{"gene":"KIFC1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"HSET (KIFC1) localizes between microtubules within the mammalian metaphase spindle (immuno-EM), consistent with a microtubule cross-linking function. Microinjection of inhibitory antibodies showed HSET activity is essential for meiotic spindle organization in murine oocytes and taxol-induced aster assembly in cultured cells. In vitro, simultaneous inhibition of HSET and Eg5 restores aster organization, demonstrating that HSET and Eg5 exert opposing forces during spindle assembly. HSET inhibition alone did not affect mitotic spindle architecture in centrosome-containing cultured cells.","method":"Immuno-EM, antibody microinjection, in vitro aster assembly assay, simultaneous inhibition of HSET and Eg5","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (immuno-EM, microinjection, in vitro reconstitution), replicated across meiotic and mitotic contexts in same study","pmids":["10525540"],"is_preprint":false},{"year":2001,"finding":"Native HSET purified from mitotic HeLa cells migrates as a ~75 kDa protein and is an active minus-end-directed motor that induces microtubule gliding at ~5 µm/min, with microtubules gliding an average of 3 µm before ceasing movement.","method":"Native protein purification from mitotic HeLa cells, in vitro microtubule gliding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical reconstitution (purification + in vitro motility assay), single lab but rigorous enzymatic characterization","pmids":["11382767"],"is_preprint":false},{"year":2003,"finding":"KIFC1 associates with importin beta and co-localizes with it on curvilinear structures associated with spermatid nuclei; KIFC1 localizes sequentially to membrane-bounded organelles, then the acrosomal vesicle, and finally the elongating acrosome during spermatogenesis, suggesting a role in acrosome formation and/or elongation via nuclear transport factor interactions.","method":"Co-immunoprecipitation (KIFC1 with importin beta), immunofluorescence localization in rat spermatids","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus immunofluorescence localization in two orthogonal methods, single lab","pmids":["12826589"],"is_preprint":false},{"year":2004,"finding":"The divergent tail domains of KIFC1 and KIFC5A determine their distinct subcellular localizations: a 19 amino acid sequence in the KIFC1 tail is sufficient to target KIFC1 to membrane-bounded organelles, whereas the KIFC5A tail contains a 43 amino acid sequence directing it to the spindle.","method":"GFP-fusion constructs with tail deletions transfected into cells; fluorescence microscopy to map localization determinants","journal":"Cell motility and the cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion mutagenesis with functional localization readout, single lab, two orthogonal approaches (GFP fusions + specific antisera)","pmids":["15236353"],"is_preprint":false},{"year":2007,"finding":"Kifc1 and Kif5B mediate minus-end and plus-end motility, respectively, of early endocytic vesicles in mouse liver. More than 90% of Kifc1-associated vesicles also contained Kif5B. Inhibition of either motor reduced vesicle fission, indicating that opposing forces from both motors are required for fission. FLAG-Kifc1 immunoprecipitated native Kif5B from 293T cells, showing the two motors can interact.","method":"In vitro vesicle motility on microtubules, antibody inhibition, co-immunoprecipitation (FLAG-Kifc1 pulldown of Kif5B)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstituted motility assay, antibody inhibition, Co-IP; multiple orthogonal methods in single lab","pmids":["17360972"],"is_preprint":false},{"year":2008,"finding":"Mutation of the nuclear localization signal (NLS) of HSET causes cytoplasmic accumulation and strong microtubule bundling. HSET overexpression in HeLa cells results in longer spindles, while RNAi knockdown results in shorter spindles without affecting pole formation. An HSET mutant with sliding activity uncoupled from ATPase activity produced shorter spindles than wild-type HSET overexpression, demonstrating that microtubule sliding (not just cross-linking) controls spindle length. Ran/importin alpha/beta regulate HSET by sequestering it in the nucleus during interphase.","method":"NLS mutagenesis, RNAi knockdown, ATPase-uncoupled motor mutant overexpression, spindle length measurement in HeLa cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal genetic approaches (NLS mutant, RNAi, ATPase-decoupled mutant) with quantitative spindle phenotype readouts, rigorous mechanistic dissection","pmids":["19116309"],"is_preprint":false},{"year":2013,"finding":"KIFC1 actively transports bare double-stranded DNA along microtubules. Mass spectrometry of DNA-bound proteins identified KIFC1 as a preferential binder of short DNA molecules. Cell-extract depletion of KIFC1 significantly decreased intracellular DNA motion, confirming active involvement of KIFC1 in intracellular DNA transport.","method":"Single-molecule in-cell imaging, in vitro motility assay with cell extracts, mass spectrometry of DNA-bound proteins, extract immunodepletion","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MS identification, extract depletion, in vitro motility), single lab","pmids":["23543461"],"is_preprint":false},{"year":2013,"finding":"AZ82, the first reported small molecule inhibitor of KIFC1, binds specifically to the KIFC1/microtubule binary complex and inhibits MT-stimulated KIFC1 ATPase activity in an ATP-competitive, MT-noncompetitive manner (Ki = 0.043 µM). AZ82 engages with KIFC1 inside cells to reverse monopolar spindles induced by Eg5 inhibition, and causes centrosome declustering in BT-549 breast cancer cells with amplified centrosomes.","method":"Biochemical ATPase assay, kinetic inhibition mode analysis, cell-based spindle assay, centrosome declustering assay","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic characterization with kinetic mode analysis plus cell-based validation; rigorous mechanistic inhibitor study","pmids":["23895133"],"is_preprint":false},{"year":2013,"finding":"CW069, an allosteric inhibitor of HSET, inhibits HSET ATPase activity in vitro and induces multipolar mitoses selectively in cancer cells containing supernumerary centrosomes, but not in normal cells with two centrosomes, establishing HSET as the mechanistic driver of centrosome clustering in those cancer cells.","method":"In vitro HSET ATPase inhibition assay, cell-based multipolar mitosis phenotype scoring, in silico compound design followed by biochemical validation","journal":"Chemistry & biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assay plus cell biology with matched controls, selective cancer-cell phenotype; rigorous tool compound characterization","pmids":["24210220"],"is_preprint":false},{"year":2013,"finding":"KIFC1 knockdown in normal diploid human primary fibroblasts (IMR-90) induces multiple MTOCs, lagging chromosomes, micronuclei, and aneuploidy, ultimately leading to cellular senescence. Double knockdown of KIFC1 and Mad2 causes apoptosis rather than senescence, placing KIFC1 in a pathway distinct from the spindle assembly checkpoint (Mad2 pathway) for bipolar MTOC formation.","method":"Lentiviral shRNA knockdown, karyotyping, senescence-associated beta-galactosidase staining, double knockdown epistasis with Mad2","journal":"Cell structure and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (KIFC1 + Mad2 double KD) plus karyotyping and senescence assays; single lab, multiple readouts","pmids":["23318213"],"is_preprint":false},{"year":2016,"finding":"A CEP215-HSET complex physically links centrosomes with spindle poles. HSET was identified as a direct binding partner of CEP215 by proteomic profiling. Targeted deletion of the HSET-binding domain of CEP215 causes centrosome detachment and HSET depletion at centrosomes. In cancer cells with centrosome amplification, the CEP215-HSET complex promotes clustering of extra centrosomes into pseudo-bipolar spindles.","method":"Proteomic profiling (MS-based interaction screen), targeted domain deletion in vertebrate cells, immunofluorescence of centrosome phenotypes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic identification plus domain-deletion functional validation, replicated in patient-derived cells; multiple orthogonal approaches","pmids":["26987684"],"is_preprint":false},{"year":2016,"finding":"SR31527, a small molecule inhibitor, binds directly to KIFC1 (Kd = 25.4 nM by bio-layer interferometry) and inhibits MT-stimulated KIFC1 ATPase activity (IC50 = 6.6 µM). STD-NMR and computational modeling indicate SR31527 binds to an allosteric site on KIFC1 distinct from the ATP-binding site. SR31527 prevents centrosome clustering in triple-negative breast cancer cells.","method":"Bio-layer interferometry (direct binding), ATPase inhibition assay, STD-NMR, computational docking, centrosome clustering cell assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding assay, enzymatic assay, and NMR structural evidence in single rigorous study; multiple orthogonal methods","pmids":["26846349"],"is_preprint":false},{"year":2017,"finding":"KIFC1 regulates the positioning and structural integrity of the Golgi apparatus in non-polarized mammalian cells. The motor domain of KIFC1 mediates recognition and binding of the Golgi, while the tail domain statically cross-links to microtubules, suggesting KIFC1 functions as a cross-linker between the Golgi and microtubules to maintain central Golgi positioning.","method":"KIFC1 domain-deletion constructs, immunofluorescence of Golgi morphology, co-localization studies in mammalian cells","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain-deletion approach with Golgi morphology readout; single lab, mechanistic model supported by localization data","pmids":["28430595"],"is_preprint":false},{"year":2018,"finding":"KIFC1 is required for export of ciliary membrane proteins from the Golgi complex in non-photoreceptor cells. After serum starvation, KIFC1 immunoreactivity appears in the Golgi region. KIFC1 knockdown inhibits export of ciliary receptors from the Golgi. KIFC1 physically interacts with ASAP1 (an ARF-GAP that regulates budding of rhodopsin transport carriers). KIFC1 depletion causes Golgi accumulation of ASAP1 and reduces centrosomal levels of IFT20 and TTBK2, impairing ciliogenesis.","method":"KIFC1 knockdown, co-immunoprecipitation (KIFC1-ASAP1 interaction), immunofluorescence of ciliary receptor trafficking, ciliogenesis assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — KD phenotype plus Co-IP of KIFC1-ASAP1 interaction, multiple trafficking readouts; single lab","pmids":["29042452"],"is_preprint":false},{"year":2018,"finding":"KIFC1 was identified as a stronger interactor with misfolded F508del-CFTR (bearing ER retention motifs) versus F508del-CFTR lacking these motifs, by LC-MS/MS proteomic interaction profiling. Decreasing KIFC1 levels or activity stabilizes the immature form of F508del-CFTR by reducing its degradation, implicating KIFC1 in early ER quality control targeting of misfolded CFTR.","method":"LC-MS/MS proteomic interaction profiling, KIFC1 siRNA knockdown and pharmacological inhibition, CFTR stability/degradation assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction validated with functional KD/inhibition assays; single lab, two orthogonal methods","pmids":["30066085"],"is_preprint":false},{"year":2018,"finding":"KIFC1 promotes hepatocellular carcinoma EMT and metastasis via gankyrin/AKT/TWIST1 signaling. KIFC1 knockdown inhibits gankyrin-dependent AKT activation; inhibiting gankyrin reverses the EMT induced by KIFC1. miR-532-3p directly regulates KIFC1 expression.","method":"KIFC1 knockdown/overexpression in HCC cell lines and in vivo xenograft, luciferase reporter for miR-532-3p targeting, pathway inhibition epistasis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (KIFC1 → gankyrin → AKT/TWIST1) with in vitro and in vivo validation, single lab","pmids":["30115976"],"is_preprint":false},{"year":2019,"finding":"KIFC1 interacts with HMGA1, an architectural transcription factor, and enhances HMGA1 transcriptional activity. HMGA1 binds to the promoters of Stat3, MMP2, and EMT-related genes to promote transcription. The upstream transcription factor TCF-4 activates KIFC1 expression. These interactions were demonstrated by co-immunoprecipitation, ChIP, and dual-luciferase reporter assays.","method":"Co-immunoprecipitation (KIFC1-HMGA1), ChIP assay, dual-luciferase reporter assay, KIFC1 knockdown in HCC cells","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus luciferase reporter, three orthogonal methods; single lab","pmids":["31340839"],"is_preprint":false},{"year":2019,"finding":"KIFC1 participates in DNA synthesis regulation during S phase and chromatin maintenance during mitosis. KIFC1 deletion prolongs S phase, causes aberrant nuclear membrane morphology with degradation of lamin B and lamin A/C, disrupts metaphase spindle assembly, and leads to micronuclei and aneuploidy. KIFC1 may transport replication-related proteins into the nucleus to facilitate S phase progression.","method":"KIFC1 knockout in human cells (kifc1-/-), cell cycle kinetics analysis, nuclear membrane/lamin immunostaining, spindle assembly assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple cellular readouts (cell cycle, nuclear morphology, spindle); single lab","pmids":["31127080"],"is_preprint":false},{"year":2019,"finding":"KIFC1 is an organizer of microtubules in axons of postmitotic neurons. Partial RNAi depletion, pharmacological inhibition, and expression of mutant KIFC1 constructs demonstrate that KIFC1 slides microtubules in an ATP-dependent manner and cross-links them in an ATP-independent manner to oppose subsequent sliding by other motors, regulating axonal growth, retraction, and growth cone morphology.","method":"RNAi in rat neurons, KIFC1 pharmacological inhibitors, mutant KIFC1 construct expression, live imaging of microtubule organization and axon morphology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent loss-of-function approaches (RNAi, inhibitor, dominant-negative mutant) with consistent phenotypes; mechanistic dissection of ATP-dependent vs. ATP-independent modes","pmids":["30804089"],"is_preprint":false},{"year":2020,"finding":"IFT proteins (including IFT88) directly interact with HSET (KIFC1) and are required together with HSET for efficient centrosome clustering in cancer cells with supernumerary centrosomes. siRNA knockdown of IFT proteins or AID-inducible degradation of IFT88 combined with HSET inhibition impairs clustering dynamics.","method":"siRNA knockdown of IFT proteins, AID-inducible IFT88 degradation, small-molecule HSET inhibition, direct interaction assay, live imaging of centrosome clustering","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction established, multiple genetic approaches (siRNA + AID system) combined with pharmacological inhibition and live imaging; multi-method rigorous study","pmids":["32270908"],"is_preprint":false},{"year":2020,"finding":"TRIM8 interacts with KIFC1 and KIF11/Eg5 in mouse embryonic neural stem cells (identified by proteomics). TRIM8 localizes to the mitotic spindle during mitosis and plays a role in centrosome separation at the beginning of mitosis, with downstream impact on chromosomal stability.","method":"Proteomic interaction screen (TRIM8 interactome by MS), immunofluorescence of TRIM8 at mitotic spindle, centrosome separation assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — MS-based interaction identification plus functional localization; interaction not validated by reciprocal Co-IP in abstract","pmids":["31904480"],"is_preprint":false},{"year":2021,"finding":"ATM and ATR kinases phosphorylate KIFC1 at Ser26 under DNA damaging conditions. This phosphorylation selectively maintains centrosome clustering in cancer cells with amplified centrosomes, promoting drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation at Ser26 represses centrosome clustering.","method":"In vivo phosphorylation assay, phosphorylation-site mutagenesis (Ser26), ATM/ATR inhibition, centrosome clustering assay, tumor recurrence models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific phosphorylation identified with mutagenesis validation, kinase assignment by ATM/ATR inhibitors, multiple cellular and in vivo readouts","pmids":["33397932"],"is_preprint":false},{"year":2022,"finding":"KIFC1 depletion in mouse oocytes causes failure of polar body extrusion, disrupted meiotic spindle formation, and chromosome misalignment. KIFC1 affects tubulin acetylation via HDAC6 and NAT10. Mass spectrometry showed KIFC1 associates with actin nucleation factors; KIFC1 depletion causes aberrant distribution of actin filaments, abnormal formin 2 and ARP2/3 complex expression, and disrupted endoplasmic reticulum distribution, impairing actin-dependent spindle migration.","method":"KIFC1 depletion (morpholino/siRNA), mass spectrometry interaction screen, rescue by exogenous KIFC1 mRNA, immunofluorescence of tubulin acetylation and actin distribution","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — loss-of-function with mRNA rescue, MS-identified actin nucleation factor interactions, multiple orthogonal cellular phenotype readouts","pmids":["35142352"],"is_preprint":false},{"year":2022,"finding":"KIFC1 regulates the trajectory of neuronal migration. Depletion of KIFC1 causes neurons to migrate off their appropriate path. KIFC1 cross-linking of microtubules into a non-sliding mode is necessary for dynein-driven forces to achieve sufficient traction to thrust the soma forward. Asymmetric KIFC1-driven microtubule sliding enables soma tilting for midcourse trajectory corrections. KIFC1 also contributes to interkinetic nuclear migration during earlier neuronal development.","method":"RNAi in rat migratory neurons in vitro, in vivo mouse brain electroporation, ectopic expression of mutant KIFC1 forms (sliding vs. cross-linking mutants)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo loss-of-function plus mechanistic mutant constructs distinguishing sliding vs cross-linking modes; replicated across two experimental systems","pmids":["35046122"],"is_preprint":false},{"year":2024,"finding":"HSET (KIFC1) and KlpA are non-processive kinesin-14 motors that produce single load-dependent power strokes (~30 nm for HSET) per microtubule encounter. Each homodimer generates ~0.5 pN force. When assembled in teams, multiple motors cooperate to generate forces ≥1 pN and exhibit increased MT-sliding velocities, demonstrating cooperative behavior is essential for their cellular functions.","method":"Single-molecule optical trap force measurements, in vitro MT-sliding assays with multiple motor assemblies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct single-molecule force spectroscopy with quantitative biophysical characterization; peer-reviewed and replicated across two kinesin-14 motors","pmids":["39095439"],"is_preprint":false},{"year":2023,"finding":"HSET (KIFC1) and KlpA are non-processive microtubule motors that function under load with single power strokes per MT encounter (~30-35 nm), generating ~0.5 pN per homodimer; cooperative team activity increases both force and MT-sliding velocity.","method":"Single-molecule optical trap force spectroscopy, in vitro MT-sliding assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — rigorous biophysical reconstitution in preprint; superseded by peer-reviewed version (PMID 39095439), included for completeness","pmids":["37333225"],"is_preprint":true},{"year":2025,"finding":"OTUD6B deubiquitinase interacts with KIFC1 and prevents its polyubiquitination and premature degradation during mitosis. In OTUD6B-deficient cells, KIFC1 is prematurely degraded, leading to increased multipolar spindles without centrosome amplification. Phenotypic rescue depends on OTUD6B catalytic activity and is recapitulated by KIFC1 overexpression, establishing OTUD6B as a writer/eraser controlling KIFC1 stability via ubiquitination.","method":"Parallel siRNA screens of deubiquitinases, co-immunoprecipitation (OTUD6B-KIFC1), polyubiquitination assay, catalytic-dead OTUD6B mutant rescue, KIFC1 overexpression rescue, CRISPR-Cas9 OTUD6B knockout","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP, ubiquitination assay, catalytic mutant and overexpression rescues, CRISPR KO; multiple orthogonal methods in single rigorous study","pmids":["39789388"],"is_preprint":false},{"year":2024,"finding":"CDK1 directly phosphorylates KIFC1 in endometrial carcinoma cells (shown by Co-IP of CDK1 and KIFC1, and detection of phosphorylated KIFC1). CDK1-mediated KIFC1 phosphorylation activates the PI3K/AKT pathway to promote tumor proliferation and invasion.","method":"Co-immunoprecipitation (CDK1-KIFC1 interaction), western blot for phospho-KIFC1, PI3K/AKT pathway activation assay, CDK1 knockdown in vivo and in vitro","journal":"Journal of gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrates interaction and phosphorylation is detected, with functional pathway readout; single lab, direct kinase assay not described","pmids":["38456590"],"is_preprint":false},{"year":2024,"finding":"KIFC1 inhibits the E3 ubiquitin ligase TRIM37, thereby preventing ubiquitination and degradation of PLK4, which promotes centrosome amplification and endometrial cancer progression. KIFC1 overexpression increases centrosome number and chromosomal instability; this depends on KIFC1's regulation of TRIM37-PLK4 axis.","method":"KIFC1/TRIM37 knockdown and overexpression, PLK4 ubiquitination assay, centrosome number quantification, in vivo xenograft model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus genetic epistasis (KIFC1 → TRIM37 → PLK4 stability), functional centrosome readout; single lab","pmids":["39349439"],"is_preprint":false},{"year":2024,"finding":"USP25, a deubiquitinating enzyme, stabilizes KIFC1 protein through deubiquitination, promoting its accumulation in cervical cancer cells. USP25 suppression decreases KIFC1 and MYCBP levels; reintroduction of KIFC1 into USP25-deficient cells restores MYCBP expression, placing USP25 upstream of KIFC1 in a USP25/KIFC1/MYCBP signaling axis.","method":"USP25 and KIFC1 knockdown/overexpression, ubiquitination assay, epistasis rescue experiments (KIFC1 re-expression in USP25-KD cells), in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitination assay plus genetic epistasis rescue, single lab","pmids":["40379626"],"is_preprint":false},{"year":2024,"finding":"KIFC1 interacts with KPNA2 (karyopherin alpha 2) in bladder cancer cells (co-immunoprecipitation). The KPNA2-KIFC1 interaction facilitates G2/M phase transition and promotes tumor progression via PI3K/AKT pathway activation.","method":"Co-immunoprecipitation (KPNA2-KIFC1), cell cycle analysis, PI3K/AKT pathway assay","journal":"Cellular & molecular biology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with pathway assay; mechanism not further dissected","pmids":["39956902"],"is_preprint":false},{"year":2024,"finding":"ELK1 binds to the KIFC1 promoter and activates KIFC1 transcription in breast cancer cells (validated by dual-luciferase reporter assay and ChIP). KIFC1 overexpression increases intracellular GSH levels, reduces ROS, and promotes proliferation; GSH synthesis inhibitor (BSO) attenuates this proliferative effect, linking KIFC1 to glutathione metabolism regulation.","method":"ChIP assay, dual-luciferase reporter, GSH/GSSG measurement, ROS assay, BSO rescue experiment","journal":"The journal of obstetrics and gynaecology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter validate transcription factor binding; functional GSH pathway link supported by pharmacological rescue; single lab","pmids":["37339943"],"is_preprint":false},{"year":2024,"finding":"KIFC1 binds to and stabilizes BUB1B by competing with ubiquitination, reducing BUB1B degradation in pancreatic cancer cells. Rescue experiments showed that BUB1B overexpression reverses the growth inhibition caused by KIFC1 knockdown, placing BUB1B downstream of KIFC1.","method":"Co-immunoprecipitation (KIFC1-BUB1B), ubiquitination assay, epistasis rescue (BUB1B overexpression in KIFC1-KD cells), in vivo xenograft","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus genetic epistasis rescue, single lab","pmids":["40857057"],"is_preprint":false},{"year":2024,"finding":"KIFC1 interacts with Aurora B kinase (identified by proteomics in ESCC cells). KIFC1 knockdown reduces Aurora B distribution on the metaphase plate and substantially inhibits phosphorylation of Histone H3 (canonical Aurora B substrate), suggesting KIFC1 transports or positions Aurora B at the kinetochore region.","method":"Proteomics (mass spectrometry) to identify KIFC1 binding partners, immunofluorescence of Aurora B, Histone H3 phosphorylation assay after KIFC1 knockdown","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MS-identified interaction not validated by reciprocal Co-IP; single lab, indirect evidence for transport function","pmids":["37955677"],"is_preprint":false},{"year":2024,"finding":"KIFC1 interacts with FXR1, an RNA-binding protein, and this interaction stabilizes MAD2L1 mRNA in an m6A-dependent manner. KIFC1 knockout induces cellular senescence in soft tissue sarcoma cells via FXR1-dependent MAD2L1 mRNA regulation.","method":"Co-immunoprecipitation (KIFC1-FXR1 interaction), RNA stability assay, m6A-dependent mRNA analysis, KIFC1 KO in vitro and PDX models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of KIFC1-FXR1 plus mRNA stability and m6A assays; single lab, multiple methods","pmids":["39387242"],"is_preprint":false},{"year":2024,"finding":"FOXD1 binds to the KIFC1 promoter (validated by ChIP and dual-luciferase reporter assays) and activates KIFC1 transcription, promoting aerobic glycolysis and cisplatin resistance in breast cancer cells. Overexpression of FOXD1 reverses the inhibitory effects of KIFC1 knockdown on cisplatin resistance.","method":"ChIP assay, dual-luciferase reporter, KIFC1 and FOXD1 knockdown/overexpression, glycolysis measurements (ECAR, glucose, lactate), epistasis rescue","journal":"Reproductive biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase validate promoter binding; epistasis rescue links FOXD1 upstream of KIFC1; single lab","pmids":["39541848"],"is_preprint":false},{"year":2025,"finding":"In TNBC cells, nuclear KIFC1 interacts with the tumor suppressor MYH9 (myosin heavy chain 9). This interaction is more prominent in African American TNBC-derived cells than European American cells. KIFC1 KO in AA TNBC cells significantly inhibited proliferation, migration, and invasion, with RNA sequencing showing downregulation of migration/invasion/metastasis genes, but these effects were not seen in EA cells.","method":"Co-immunoprecipitation (KIFC1-MYH9), KIFC1 CRISPR-Cas9 knockout, RNA sequencing, pharmacological inhibition","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP validated interaction plus CRISPR KO phenotype; single lab, two orthogonal approaches","pmids":["38902769"],"is_preprint":false}],"current_model":"KIFC1/HSET is a minus-end-directed, non-processive kinesin-14 motor that produces load-dependent power strokes (~30 nm, ~0.5 pN per homodimer) and cooperates in teams to cross-link and slide antiparallel microtubules; it is regulated by Ran/importin α/β (nuclear sequestration in interphase), phosphorylated at Ser26 by ATM/ATR under DNA damage (enhancing centrosome clustering), ubiquitinated and stabilized by the deubiquitinase OTUD6B during mitosis, and transcriptionally driven by ELK1, C/EBPβ, and TCF-4 in various cancer contexts; it functions in mitotic and meiotic spindle assembly (opposing Eg5 to establish force balance), centrosome clustering in cancer cells (via a CEP215-HSET complex and cooperation with IFT proteins), axonal microtubule organization (ATP-dependent sliding plus ATP-independent cross-linking), neuronal migration trajectory control, vesicular/endosomal trafficking (including early endosome fission with Kif5B, Golgi positioning, and ciliary membrane protein export via ASAP1 interaction), intracellular DNA transport, spermatid acrosome biogenesis and nuclear shaping, ER quality control targeting of misfolded CFTR, and cancer cell signaling (through HMGA1 transcriptional activation, TRIM37/PLK4 centrosome amplification, KPNA2-PI3K/AKT, and FXR1-MAD2L1 mRNA stability axes)."},"narrative":{"mechanistic_narrative":"KIFC1 (HSET) is a minus-end-directed, non-processive kinesin-14 motor that cross-links and slides antiparallel microtubules to organize bipolar spindle architecture and broader microtubule arrays [PMID:10525540, PMID:11382767]. Single-molecule force spectroscopy shows each homodimer produces a single load-dependent power stroke (~30 nm, ~0.5 pN), with motors cooperating in teams to generate forces ≥1 pN and faster microtubule sliding, establishing that cooperative ensemble behavior underlies its cellular roles [PMID:39095439]. During spindle assembly, KIFC1 opposes the plus-end motor Eg5 to balance forces, and its microtubule-sliding activity—not cross-linking alone—sets spindle length, with activity gated by Ran/importin α/β sequestration in the interphase nucleus [PMID:10525540, PMID:19116309]. The motor and tail domains are functionally separable: the tail mediates static microtubule cross-linking while the motor domain executes ATP-dependent sliding, a duality that organizes axonal microtubules and steers neuronal migration by providing traction for dynein-driven forces and enabling asymmetric soma tilting [PMID:30804089, PMID:35046122]. In cancer cells with supernumerary centrosomes, KIFC1 drives clustering of extra centrosomes into pseudo-bipolar spindles via a CEP215–HSET complex and cooperation with IFT proteins, a function selectively required by amplified-centrosome cells and exploitable by specific small-molecule inhibitors (AZ82, CW069, SR31527) that cause centrosome declustering and multipolar mitosis without harming normal diploid cells [PMID:26987684, PMID:32270908, PMID:23895133, PMID:24210220, PMID:26846349]. KIFC1 stability and activity are post-translationally controlled: ATM/ATR phosphorylate Ser26 under DNA damage to enhance centrosome clustering and drug resistance, while the deubiquitinase OTUD6B prevents premature mitotic degradation [PMID:33397932, PMID:39789388]. Beyond mitosis, KIFC1 contributes to early endosome fission with Kif5B, Golgi positioning, ciliary membrane-protein export through ASAP1, ER quality-control targeting of misfolded CFTR, intracellular DNA transport, and spermatid acrosome biogenesis [PMID:17360972, PMID:28430595, PMID:29042452, PMID:30066085, PMID:23543461, PMID:12826589]. KIFC1 is recurrently overexpressed in cancers, where it is transcriptionally driven by factors including ELK1, TCF-4, and FOXD1 and acts through downstream signaling axes (gankyrin/AKT/TWIST1, HMGA1, TRIM37/PLK4) to promote proliferation, EMT, and chromosomal instability [PMID:31340839, PMID:30115976, PMID:39349439, PMID:37339943, PMID:39541848].","teleology":[{"year":1999,"claim":"Established that KIFC1/HSET is a spindle-associated microtubule cross-linker whose force opposes Eg5, answering whether it actively shapes spindle architecture.","evidence":"Immuno-EM, inhibitory-antibody microinjection in oocytes, and in vitro aster assembly with simultaneous HSET/Eg5 inhibition","pmids":["10525540"],"confidence":"High","gaps":["Did not resolve motor directionality or biophysical force output","No role demonstrated in centrosome-containing mitotic spindle architecture"]},{"year":2001,"claim":"Defined HSET biochemically as an active minus-end-directed motor, converting the cross-linker concept into a measured motility activity.","evidence":"Native protein purification from mitotic HeLa cells and in vitro microtubule gliding assay","pmids":["11382767"],"confidence":"High","gaps":["Non-processive behavior and force per motor not quantified","Regulation of motor activity in cells not addressed"]},{"year":2003,"claim":"Linked KIFC1 to nuclear transport machinery and spermatid acrosome biogenesis, broadening its role beyond the spindle.","evidence":"Co-IP of KIFC1 with importin beta and immunofluorescence in rat spermatids","pmids":["12826589"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Direct cargo carried during acrosome formation not identified"]},{"year":2004,"claim":"Mapped tail-domain sequences that route KIFC1 to organelles versus the spindle, showing localization is encoded by short divergent tail segments.","evidence":"GFP-fusion tail-deletion constructs with fluorescence localization mapping","pmids":["15236353"],"confidence":"Medium","gaps":["Binding partners recognized by the targeting sequences not identified","Functional consequence of organelle targeting untested"]},{"year":2007,"claim":"Showed KIFC1 cooperates with the plus-end motor Kif5B to drive early endosome fission, extending its mechanics to vesicle trafficking.","evidence":"In vitro vesicle motility, antibody inhibition, and FLAG-Kifc1 Co-IP of Kif5B from 293T cells","pmids":["17360972"],"confidence":"High","gaps":["Direct vs. adaptor-mediated KIFC1-Kif5B coupling not resolved","Vesicle adaptor linking motor to endosome unknown"]},{"year":2008,"claim":"Demonstrated that sliding activity (not cross-linking alone) sets spindle length and that Ran/importin sequesters HSET in the interphase nucleus, defining its spatial regulation.","evidence":"NLS mutagenesis, RNAi, and ATPase-uncoupled motor mutant with quantitative spindle-length readouts in HeLa cells","pmids":["19116309"],"confidence":"High","gaps":["Importin binding sites on HSET not mapped","How nuclear release is timed at mitotic entry not detailed"]},{"year":2013,"claim":"Identified KIFC1 as the mechanistic driver of centrosome clustering in cancer cells with supernumerary centrosomes, validated by specific small-molecule inhibitors and loss-of-function in diploid cells.","evidence":"ATPase inhibitor characterization (AZ82, CW069) with kinetic mode analysis and centrosome declustering/multipolar assays; shRNA in IMR-90 fibroblasts with Mad2 epistasis","pmids":["23895133","24210220","23318213"],"confidence":"High","gaps":["Molecular partners mediating clustering at centrosomes not yet defined in these studies","Selectivity basis for cancer vs. normal cells unexplained"]},{"year":2013,"claim":"Revealed an unexpected activity: KIFC1 actively transports bare double-stranded DNA along microtubules.","evidence":"Single-molecule in-cell imaging, mass spectrometry of DNA-bound proteins, and extract immunodepletion motility assays","pmids":["23543461"],"confidence":"Medium","gaps":["Physiological context and cargo specificity of DNA transport unclear","Direct vs. adaptor-mediated DNA binding not resolved"]},{"year":2016,"claim":"Defined the CEP215-HSET complex as the physical bridge linking centrosomes to spindle poles and mediating clustering of extra centrosomes.","evidence":"Proteomic interaction profiling, CEP215 HSET-binding-domain deletion, and centrosome phenotype imaging including patient-derived cells","pmids":["26987684"],"confidence":"High","gaps":["Structural basis of CEP215-HSET binding not determined","Whether SR31527/CEP215 act in the same pathway not directly tested"]},{"year":2016,"claim":"Provided direct-binding and structural evidence for an allosteric inhibitor site on KIFC1, supporting it as a druggable anticancer target.","evidence":"Bio-layer interferometry, ATPase inhibition, STD-NMR and docking, and centrosome clustering assay in TNBC cells (SR31527)","pmids":["26846349"],"confidence":"High","gaps":["Co-crystal structure of inhibitor bound to KIFC1 absent","In vivo efficacy and selectivity not established here"]},{"year":2017,"claim":"Extended KIFC1's cross-linking role to organelle positioning, showing it tethers the Golgi to microtubules.","evidence":"KIFC1 domain-deletion constructs with Golgi morphology and co-localization readouts","pmids":["28430595"],"confidence":"Medium","gaps":["Golgi receptor recognized by the motor domain unknown","Single-lab localization-based model without biochemical reconstitution"]},{"year":2018,"claim":"Connected KIFC1 to ciliogenesis through Golgi export of ciliary membrane proteins and an ASAP1 interaction, plus a role in ER quality control of misfolded CFTR.","evidence":"KIFC1 knockdown with ciliary-receptor trafficking and ciliogenesis assays, KIFC1-ASAP1 Co-IP; LC-MS/MS interaction profiling with F508del-CFTR and stability assays","pmids":["29042452","30066085"],"confidence":"Medium","gaps":["Whether KIFC1 transports CFTR or merely associates is unresolved","Directness of ASAP1 interaction and shared adaptors not detailed"]},{"year":2019,"claim":"Established KIFC1 as an organizer of axonal microtubules and a regulator of S-phase/chromatin maintenance, separating its ATP-dependent sliding from ATP-independent cross-linking.","evidence":"RNAi, pharmacological inhibition, and mutant constructs in rat neurons; kifc1-/- human cells with cell-cycle, lamin, and spindle readouts","pmids":["30804089","31127080"],"confidence":"High","gaps":["Replication-related cargos transported during S phase not identified","Mechanism of lamin degradation upon KIFC1 loss unclear"]},{"year":2019,"claim":"Identified KIFC1 as a transcriptional co-activator of HMGA1 driven downstream of TCF-4, linking its overexpression to cancer gene programs.","evidence":"KIFC1-HMGA1 Co-IP, ChIP, and dual-luciferase reporter assays in HCC cells","pmids":["31340839"],"confidence":"Medium","gaps":["How a microtubule motor enters the nucleus to co-activate transcription unexplained","Direct DNA or chromatin engagement by KIFC1 not shown"]},{"year":2020,"claim":"Showed IFT proteins directly cooperate with HSET for efficient centrosome clustering, integrating ciliary trafficking machinery into the clustering mechanism.","evidence":"siRNA and AID-inducible IFT88 degradation combined with HSET inhibition and live imaging","pmids":["32270908"],"confidence":"High","gaps":["Mechanistic step at which IFT proteins act during clustering not defined","Whether IFT-HSET complex is the same as CEP215-HSET complex untested"]},{"year":2021,"claim":"Defined ATM/ATR phosphorylation of KIFC1 at Ser26 as a DNA-damage-induced switch that maintains centrosome clustering and promotes drug resistance.","evidence":"In vivo phosphorylation assay, Ser26 mutagenesis, ATM/ATR inhibition, clustering and tumor-recurrence models","pmids":["33397932"],"confidence":"High","gaps":["How Ser26 phosphorylation alters motor mechanics or partner binding unresolved","Phosphatase reversing this mark unidentified"]},{"year":2022,"claim":"Established KIFC1 as essential for oocyte meiotic spindle and migration, acting through tubulin acetylation regulators and actin-nucleation machinery, and as a steering factor in neuronal migration.","evidence":"KIFC1 depletion with mRNA rescue, MS interaction screens, and imaging of tubulin acetylation/actin in oocytes; RNAi and sliding-vs-crosslinking mutants in vitro and in mouse brain","pmids":["35142352","35046122"],"confidence":"High","gaps":["Mechanism coupling KIFC1 to HDAC6/NAT10 and actin factors not biochemically resolved","How crosslinking provides traction for dynein not directly visualized"]},{"year":2024,"claim":"Quantified the biophysical basis of KIFC1 function: non-processive single power strokes per encounter with cooperative force amplification by motor teams.","evidence":"Single-molecule optical-trap force spectroscopy and in vitro multi-motor MT-sliding assays","pmids":["39095439"],"confidence":"High","gaps":["Stoichiometry of cooperative teams in vivo unknown","How post-translational marks modulate force output untested"]},{"year":2024,"claim":"Expanded the cancer post-translational and signaling network of KIFC1, including CDK1 phosphorylation, TRIM37/PLK4 centrosome amplification, deubiquitinase stabilization, and multiple RNA/transcription axes.","evidence":"Co-IP, ubiquitination assays, epistasis rescue, and transcription-factor ChIP/luciferase across endometrial, cervical, pancreatic, sarcoma, bladder, and breast cancer models (CDK1, TRIM37/PLK4, USP25, FXR1/MAD2L1, ELK1, FOXD1, BUB1B, MYH9)","pmids":["38456590","39349439","40379626","39387242","37339943","39541848","40857057","38902769"],"confidence":"Medium","gaps":["Several interactions rest on single Co-IPs without reciprocal validation","Direct kinase assays for CDK1-KIFC1 phosphorylation not described","Mechanistic unification of these context-specific axes incomplete"]},{"year":2025,"claim":"Defined OTUD6B as a deubiquitinase that protects KIFC1 from premature mitotic degradation, identifying a stability control independent of centrosome amplification.","evidence":"DUB siRNA screen, OTUD6B-KIFC1 Co-IP, polyubiquitination assay, catalytic-dead and overexpression rescues, and CRISPR OTUD6B knockout","pmids":["39789388"],"confidence":"High","gaps":["E3 ligase opposing OTUD6B on KIFC1 not identified","Mitotic timing signal triggering KIFC1 deubiquitination unknown"]},{"year":null,"claim":"How KIFC1's distinct activities—spindle/centrosome mechanics, organelle and vesicle positioning, DNA/cargo transport, and nuclear transcriptional co-activation—are partitioned and coordinated by its post-translational marks and tail-domain partners remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking specific PTMs/partners to each functional mode","Structural basis for cargo selection by motor vs. tail domain not determined","How a cytoskeletal motor exerts nuclear transcriptional functions mechanistically unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[1,5,18,24]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[7,11,18,24]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,5,12,23]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[10,19,21]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[12,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[18,23]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,5,17]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[18,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,28]}],"complexes":["CEP215-HSET complex"],"partners":["KIF5B","CEP215","ASAP1","OTUD6B","HMGA1","FXR1","KPNA2","TRIM37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BW19","full_name":"Kinesin-like protein KIFC1","aliases":["Kinesin-like protein 2","Kinesin-related protein HSET"],"length_aa":673,"mass_kda":73.7,"function":"Minus end-directed microtubule-dependent motor required for bipolar spindle formation (PubMed:15843429). May contribute to movement of early endocytic vesicles (By similarity). Regulates cilium formation and structure (By similarity)","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle; Early endosome","url":"https://www.uniprot.org/uniprotkb/Q9BW19/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIFC1","classification":"Not Classified","n_dependent_lines":80,"n_total_lines":1208,"dependency_fraction":0.06622516556291391},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000237649","cell_line_id":"CID001429","localizations":[{"compartment":"cytoskeleton","grade":3}],"interactors":[{"gene":"NUP153","stoichiometry":4.0},{"gene":"ARPC2","stoichiometry":0.2},{"gene":"DYNC2LI1","stoichiometry":0.2},{"gene":"KPNA2","stoichiometry":0.2},{"gene":"KPNB1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"TNPO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001429","total_profiled":1310},"omim":[{"mim_id":"617720","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 42; PPP1R42","url":"https://www.omim.org/entry/617720"},{"mim_id":"615216","title":"KINESIN FAMILY MEMBER C2; KIFC2","url":"https://www.omim.org/entry/615216"},{"mim_id":"609367","title":"KINESIN FAMILY BINDING PROTEIN; KIFBP","url":"https://www.omim.org/entry/609367"},{"mim_id":"603763","title":"KINESIN FAMILY MEMBER C1; KIFC1","url":"https://www.omim.org/entry/603763"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":37.4},{"tissue":"lymphoid tissue","ntpm":44.2}],"url":"https://www.proteinatlas.org/search/KIFC1"},"hgnc":{"alias_symbol":["HSET"],"prev_symbol":["KNSL2"]},"alphafold":{"accession":"Q9BW19","domains":[{"cath_id":"3.40.850.10","chopping":"311-318_376-574_587-660","consensus_level":"high","plddt":90.0433,"start":311,"end":660},{"cath_id":"1.20.5","chopping":"163-308","consensus_level":"medium","plddt":92.8429,"start":163,"end":308}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BW19","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BW19-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BW19-F1-predicted_aligned_error_v6.png","plddt_mean":77.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIFC1","jax_strain_url":"https://www.jax.org/strain/search?query=KIFC1"},"sequence":{"accession":"Q9BW19","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BW19.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BW19/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BW19"}},"corpus_meta":[{"pmid":"10525540","id":"PMC_10525540","title":"The 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Microinjection of inhibitory antibodies showed HSET activity is essential for meiotic spindle organization in murine oocytes and taxol-induced aster assembly in cultured cells. In vitro, simultaneous inhibition of HSET and Eg5 restores aster organization, demonstrating that HSET and Eg5 exert opposing forces during spindle assembly. HSET inhibition alone did not affect mitotic spindle architecture in centrosome-containing cultured cells.\",\n      \"method\": \"Immuno-EM, antibody microinjection, in vitro aster assembly assay, simultaneous inhibition of HSET and Eg5\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (immuno-EM, microinjection, in vitro reconstitution), replicated across meiotic and mitotic contexts in same study\",\n      \"pmids\": [\"10525540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Native HSET purified from mitotic HeLa cells migrates as a ~75 kDa protein and is an active minus-end-directed motor that induces microtubule gliding at ~5 µm/min, with microtubules gliding an average of 3 µm before ceasing movement.\",\n      \"method\": \"Native protein purification from mitotic HeLa cells, in vitro microtubule gliding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical reconstitution (purification + in vitro motility assay), single lab but rigorous enzymatic characterization\",\n      \"pmids\": [\"11382767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KIFC1 associates with importin beta and co-localizes with it on curvilinear structures associated with spermatid nuclei; KIFC1 localizes sequentially to membrane-bounded organelles, then the acrosomal vesicle, and finally the elongating acrosome during spermatogenesis, suggesting a role in acrosome formation and/or elongation via nuclear transport factor interactions.\",\n      \"method\": \"Co-immunoprecipitation (KIFC1 with importin beta), immunofluorescence localization in rat spermatids\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus immunofluorescence localization in two orthogonal methods, single lab\",\n      \"pmids\": [\"12826589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The divergent tail domains of KIFC1 and KIFC5A determine their distinct subcellular localizations: a 19 amino acid sequence in the KIFC1 tail is sufficient to target KIFC1 to membrane-bounded organelles, whereas the KIFC5A tail contains a 43 amino acid sequence directing it to the spindle.\",\n      \"method\": \"GFP-fusion constructs with tail deletions transfected into cells; fluorescence microscopy to map localization determinants\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion mutagenesis with functional localization readout, single lab, two orthogonal approaches (GFP fusions + specific antisera)\",\n      \"pmids\": [\"15236353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Kifc1 and Kif5B mediate minus-end and plus-end motility, respectively, of early endocytic vesicles in mouse liver. More than 90% of Kifc1-associated vesicles also contained Kif5B. Inhibition of either motor reduced vesicle fission, indicating that opposing forces from both motors are required for fission. FLAG-Kifc1 immunoprecipitated native Kif5B from 293T cells, showing the two motors can interact.\",\n      \"method\": \"In vitro vesicle motility on microtubules, antibody inhibition, co-immunoprecipitation (FLAG-Kifc1 pulldown of Kif5B)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstituted motility assay, antibody inhibition, Co-IP; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"17360972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mutation of the nuclear localization signal (NLS) of HSET causes cytoplasmic accumulation and strong microtubule bundling. HSET overexpression in HeLa cells results in longer spindles, while RNAi knockdown results in shorter spindles without affecting pole formation. An HSET mutant with sliding activity uncoupled from ATPase activity produced shorter spindles than wild-type HSET overexpression, demonstrating that microtubule sliding (not just cross-linking) controls spindle length. Ran/importin alpha/beta regulate HSET by sequestering it in the nucleus during interphase.\",\n      \"method\": \"NLS mutagenesis, RNAi knockdown, ATPase-uncoupled motor mutant overexpression, spindle length measurement in HeLa cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal genetic approaches (NLS mutant, RNAi, ATPase-decoupled mutant) with quantitative spindle phenotype readouts, rigorous mechanistic dissection\",\n      \"pmids\": [\"19116309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIFC1 actively transports bare double-stranded DNA along microtubules. Mass spectrometry of DNA-bound proteins identified KIFC1 as a preferential binder of short DNA molecules. Cell-extract depletion of KIFC1 significantly decreased intracellular DNA motion, confirming active involvement of KIFC1 in intracellular DNA transport.\",\n      \"method\": \"Single-molecule in-cell imaging, in vitro motility assay with cell extracts, mass spectrometry of DNA-bound proteins, extract immunodepletion\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MS identification, extract depletion, in vitro motility), single lab\",\n      \"pmids\": [\"23543461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AZ82, the first reported small molecule inhibitor of KIFC1, binds specifically to the KIFC1/microtubule binary complex and inhibits MT-stimulated KIFC1 ATPase activity in an ATP-competitive, MT-noncompetitive manner (Ki = 0.043 µM). AZ82 engages with KIFC1 inside cells to reverse monopolar spindles induced by Eg5 inhibition, and causes centrosome declustering in BT-549 breast cancer cells with amplified centrosomes.\",\n      \"method\": \"Biochemical ATPase assay, kinetic inhibition mode analysis, cell-based spindle assay, centrosome declustering assay\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic characterization with kinetic mode analysis plus cell-based validation; rigorous mechanistic inhibitor study\",\n      \"pmids\": [\"23895133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CW069, an allosteric inhibitor of HSET, inhibits HSET ATPase activity in vitro and induces multipolar mitoses selectively in cancer cells containing supernumerary centrosomes, but not in normal cells with two centrosomes, establishing HSET as the mechanistic driver of centrosome clustering in those cancer cells.\",\n      \"method\": \"In vitro HSET ATPase inhibition assay, cell-based multipolar mitosis phenotype scoring, in silico compound design followed by biochemical validation\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assay plus cell biology with matched controls, selective cancer-cell phenotype; rigorous tool compound characterization\",\n      \"pmids\": [\"24210220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIFC1 knockdown in normal diploid human primary fibroblasts (IMR-90) induces multiple MTOCs, lagging chromosomes, micronuclei, and aneuploidy, ultimately leading to cellular senescence. Double knockdown of KIFC1 and Mad2 causes apoptosis rather than senescence, placing KIFC1 in a pathway distinct from the spindle assembly checkpoint (Mad2 pathway) for bipolar MTOC formation.\",\n      \"method\": \"Lentiviral shRNA knockdown, karyotyping, senescence-associated beta-galactosidase staining, double knockdown epistasis with Mad2\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (KIFC1 + Mad2 double KD) plus karyotyping and senescence assays; single lab, multiple readouts\",\n      \"pmids\": [\"23318213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A CEP215-HSET complex physically links centrosomes with spindle poles. HSET was identified as a direct binding partner of CEP215 by proteomic profiling. Targeted deletion of the HSET-binding domain of CEP215 causes centrosome detachment and HSET depletion at centrosomes. In cancer cells with centrosome amplification, the CEP215-HSET complex promotes clustering of extra centrosomes into pseudo-bipolar spindles.\",\n      \"method\": \"Proteomic profiling (MS-based interaction screen), targeted domain deletion in vertebrate cells, immunofluorescence of centrosome phenotypes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic identification plus domain-deletion functional validation, replicated in patient-derived cells; multiple orthogonal approaches\",\n      \"pmids\": [\"26987684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SR31527, a small molecule inhibitor, binds directly to KIFC1 (Kd = 25.4 nM by bio-layer interferometry) and inhibits MT-stimulated KIFC1 ATPase activity (IC50 = 6.6 µM). STD-NMR and computational modeling indicate SR31527 binds to an allosteric site on KIFC1 distinct from the ATP-binding site. SR31527 prevents centrosome clustering in triple-negative breast cancer cells.\",\n      \"method\": \"Bio-layer interferometry (direct binding), ATPase inhibition assay, STD-NMR, computational docking, centrosome clustering cell assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding assay, enzymatic assay, and NMR structural evidence in single rigorous study; multiple orthogonal methods\",\n      \"pmids\": [\"26846349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIFC1 regulates the positioning and structural integrity of the Golgi apparatus in non-polarized mammalian cells. The motor domain of KIFC1 mediates recognition and binding of the Golgi, while the tail domain statically cross-links to microtubules, suggesting KIFC1 functions as a cross-linker between the Golgi and microtubules to maintain central Golgi positioning.\",\n      \"method\": \"KIFC1 domain-deletion constructs, immunofluorescence of Golgi morphology, co-localization studies in mammalian cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain-deletion approach with Golgi morphology readout; single lab, mechanistic model supported by localization data\",\n      \"pmids\": [\"28430595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIFC1 is required for export of ciliary membrane proteins from the Golgi complex in non-photoreceptor cells. After serum starvation, KIFC1 immunoreactivity appears in the Golgi region. KIFC1 knockdown inhibits export of ciliary receptors from the Golgi. KIFC1 physically interacts with ASAP1 (an ARF-GAP that regulates budding of rhodopsin transport carriers). KIFC1 depletion causes Golgi accumulation of ASAP1 and reduces centrosomal levels of IFT20 and TTBK2, impairing ciliogenesis.\",\n      \"method\": \"KIFC1 knockdown, co-immunoprecipitation (KIFC1-ASAP1 interaction), immunofluorescence of ciliary receptor trafficking, ciliogenesis assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — KD phenotype plus Co-IP of KIFC1-ASAP1 interaction, multiple trafficking readouts; single lab\",\n      \"pmids\": [\"29042452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIFC1 was identified as a stronger interactor with misfolded F508del-CFTR (bearing ER retention motifs) versus F508del-CFTR lacking these motifs, by LC-MS/MS proteomic interaction profiling. Decreasing KIFC1 levels or activity stabilizes the immature form of F508del-CFTR by reducing its degradation, implicating KIFC1 in early ER quality control targeting of misfolded CFTR.\",\n      \"method\": \"LC-MS/MS proteomic interaction profiling, KIFC1 siRNA knockdown and pharmacological inhibition, CFTR stability/degradation assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction validated with functional KD/inhibition assays; single lab, two orthogonal methods\",\n      \"pmids\": [\"30066085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIFC1 promotes hepatocellular carcinoma EMT and metastasis via gankyrin/AKT/TWIST1 signaling. KIFC1 knockdown inhibits gankyrin-dependent AKT activation; inhibiting gankyrin reverses the EMT induced by KIFC1. miR-532-3p directly regulates KIFC1 expression.\",\n      \"method\": \"KIFC1 knockdown/overexpression in HCC cell lines and in vivo xenograft, luciferase reporter for miR-532-3p targeting, pathway inhibition epistasis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (KIFC1 → gankyrin → AKT/TWIST1) with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"30115976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIFC1 interacts with HMGA1, an architectural transcription factor, and enhances HMGA1 transcriptional activity. HMGA1 binds to the promoters of Stat3, MMP2, and EMT-related genes to promote transcription. The upstream transcription factor TCF-4 activates KIFC1 expression. These interactions were demonstrated by co-immunoprecipitation, ChIP, and dual-luciferase reporter assays.\",\n      \"method\": \"Co-immunoprecipitation (KIFC1-HMGA1), ChIP assay, dual-luciferase reporter assay, KIFC1 knockdown in HCC cells\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus luciferase reporter, three orthogonal methods; single lab\",\n      \"pmids\": [\"31340839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIFC1 participates in DNA synthesis regulation during S phase and chromatin maintenance during mitosis. KIFC1 deletion prolongs S phase, causes aberrant nuclear membrane morphology with degradation of lamin B and lamin A/C, disrupts metaphase spindle assembly, and leads to micronuclei and aneuploidy. KIFC1 may transport replication-related proteins into the nucleus to facilitate S phase progression.\",\n      \"method\": \"KIFC1 knockout in human cells (kifc1-/-), cell cycle kinetics analysis, nuclear membrane/lamin immunostaining, spindle assembly assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple cellular readouts (cell cycle, nuclear morphology, spindle); single lab\",\n      \"pmids\": [\"31127080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIFC1 is an organizer of microtubules in axons of postmitotic neurons. Partial RNAi depletion, pharmacological inhibition, and expression of mutant KIFC1 constructs demonstrate that KIFC1 slides microtubules in an ATP-dependent manner and cross-links them in an ATP-independent manner to oppose subsequent sliding by other motors, regulating axonal growth, retraction, and growth cone morphology.\",\n      \"method\": \"RNAi in rat neurons, KIFC1 pharmacological inhibitors, mutant KIFC1 construct expression, live imaging of microtubule organization and axon morphology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent loss-of-function approaches (RNAi, inhibitor, dominant-negative mutant) with consistent phenotypes; mechanistic dissection of ATP-dependent vs. ATP-independent modes\",\n      \"pmids\": [\"30804089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IFT proteins (including IFT88) directly interact with HSET (KIFC1) and are required together with HSET for efficient centrosome clustering in cancer cells with supernumerary centrosomes. siRNA knockdown of IFT proteins or AID-inducible degradation of IFT88 combined with HSET inhibition impairs clustering dynamics.\",\n      \"method\": \"siRNA knockdown of IFT proteins, AID-inducible IFT88 degradation, small-molecule HSET inhibition, direct interaction assay, live imaging of centrosome clustering\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction established, multiple genetic approaches (siRNA + AID system) combined with pharmacological inhibition and live imaging; multi-method rigorous study\",\n      \"pmids\": [\"32270908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM8 interacts with KIFC1 and KIF11/Eg5 in mouse embryonic neural stem cells (identified by proteomics). TRIM8 localizes to the mitotic spindle during mitosis and plays a role in centrosome separation at the beginning of mitosis, with downstream impact on chromosomal stability.\",\n      \"method\": \"Proteomic interaction screen (TRIM8 interactome by MS), immunofluorescence of TRIM8 at mitotic spindle, centrosome separation assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — MS-based interaction identification plus functional localization; interaction not validated by reciprocal Co-IP in abstract\",\n      \"pmids\": [\"31904480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATM and ATR kinases phosphorylate KIFC1 at Ser26 under DNA damaging conditions. This phosphorylation selectively maintains centrosome clustering in cancer cells with amplified centrosomes, promoting drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation at Ser26 represses centrosome clustering.\",\n      \"method\": \"In vivo phosphorylation assay, phosphorylation-site mutagenesis (Ser26), ATM/ATR inhibition, centrosome clustering assay, tumor recurrence models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific phosphorylation identified with mutagenesis validation, kinase assignment by ATM/ATR inhibitors, multiple cellular and in vivo readouts\",\n      \"pmids\": [\"33397932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIFC1 depletion in mouse oocytes causes failure of polar body extrusion, disrupted meiotic spindle formation, and chromosome misalignment. KIFC1 affects tubulin acetylation via HDAC6 and NAT10. Mass spectrometry showed KIFC1 associates with actin nucleation factors; KIFC1 depletion causes aberrant distribution of actin filaments, abnormal formin 2 and ARP2/3 complex expression, and disrupted endoplasmic reticulum distribution, impairing actin-dependent spindle migration.\",\n      \"method\": \"KIFC1 depletion (morpholino/siRNA), mass spectrometry interaction screen, rescue by exogenous KIFC1 mRNA, immunofluorescence of tubulin acetylation and actin distribution\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — loss-of-function with mRNA rescue, MS-identified actin nucleation factor interactions, multiple orthogonal cellular phenotype readouts\",\n      \"pmids\": [\"35142352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIFC1 regulates the trajectory of neuronal migration. Depletion of KIFC1 causes neurons to migrate off their appropriate path. KIFC1 cross-linking of microtubules into a non-sliding mode is necessary for dynein-driven forces to achieve sufficient traction to thrust the soma forward. Asymmetric KIFC1-driven microtubule sliding enables soma tilting for midcourse trajectory corrections. KIFC1 also contributes to interkinetic nuclear migration during earlier neuronal development.\",\n      \"method\": \"RNAi in rat migratory neurons in vitro, in vivo mouse brain electroporation, ectopic expression of mutant KIFC1 forms (sliding vs. cross-linking mutants)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo loss-of-function plus mechanistic mutant constructs distinguishing sliding vs cross-linking modes; replicated across two experimental systems\",\n      \"pmids\": [\"35046122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSET (KIFC1) and KlpA are non-processive kinesin-14 motors that produce single load-dependent power strokes (~30 nm for HSET) per microtubule encounter. Each homodimer generates ~0.5 pN force. When assembled in teams, multiple motors cooperate to generate forces ≥1 pN and exhibit increased MT-sliding velocities, demonstrating cooperative behavior is essential for their cellular functions.\",\n      \"method\": \"Single-molecule optical trap force measurements, in vitro MT-sliding assays with multiple motor assemblies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct single-molecule force spectroscopy with quantitative biophysical characterization; peer-reviewed and replicated across two kinesin-14 motors\",\n      \"pmids\": [\"39095439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSET (KIFC1) and KlpA are non-processive microtubule motors that function under load with single power strokes per MT encounter (~30-35 nm), generating ~0.5 pN per homodimer; cooperative team activity increases both force and MT-sliding velocity.\",\n      \"method\": \"Single-molecule optical trap force spectroscopy, in vitro MT-sliding assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous biophysical reconstitution in preprint; superseded by peer-reviewed version (PMID 39095439), included for completeness\",\n      \"pmids\": [\"37333225\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD6B deubiquitinase interacts with KIFC1 and prevents its polyubiquitination and premature degradation during mitosis. In OTUD6B-deficient cells, KIFC1 is prematurely degraded, leading to increased multipolar spindles without centrosome amplification. Phenotypic rescue depends on OTUD6B catalytic activity and is recapitulated by KIFC1 overexpression, establishing OTUD6B as a writer/eraser controlling KIFC1 stability via ubiquitination.\",\n      \"method\": \"Parallel siRNA screens of deubiquitinases, co-immunoprecipitation (OTUD6B-KIFC1), polyubiquitination assay, catalytic-dead OTUD6B mutant rescue, KIFC1 overexpression rescue, CRISPR-Cas9 OTUD6B knockout\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP, ubiquitination assay, catalytic mutant and overexpression rescues, CRISPR KO; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"39789388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CDK1 directly phosphorylates KIFC1 in endometrial carcinoma cells (shown by Co-IP of CDK1 and KIFC1, and detection of phosphorylated KIFC1). CDK1-mediated KIFC1 phosphorylation activates the PI3K/AKT pathway to promote tumor proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation (CDK1-KIFC1 interaction), western blot for phospho-KIFC1, PI3K/AKT pathway activation assay, CDK1 knockdown in vivo and in vitro\",\n      \"journal\": \"Journal of gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrates interaction and phosphorylation is detected, with functional pathway readout; single lab, direct kinase assay not described\",\n      \"pmids\": [\"38456590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIFC1 inhibits the E3 ubiquitin ligase TRIM37, thereby preventing ubiquitination and degradation of PLK4, which promotes centrosome amplification and endometrial cancer progression. KIFC1 overexpression increases centrosome number and chromosomal instability; this depends on KIFC1's regulation of TRIM37-PLK4 axis.\",\n      \"method\": \"KIFC1/TRIM37 knockdown and overexpression, PLK4 ubiquitination assay, centrosome number quantification, in vivo xenograft model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus genetic epistasis (KIFC1 → TRIM37 → PLK4 stability), functional centrosome readout; single lab\",\n      \"pmids\": [\"39349439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP25, a deubiquitinating enzyme, stabilizes KIFC1 protein through deubiquitination, promoting its accumulation in cervical cancer cells. USP25 suppression decreases KIFC1 and MYCBP levels; reintroduction of KIFC1 into USP25-deficient cells restores MYCBP expression, placing USP25 upstream of KIFC1 in a USP25/KIFC1/MYCBP signaling axis.\",\n      \"method\": \"USP25 and KIFC1 knockdown/overexpression, ubiquitination assay, epistasis rescue experiments (KIFC1 re-expression in USP25-KD cells), in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination assay plus genetic epistasis rescue, single lab\",\n      \"pmids\": [\"40379626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIFC1 interacts with KPNA2 (karyopherin alpha 2) in bladder cancer cells (co-immunoprecipitation). The KPNA2-KIFC1 interaction facilitates G2/M phase transition and promotes tumor progression via PI3K/AKT pathway activation.\",\n      \"method\": \"Co-immunoprecipitation (KPNA2-KIFC1), cell cycle analysis, PI3K/AKT pathway assay\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with pathway assay; mechanism not further dissected\",\n      \"pmids\": [\"39956902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELK1 binds to the KIFC1 promoter and activates KIFC1 transcription in breast cancer cells (validated by dual-luciferase reporter assay and ChIP). KIFC1 overexpression increases intracellular GSH levels, reduces ROS, and promotes proliferation; GSH synthesis inhibitor (BSO) attenuates this proliferative effect, linking KIFC1 to glutathione metabolism regulation.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter, GSH/GSSG measurement, ROS assay, BSO rescue experiment\",\n      \"journal\": \"The journal of obstetrics and gynaecology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter validate transcription factor binding; functional GSH pathway link supported by pharmacological rescue; single lab\",\n      \"pmids\": [\"37339943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIFC1 binds to and stabilizes BUB1B by competing with ubiquitination, reducing BUB1B degradation in pancreatic cancer cells. Rescue experiments showed that BUB1B overexpression reverses the growth inhibition caused by KIFC1 knockdown, placing BUB1B downstream of KIFC1.\",\n      \"method\": \"Co-immunoprecipitation (KIFC1-BUB1B), ubiquitination assay, epistasis rescue (BUB1B overexpression in KIFC1-KD cells), in vivo xenograft\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus genetic epistasis rescue, single lab\",\n      \"pmids\": [\"40857057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIFC1 interacts with Aurora B kinase (identified by proteomics in ESCC cells). KIFC1 knockdown reduces Aurora B distribution on the metaphase plate and substantially inhibits phosphorylation of Histone H3 (canonical Aurora B substrate), suggesting KIFC1 transports or positions Aurora B at the kinetochore region.\",\n      \"method\": \"Proteomics (mass spectrometry) to identify KIFC1 binding partners, immunofluorescence of Aurora B, Histone H3 phosphorylation assay after KIFC1 knockdown\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MS-identified interaction not validated by reciprocal Co-IP; single lab, indirect evidence for transport function\",\n      \"pmids\": [\"37955677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIFC1 interacts with FXR1, an RNA-binding protein, and this interaction stabilizes MAD2L1 mRNA in an m6A-dependent manner. KIFC1 knockout induces cellular senescence in soft tissue sarcoma cells via FXR1-dependent MAD2L1 mRNA regulation.\",\n      \"method\": \"Co-immunoprecipitation (KIFC1-FXR1 interaction), RNA stability assay, m6A-dependent mRNA analysis, KIFC1 KO in vitro and PDX models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of KIFC1-FXR1 plus mRNA stability and m6A assays; single lab, multiple methods\",\n      \"pmids\": [\"39387242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXD1 binds to the KIFC1 promoter (validated by ChIP and dual-luciferase reporter assays) and activates KIFC1 transcription, promoting aerobic glycolysis and cisplatin resistance in breast cancer cells. Overexpression of FOXD1 reverses the inhibitory effects of KIFC1 knockdown on cisplatin resistance.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter, KIFC1 and FOXD1 knockdown/overexpression, glycolysis measurements (ECAR, glucose, lactate), epistasis rescue\",\n      \"journal\": \"Reproductive biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase validate promoter binding; epistasis rescue links FOXD1 upstream of KIFC1; single lab\",\n      \"pmids\": [\"39541848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In TNBC cells, nuclear KIFC1 interacts with the tumor suppressor MYH9 (myosin heavy chain 9). This interaction is more prominent in African American TNBC-derived cells than European American cells. KIFC1 KO in AA TNBC cells significantly inhibited proliferation, migration, and invasion, with RNA sequencing showing downregulation of migration/invasion/metastasis genes, but these effects were not seen in EA cells.\",\n      \"method\": \"Co-immunoprecipitation (KIFC1-MYH9), KIFC1 CRISPR-Cas9 knockout, RNA sequencing, pharmacological inhibition\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP validated interaction plus CRISPR KO phenotype; single lab, two orthogonal approaches\",\n      \"pmids\": [\"38902769\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIFC1/HSET is a minus-end-directed, non-processive kinesin-14 motor that produces load-dependent power strokes (~30 nm, ~0.5 pN per homodimer) and cooperates in teams to cross-link and slide antiparallel microtubules; it is regulated by Ran/importin α/β (nuclear sequestration in interphase), phosphorylated at Ser26 by ATM/ATR under DNA damage (enhancing centrosome clustering), ubiquitinated and stabilized by the deubiquitinase OTUD6B during mitosis, and transcriptionally driven by ELK1, C/EBPβ, and TCF-4 in various cancer contexts; it functions in mitotic and meiotic spindle assembly (opposing Eg5 to establish force balance), centrosome clustering in cancer cells (via a CEP215-HSET complex and cooperation with IFT proteins), axonal microtubule organization (ATP-dependent sliding plus ATP-independent cross-linking), neuronal migration trajectory control, vesicular/endosomal trafficking (including early endosome fission with Kif5B, Golgi positioning, and ciliary membrane protein export via ASAP1 interaction), intracellular DNA transport, spermatid acrosome biogenesis and nuclear shaping, ER quality control targeting of misfolded CFTR, and cancer cell signaling (through HMGA1 transcriptional activation, TRIM37/PLK4 centrosome amplification, KPNA2-PI3K/AKT, and FXR1-MAD2L1 mRNA stability axes).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIFC1 (HSET) is a minus-end-directed, non-processive kinesin-14 motor that cross-links and slides antiparallel microtubules to organize bipolar spindle architecture and broader microtubule arrays [#0, #1]. Single-molecule force spectroscopy shows each homodimer produces a single load-dependent power stroke (~30 nm, ~0.5 pN), with motors cooperating in teams to generate forces \\u22651 pN and faster microtubule sliding, establishing that cooperative ensemble behavior underlies its cellular roles [#24]. During spindle assembly, KIFC1 opposes the plus-end motor Eg5 to balance forces, and its microtubule-sliding activity\\u2014not cross-linking alone\\u2014sets spindle length, with activity gated by Ran/importin \\u03b1/\\u03b2 sequestration in the interphase nucleus [#0, #5]. The motor and tail domains are functionally separable: the tail mediates static microtubule cross-linking while the motor domain executes ATP-dependent sliding, a duality that organizes axonal microtubules and steers neuronal migration by providing traction for dynein-driven forces and enabling asymmetric soma tilting [#18, #23]. In cancer cells with supernumerary centrosomes, KIFC1 drives clustering of extra centrosomes into pseudo-bipolar spindles via a CEP215\\u2013HSET complex and cooperation with IFT proteins, a function selectively required by amplified-centrosome cells and exploitable by specific small-molecule inhibitors (AZ82, CW069, SR31527) that cause centrosome declustering and multipolar mitosis without harming normal diploid cells [#10, #19, #7, #8, #11]. KIFC1 stability and activity are post-translationally controlled: ATM/ATR phosphorylate Ser26 under DNA damage to enhance centrosome clustering and drug resistance, while the deubiquitinase OTUD6B prevents premature mitotic degradation [#21, #26]. Beyond mitosis, KIFC1 contributes to early endosome fission with Kif5B, Golgi positioning, ciliary membrane-protein export through ASAP1, ER quality-control targeting of misfolded CFTR, intracellular DNA transport, and spermatid acrosome biogenesis [#4, #12, #13, #14, #6, #2]. KIFC1 is recurrently overexpressed in cancers, where it is transcriptionally driven by factors including ELK1, TCF-4, and FOXD1 and acts through downstream signaling axes (gankyrin/AKT/TWIST1, HMGA1, TRIM37/PLK4) to promote proliferation, EMT, and chromosomal instability [#16, #15, #28, #31, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that KIFC1/HSET is a spindle-associated microtubule cross-linker whose force opposes Eg5, answering whether it actively shapes spindle architecture.\",\n      \"evidence\": \"Immuno-EM, inhibitory-antibody microinjection in oocytes, and in vitro aster assembly with simultaneous HSET/Eg5 inhibition\",\n      \"pmids\": [\"10525540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve motor directionality or biophysical force output\", \"No role demonstrated in centrosome-containing mitotic spindle architecture\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined HSET biochemically as an active minus-end-directed motor, converting the cross-linker concept into a measured motility activity.\",\n      \"evidence\": \"Native protein purification from mitotic HeLa cells and in vitro microtubule gliding assay\",\n      \"pmids\": [\"11382767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Non-processive behavior and force per motor not quantified\", \"Regulation of motor activity in cells not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked KIFC1 to nuclear transport machinery and spermatid acrosome biogenesis, broadening its role beyond the spindle.\",\n      \"evidence\": \"Co-IP of KIFC1 with importin beta and immunofluorescence in rat spermatids\",\n      \"pmids\": [\"12826589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Direct cargo carried during acrosome formation not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped tail-domain sequences that route KIFC1 to organelles versus the spindle, showing localization is encoded by short divergent tail segments.\",\n      \"evidence\": \"GFP-fusion tail-deletion constructs with fluorescence localization mapping\",\n      \"pmids\": [\"15236353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding partners recognized by the targeting sequences not identified\", \"Functional consequence of organelle targeting untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed KIFC1 cooperates with the plus-end motor Kif5B to drive early endosome fission, extending its mechanics to vesicle trafficking.\",\n      \"evidence\": \"In vitro vesicle motility, antibody inhibition, and FLAG-Kifc1 Co-IP of Kif5B from 293T cells\",\n      \"pmids\": [\"17360972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. adaptor-mediated KIFC1-Kif5B coupling not resolved\", \"Vesicle adaptor linking motor to endosome unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that sliding activity (not cross-linking alone) sets spindle length and that Ran/importin sequesters HSET in the interphase nucleus, defining its spatial regulation.\",\n      \"evidence\": \"NLS mutagenesis, RNAi, and ATPase-uncoupled motor mutant with quantitative spindle-length readouts in HeLa cells\",\n      \"pmids\": [\"19116309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Importin binding sites on HSET not mapped\", \"How nuclear release is timed at mitotic entry not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified KIFC1 as the mechanistic driver of centrosome clustering in cancer cells with supernumerary centrosomes, validated by specific small-molecule inhibitors and loss-of-function in diploid cells.\",\n      \"evidence\": \"ATPase inhibitor characterization (AZ82, CW069) with kinetic mode analysis and centrosome declustering/multipolar assays; shRNA in IMR-90 fibroblasts with Mad2 epistasis\",\n      \"pmids\": [\"23895133\", \"24210220\", \"23318213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners mediating clustering at centrosomes not yet defined in these studies\", \"Selectivity basis for cancer vs. normal cells unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed an unexpected activity: KIFC1 actively transports bare double-stranded DNA along microtubules.\",\n      \"evidence\": \"Single-molecule in-cell imaging, mass spectrometry of DNA-bound proteins, and extract immunodepletion motility assays\",\n      \"pmids\": [\"23543461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context and cargo specificity of DNA transport unclear\", \"Direct vs. adaptor-mediated DNA binding not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the CEP215-HSET complex as the physical bridge linking centrosomes to spindle poles and mediating clustering of extra centrosomes.\",\n      \"evidence\": \"Proteomic interaction profiling, CEP215 HSET-binding-domain deletion, and centrosome phenotype imaging including patient-derived cells\",\n      \"pmids\": [\"26987684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CEP215-HSET binding not determined\", \"Whether SR31527/CEP215 act in the same pathway not directly tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided direct-binding and structural evidence for an allosteric inhibitor site on KIFC1, supporting it as a druggable anticancer target.\",\n      \"evidence\": \"Bio-layer interferometry, ATPase inhibition, STD-NMR and docking, and centrosome clustering assay in TNBC cells (SR31527)\",\n      \"pmids\": [\"26846349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-crystal structure of inhibitor bound to KIFC1 absent\", \"In vivo efficacy and selectivity not established here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended KIFC1's cross-linking role to organelle positioning, showing it tethers the Golgi to microtubules.\",\n      \"evidence\": \"KIFC1 domain-deletion constructs with Golgi morphology and co-localization readouts\",\n      \"pmids\": [\"28430595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Golgi receptor recognized by the motor domain unknown\", \"Single-lab localization-based model without biochemical reconstitution\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected KIFC1 to ciliogenesis through Golgi export of ciliary membrane proteins and an ASAP1 interaction, plus a role in ER quality control of misfolded CFTR.\",\n      \"evidence\": \"KIFC1 knockdown with ciliary-receptor trafficking and ciliogenesis assays, KIFC1-ASAP1 Co-IP; LC-MS/MS interaction profiling with F508del-CFTR and stability assays\",\n      \"pmids\": [\"29042452\", \"30066085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KIFC1 transports CFTR or merely associates is unresolved\", \"Directness of ASAP1 interaction and shared adaptors not detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established KIFC1 as an organizer of axonal microtubules and a regulator of S-phase/chromatin maintenance, separating its ATP-dependent sliding from ATP-independent cross-linking.\",\n      \"evidence\": \"RNAi, pharmacological inhibition, and mutant constructs in rat neurons; kifc1-/- human cells with cell-cycle, lamin, and spindle readouts\",\n      \"pmids\": [\"30804089\", \"31127080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Replication-related cargos transported during S phase not identified\", \"Mechanism of lamin degradation upon KIFC1 loss unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified KIFC1 as a transcriptional co-activator of HMGA1 driven downstream of TCF-4, linking its overexpression to cancer gene programs.\",\n      \"evidence\": \"KIFC1-HMGA1 Co-IP, ChIP, and dual-luciferase reporter assays in HCC cells\",\n      \"pmids\": [\"31340839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a microtubule motor enters the nucleus to co-activate transcription unexplained\", \"Direct DNA or chromatin engagement by KIFC1 not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed IFT proteins directly cooperate with HSET for efficient centrosome clustering, integrating ciliary trafficking machinery into the clustering mechanism.\",\n      \"evidence\": \"siRNA and AID-inducible IFT88 degradation combined with HSET inhibition and live imaging\",\n      \"pmids\": [\"32270908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic step at which IFT proteins act during clustering not defined\", \"Whether IFT-HSET complex is the same as CEP215-HSET complex untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined ATM/ATR phosphorylation of KIFC1 at Ser26 as a DNA-damage-induced switch that maintains centrosome clustering and promotes drug resistance.\",\n      \"evidence\": \"In vivo phosphorylation assay, Ser26 mutagenesis, ATM/ATR inhibition, clustering and tumor-recurrence models\",\n      \"pmids\": [\"33397932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser26 phosphorylation alters motor mechanics or partner binding unresolved\", \"Phosphatase reversing this mark unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established KIFC1 as essential for oocyte meiotic spindle and migration, acting through tubulin acetylation regulators and actin-nucleation machinery, and as a steering factor in neuronal migration.\",\n      \"evidence\": \"KIFC1 depletion with mRNA rescue, MS interaction screens, and imaging of tubulin acetylation/actin in oocytes; RNAi and sliding-vs-crosslinking mutants in vitro and in mouse brain\",\n      \"pmids\": [\"35142352\", \"35046122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling KIFC1 to HDAC6/NAT10 and actin factors not biochemically resolved\", \"How crosslinking provides traction for dynein not directly visualized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Quantified the biophysical basis of KIFC1 function: non-processive single power strokes per encounter with cooperative force amplification by motor teams.\",\n      \"evidence\": \"Single-molecule optical-trap force spectroscopy and in vitro multi-motor MT-sliding assays\",\n      \"pmids\": [\"39095439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of cooperative teams in vivo unknown\", \"How post-translational marks modulate force output untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the cancer post-translational and signaling network of KIFC1, including CDK1 phosphorylation, TRIM37/PLK4 centrosome amplification, deubiquitinase stabilization, and multiple RNA/transcription axes.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, epistasis rescue, and transcription-factor ChIP/luciferase across endometrial, cervical, pancreatic, sarcoma, bladder, and breast cancer models (CDK1, TRIM37/PLK4, USP25, FXR1/MAD2L1, ELK1, FOXD1, BUB1B, MYH9)\",\n      \"pmids\": [\"38456590\", \"39349439\", \"40379626\", \"39387242\", \"37339943\", \"39541848\", \"40857057\", \"38902769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several interactions rest on single Co-IPs without reciprocal validation\", \"Direct kinase assays for CDK1-KIFC1 phosphorylation not described\", \"Mechanistic unification of these context-specific axes incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined OTUD6B as a deubiquitinase that protects KIFC1 from premature mitotic degradation, identifying a stability control independent of centrosome amplification.\",\n      \"evidence\": \"DUB siRNA screen, OTUD6B-KIFC1 Co-IP, polyubiquitination assay, catalytic-dead and overexpression rescues, and CRISPR OTUD6B knockout\",\n      \"pmids\": [\"39789388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase opposing OTUD6B on KIFC1 not identified\", \"Mitotic timing signal triggering KIFC1 deubiquitination unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KIFC1's distinct activities\\u2014spindle/centrosome mechanics, organelle and vesicle positioning, DNA/cargo transport, and nuclear transcriptional co-activation\\u2014are partitioned and coordinated by its post-translational marks and tail-domain partners remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking specific PTMs/partners to each functional mode\", \"Structural basis for cargo selection by motor vs. tail domain not determined\", \"How a cytoskeletal motor exerts nuclear transcriptional functions mechanistically unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [1, 5, 18, 24]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [7, 11, 18, 24]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 5, 12, 23]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [10, 19, 21]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [18, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5, 17]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [18, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 28]}\n    ],\n    \"complexes\": [\"CEP215-HSET complex\"],\n    \"partners\": [\"KIF5B\", \"CEP215\", \"ASAP1\", \"OTUD6B\", \"HMGA1\", \"FXR1\", \"KPNA2\", \"TRIM37\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}