timely abscission [#35]. Beyond mitosis, the C-terminal domain suppresses PARP-1 enzymatic activity and is released upon CaMKII-mediated dissociation to support neuron survival, and a patient epilepsy mutation (R728Q) strengthening the KIF4A-PARP1 interaction perturbs the PARP1-TrkB-KCC2 pathway and seizure susceptibility [#8, #40]. As a transport motor its tail domain binds and anterogradely delivers cargoes including L1, ribosomal protein P0, and \\u03b21 integrin into axons, and its ATPase activity drives surface delivery of the NTCP receptor required for HBV/HDV entry [#3, #12, #17, #37]. KIF4A additionally associates with BRCA2 and is recruited to DNA damage sites to support Rad51-dependent homologous recombination [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the foundational identity of KIF4 as a motor protein, defining its enzymatic and structural basis for force generation along microtubules.\",\n      \"evidence\": \"cDNA cloning, ATPase and motility assays, and electron microscopy of Sf9-expressed mouse protein\",\n      \"pmids\": [\"7929562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo and physiological substrates not yet defined\", \"Mitotic role not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined KIF4 as an anterograde axonal transport motor, linking its motility to delivery of a specific neuronal cargo required for axon growth.\",\n      \"evidence\": \"Subcellular fractionation, immunoisolation, and antisense knockdown with L1 cargo phenotype in neurons\",\n      \"pmids\": [\"10747093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct tail-cargo binding interface not mapped here\", \"Did not address mitotic functions\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed a central mitotic role by establishing the PRC1-KIF4A interaction as the determinant of central spindle and midzone organization.\",\n      \"evidence\": \"RNAi, Co-IP, live imaging, domain mapping, and motor-dead rescue in human cells\",\n      \"pmids\": [\"15297875\", \"15625105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of microtubule sliding not yet reconstituted\", \"Phosphoregulation of the PRC1 pool not yet defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the condensin I/II interaction and chromosome-arm localization, placing KIF4A in chromosome condensation and segregation.\",\n      \"evidence\": \"RNAi with chromosome morphology readouts and Co-IP with condensin complexes\",\n      \"pmids\": [\"15326200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve condensin I vs II specificity\", \"Phospho-dependence of localization unknown at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Uncovered a non-motor enzymatic-regulatory function, showing KIF4's C-terminus suppresses PARP-1 to control neuronal survival via calcium signaling.\",\n      \"evidence\": \"In vitro PARP-1 activity assay, Co-IP, live imaging, and CaMKII manipulation\",\n      \"pmids\": [\"16630823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PARP-1 suppression not defined\", \"Connection to downstream survival effectors limited\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected KIF4A to genome maintenance through a BRCA2 association required for Rad51 recruitment and homologous recombination.\",\n      \"evidence\": \"Co-IP with domain mapping, laser micro-irradiation, I-SceI HR assay, and clonogenic survival\",\n      \"pmids\": [\"18604178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether motor activity is required at damage sites unresolved\", \"Mechanism of Rad51 IRIF support unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the axonal cargo repertoire and mapped the tail domain interaction with the ribosomal protein P0, defining transport of translational machinery.\",\n      \"evidence\": \"Co-IP, domain deletion/mutation, RNAi, and immunofluorescence in DRG neurons\",\n      \"pmids\": [\"19158085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo selectivity mechanism not fully defined\", \"Single-lab functional data\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined KIF4 and condensin as a mutually dependent, parallel pathway for lateral chromatid compaction acting in opposition to topoisomerase IIa.\",\n      \"evidence\": \"Single and double RNAi epistasis, in vitro chromosome structure assay, and morphology analysis\",\n      \"pmids\": [\"23166350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical activation of condensin not yet shown\", \"Phospho- and metal-cofactor requirements not addressed here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established phosphoregulatory control of the central spindle pool by defining a PP2A-B56-Aurora B negative feedback loop tuning KIF4A ATPase and spindle growth.\",\n      \"evidence\": \"In vitro phosphatase assays, RNAi epistasis, and phospho-specific antibodies with spindle length measurement\",\n      \"pmids\": [\"25512391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial restriction mechanism of the feedback loop partially defined\", \"Did not address arm pool regulation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved condensin I (not II) as the specific mitotic partner and showed motor-activity-dependent loading of condensin I onto chromosome axes.\",\n      \"evidence\": \"Co-IP, motor mutant analysis, and RNAi with chromosome readouts\",\n      \"pmids\": [\"27633014\", \"27108885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interface with condensin not yet mapped\", \"Did not distinguish phospho-sites driving the interaction\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped the specific molecular determinants of chromosome-arm targeting: Cdk1 phosphorylation at T1161/S1186 and Fe-S cluster coordination via the cysteine-rich domain.\",\n      \"evidence\": \"Phospho-mimetic/non-phosphorylatable mutants, forced-localization rescue, Co-IP, and in vitro Fe-S binding with CIA machinery epistasis\",\n      \"pmids\": [\"29771379\", \"30576375\", \"29848660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of the Fe-S cluster in catalysis vs structure not resolved\", \"Integration of phosphorylation and metal cofactor signals unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reconstituted the PRC1-KIF4A microtubule-sliding mechanism, revealing geometry-dependent end-tagging that self-limits antiparallel overlap size.\",\n      \"evidence\": \"In vitro microtubule sliding reconstitution with TIRF and quantitative end-tag analysis; Xenopus extract recruitment assays\",\n      \"pmids\": [\"30353849\", \"29187577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of overlap scaling not quantified\", \"Regulation of end-tagging by kinases not tested in vitro\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Added a competing AMPK input at the S801 motif, integrating metabolic signaling into central spindle length control.\",\n      \"evidence\": \"In vitro kinase assay, phosphoproteomics, and AMPK perturbation with spindle measurement\",\n      \"pmids\": [\"28992084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological metabolic conditions activating this control not defined\", \"Interplay with Aurora B/PP2A loop in vivo incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Separated the two mitotic pools functionally, showing Aurora A activates the condensin I pool for congression while Aurora B governs the PRC1 central-spindle pool.\",\n      \"evidence\": \"Partner-binding-deficient and Aurora-regulation-deficient point mutants with phenotypic readouts\",\n      \"pmids\": [\"31881080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial segregation of Aurora A vs B inputs not fully resolved\", \"Crosstalk between pools unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified SUMOylation at K460 as a post-translational switch coupling KIF4A to stathmin-1 to time abscission.\",\n      \"evidence\": \"CRISPR SUMO-site editing, SUMO mapping, binding affinity, and cytokinesis timing assays\",\n      \"pmids\": [\"32591481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase for K460 not identified\", \"Mechanistic link between STMN1 and abscission machinery incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established KIF4A together with EG5 as the force-generating system for anaphase spindle elongation via midzone microtubule sliding.\",\n      \"evidence\": \"CRISPR, dual depletion, tubulin photoactivation, STED and expansion microscopy\",\n      \"pmids\": [\"33910056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative force contributions of each motor not separated\", \"Mechanism of EG5-KIF4A coordination unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an interphase membrane-transport role, showing KIF4A ATPase activity drives surface delivery of the NTCP receptor exploited for HBV/HDV entry.\",\n      \"evidence\": \"siRNA, ATPase-null mutant rescue, fractionation, Co-IP, and HBV infection assay\",\n      \"pmids\": [\"35312737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NTCP-tail binding interface not mapped\", \"Regulation of this transport not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the direct molecular mechanism of condensin activation, showing a KIF4A C-terminal SLiM binds NCAPG to displace auto-inhibition and stimulate condensin I ATPase and loop extrusion.\",\n      \"evidence\": \"Reconstituted direct binding, competitive binding, in vitro ATPase, and DNA loop extrusion assays\",\n      \"pmids\": [\"39690239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How motor translocation couples to SLiM-driven activation in vivo unresolved\", \"Structural model of the displaced auto-inhibitory state not provided\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked KIF4A to a Mendelian-relevant neurological phenotype, with an epilepsy patient R728Q mutation strengthening KIF4-PARP1 binding and disrupting the PARP1-TrkB-KCC2 axis.\",\n      \"evidence\": \"Patient mutation, R728Q knock-in mouse, Co-IP affinity, neuromorphology, and NAD rescue\",\n      \"pmids\": [\"36482480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability beyond this mutation unknown\", \"Causal chain from PARP1 to seizure circuitry incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KIF4A's motor translocation is mechanically coupled to its diverse regulatory outputs—condensin SLiM-driven activation, PARP-1 suppression, and selective cargo loading—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying structural model links motor cycling to non-motor C-terminal activities\", \"Switch logic integrating phosphorylation, SUMOylation, and Fe-S coordination not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 37]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 26, 36]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 41]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [11, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6, 28, 30]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 5, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5, 6, 32, 36]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13, 20, 41]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 12, 17, 37]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 16, 40]}\n    ],\n    \"complexes\": [\n      \"condensin I (KIF4A-condensin I complex)\",\n      \"PRC1-KIF4A central spindle module\"\n    ],\n    \"partners\": [\n      \"PRC1\",\n      \"NCAPG\",\n      \"BRCA2\",\n      \"PARP1\",\n      \"STMN1\",\n      \"EB1\",\n      \"TPX2\",\n      \"EG5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}