{"gene":"KIF15","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2000,"finding":"KIF15/Hklp2 interacts with the forkhead-associated (FHA) domain of Ki-67 antigen (pKi-67); the interaction domain of Hklp2 was mapped to residues 1017-1237, which is phosphorylated by mitotic but not interphase HeLa cell extracts. The interaction is strongest in mitotic extract, and immunofluorescence shows co-localization at the periphery of mitotic chromosomes near centromeres.","method":"Yeast two-hybrid screening, in vitro phosphorylation assay with mitotic/interphase cell extracts, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus in vitro phosphorylation plus immunofluorescence, single lab, multiple orthogonal methods","pmids":["10878014"],"is_preprint":false},{"year":2003,"finding":"In mitotic cells, Kif15 localizes to spindle poles and microtubules during prometaphase to early anaphase, then relocates to the actin-based cleavage furrow during cytokinesis. In interphase fibroblasts, Kif15 localizes to actin bundles but not microtubules. In cultured neurons, Kif15 localizes specifically to bundled microtubules and is enriched in stalled growth cones and dendrites. Migratory neurons show pronounced Kif15 enrichment, suggesting a role in limiting independent microtubule movements.","method":"Immunofluorescence microscopy, subcellular fractionation/localization in multiple cell types","journal":"Journal of neurocytology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunofluorescence localization across multiple cell types and developmental contexts, single lab","pmids":["14618103"],"is_preprint":false},{"year":2009,"finding":"Kif15/Hklp2 cooperates with Eg5 to promote bipolar spindle assembly. While dispensable when Eg5 is fully active, Kif15 becomes essential when Eg5 is partially inhibited. Ectopic overexpression of Kif15 can fully reconstitute bipolar spindle assembly in the complete absence of Eg5 activity. This activity depends on Kif15's interaction with the microtubule-associated protein TPX2, and requires both its motor domain and its TPX2-binding capability, suggesting the Kif15-TPX2 complex crosslinks and slides antiparallel microtubules to drive centrosome separation.","method":"RNAi knockdown, Eg5 inhibitor (monastrol/STLC), ectopic overexpression, live-cell imaging, epistasis analysis","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, drug inhibition, overexpression rescue, live imaging), replicated across conditions, clear epistasis","pmids":["19818618"],"is_preprint":false},{"year":2011,"finding":"Hklp2/Kif15 drives bipolar spindle assembly in Eg5-inhibited cells through a mechanism involving altered microtubule dynamics. Depletion of TOGp or low-dose nocodazole enables Hklp2/Kif15-dependent bipolarization through formation of acentrosomal poles, a mechanism reminiscent of meiosis. Once bipolar spindles form via Kif15, they no longer require altered microtubule dynamics to maintain bipolarity.","method":"Live cell imaging, siRNA depletion, pharmacological inhibition (Eg5 inhibitors, nocodazole)","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging plus RNAi plus drug epistasis, single lab","pmids":["22024925"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of the Kif15 motor domain was solved; the motor domain contains ADP in the catalytic site but is captured in an 'ATP-like' configuration with the neck linker docked to the catalytic core. Biochemical and kinetic characterization revealed differences in microtubule interaction mode between Kif15 and Eg5, indicating profound differences in their mechanism of action consistent with distinct microtubule cross-linking and sliding.","method":"X-ray crystallography, biochemical/kinetic characterization, microtubule co-sedimentation assay","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical validation, single lab but multiple orthogonal methods including structural and kinetic data","pmids":["24419385"],"is_preprint":false},{"year":2014,"finding":"Full-length hKif15 is a plus-end-directed processive homotetramer that steps against loads up to 3.5 pN. hKif15 is the first kinesin shown to switch microtubule tracks at intersections, enabling navigation through microtubule networks. hKif15 tetramers crosslink microtubules independently of hTpx2; instead, hTpx2 inhibits hKif15 stepping when microtubule-bound.","method":"In vitro reconstitution of full-length hKif15 and hTpx2, single-molecule optical trapping, TIRF microscopy, motility assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified full-length proteins, single-molecule optical trapping and fluorescence microscopy, multiple orthogonal assays","pmids":["24668168"],"is_preprint":false},{"year":2014,"finding":"Kif15 accumulates specifically on kinetochore fiber (K-fiber) microtubule bundles via an intrinsic two-step mechanism: (1) Kif15 is self-repressed by its C-terminus, and (2) a non-motor MT-binding site enables dimeric Kif15 to crosslink and slide MTs, with two-MT binding activating Kif15 and driving its accumulation and motility on MT bundles but not individual MTs. This demonstrates that Kif15 K-fiber targeting does not require TPX2 loading as previously proposed.","method":"In vitro MT-binding and motility assays, deletion/truncation analysis, TIRF microscopy, MT co-pelleting","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with truncations/mutagenesis, TIRF imaging, pelleting assays; single lab but multiple orthogonal methods","pmids":["25264249"],"is_preprint":false},{"year":2014,"finding":"KIF15-dependent resistance to Eg5/KIF11 inhibitor SB743921 can be overcome by Aurora A kinase inhibitors, which synergistically promote monoastral spindle formation and mitotic catastrophe. A KIF15-dependent resistance cell model was developed, demonstrating that KIF15 upregulation mediates Eg5-inhibitor resistance and that Aurora A inhibition overrides this resistance.","method":"Drug resistance cell model, live-cell imaging, isobologram synergy analysis, siRNA knockdown","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging plus pharmacological epistasis plus resistance model, single lab, multiple methods","pmids":["24950801"],"is_preprint":false},{"year":2014,"finding":"KIF15 functions as a significant inhibitor of endocytic trafficking of α2 integrin. KIF15 mediates plasma membrane localization of the alternative clathrin adaptor Dab2, thereby impinging on pathways regulating α2 integrin internalization.","method":"Quantitative fluorescence-microscopy-based RNAi screen (386 genes), siRNA validation, integrin trafficking assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi screen with validation, integrin trafficking functional readout, Dab2 localization assay, single lab","pmids":["24659801"],"is_preprint":false},{"year":2016,"finding":"The C-terminal domain of TPX2 contributes to localization of Kif15 to spindle microtubules in cells and suppresses motor walking in vitro. Kif15-dependent bipolar spindle formation in vivo requires the C-terminal domain of TPX2. GFP-Kif15 fluorescent puncta move toward the spindle equator at a rate equivalent to microtubule growth; reduction of microtubule growth with paclitaxel suppresses GFP-Kif15 motility, demonstrating that dynamic microtubules contribute to Kif15 behavior.","method":"In vitro motility assays, live-cell imaging, TIRF microscopy, TPX2 truncation/domain analysis, paclitaxel treatment","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo complementary approaches, domain deletion analysis, live imaging, single lab","pmids":["27852894"],"is_preprint":false},{"year":2017,"finding":"Kif15 dimers generate forces to slide antiparallel microtubules apart via a mechanism dependent on the non-motor microtubule-binding tail domain, which interacts with the microtubule E-hook with a rupture force higher than the motor stall force, enabling productive force generation. Parallel microtubule bundles remain stationary with only a small antagonizing force. Stochastic simulations confirm the essential role of the tail domain for load storage.","method":"Single-molecule optical tweezers, in vitro MT gliding and optical trapping fluorescence assay, stochastic simulation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule optical trapping reconstitution with multiple assay formats plus computational modeling, single lab","pmids":["28918951"],"is_preprint":false},{"year":2017,"finding":"KBP (kinesin-binding protein) is identified as a specific interaction partner of Kif15 in mitosis. KBP promotes localization of Kif15 to the spindle equator near chromosomes. Both Kif15 and KBP are required for chromosome alignment to the metaphase plate and assembly of stable kinetochore fibers of correct length.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, live-cell imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional knockdown phenotypes plus localization, single lab","pmids":["28445502"],"is_preprint":false},{"year":2017,"finding":"KIF15 promotes pancreatic cancer cell proliferation via the MEK-ERK signaling pathway; KIF15 upregulation increases cyclin D1, CDK2, and phospho-RB levels, promotes G1/S transition, and elevates p-MEK and p-ERK levels. MEK-ERK inhibitor PD98059 blocks KIF15-mediated proliferation in vivo and in vitro.","method":"siRNA knockdown, overexpression, western blot, cell cycle analysis, in vivo xenograft, MEK inhibitor treatment","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with pathway inhibitor epistasis, in vitro and in vivo, single lab","pmids":["28595260"],"is_preprint":false},{"year":2018,"finding":"KIF15 motility differs significantly from Eg5. KIF15-IN-1 is a potent inhibitor of KIF15 motility. MT gliding powered by KIF15 and Eg5 only ceases when both motors are inhibited. Pairing KIF15-IN-1 with Eg5 inhibitors synergistically reduces cancer cell growth, supporting a combination drug strategy.","method":"Single-molecule optical trapping, MT-gliding assay, cancer cell viability assay, drug combination analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule optical trapping plus MT-gliding assay plus cell viability, multiple orthogonal methods, single lab","pmids":["29703754"],"is_preprint":false},{"year":2018,"finding":"CRISPR/Cas9-mediated kif15 knockout in zebrafish accelerates axonal outgrowth and increases axon length in primary motor neurons and Rohon-Beard sensory neurons, while reducing axon branching. After laser-induced axon injury in R-B sensory neurons, kif15 knockout significantly increases regenerative velocity.","method":"CRISPR/Cas9 gene knockout in zebrafish, live imaging of transgenic/labeled neurons, laser axotomy and regeneration assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo CRISPR knockout with live imaging and axon regeneration functional readout, comparison of homo/heterozygotes to wildtype","pmids":["30411440"],"is_preprint":false},{"year":2018,"finding":"GW108X (an oxindole) inhibits Kif15 in vitro with a mechanism of action distinct from the commercially available Kif15-IN-1 inhibitor, providing a novel chemical probe for Kif15 inhibition.","method":"In vitro kinesin ATPase/motility assay, small molecule screen of kinase inhibitor library","journal":"Bioorganic & medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assay demonstrating inhibition, single lab, single method described","pmids":["30528696"],"is_preprint":false},{"year":2019,"finding":"Kinesin-binding protein (KBP) directly inhibits KIF18A and KIF15 motor activity by preventing microtubule binding, as demonstrated by gliding filament and microtubule co-pelleting assays. KBP overexpression disrupts chromosome movement/alignment and decreases spindle length (phenotypes matching KIF18A and KIF15 deficiency). KBP depletion causes lagging chromosomes in anaphase, recapitulated by KIF15 and KIF18A overexpression.","method":"Gliding filament assay, MT co-pelleting assay, overexpression, siRNA knockdown, live-cell imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro inhibition of motor-microtubule binding demonstrated by two biochemical assays plus functional cell biology, single lab but multiple orthogonal methods","pmids":["30709852"],"is_preprint":false},{"year":2020,"finding":"KIF15 directly binds the N-terminus of AR and AR-V7, and prevents AR/AR-V7 protein degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7, thereby stabilizing AR protein and promoting enzalutamide resistance. In turn, transcriptionally active AR stimulates KIF15 expression, forming a reciprocal feedback loop.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, AR protein stability assay, xenograft model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo model, single lab, multiple orthogonal methods","pmids":["33277366"],"is_preprint":false},{"year":2020,"finding":"B7-H3 regulates KIF15 expression (via NF-κB-independent pathway); KIF15 in turn activates ERK1/2 signaling to confer radioresistance in colorectal cancer. siRNA-mediated KIF15 silencing or KIF15 inhibitor (SB743921) abolishes B7-H3-mediated radioresistance both in vitro and in vivo.","method":"RNA sequencing, siRNA knockdown, pharmacological inhibition, clonogenic survival assay, in vivo tumor model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis analysis with RNAseq identification plus siRNA and inhibitor validation in vitro and in vivo, single lab","pmids":["33011740"],"is_preprint":false},{"year":2021,"finding":"KIF15 is essential for spermatid transport in Sertoli cells; KIF15 knockdown by RNAi impedes blood-testis barrier function through disruption of microtubule, actin, vimentin, and septin cytoskeletal organization in Sertoli cells.","method":"RNAi knockdown in primary Sertoli cells, immunofluorescence for cytoskeletal proteins, tight junction barrier function assay","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with functional barrier readout and multi-cytoskeletal phenotype assessment, single lab","pmids":["33453102"],"is_preprint":false},{"year":2021,"finding":"Pharmacological inhibition of Kif15-microtubule binding (not its motor activity) reduces the mechanical integrity of k-fibers (kinetochore fiber bundles), demonstrating that Kif15 acts as a microtubule cross-linker to fortify and repair k-fibers rather than primarily through its motor activity.","method":"Laser ablation of k-fibers, pharmacological inhibition with motor-null (rigor) vs. MT-binding inhibitors, live-cell imaging","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — laser ablation plus differential pharmacological inhibition (rigor vs MT-binding), live imaging, single lab","pmids":["34668719"],"is_preprint":false},{"year":2021,"finding":"KIF15 binds to EGFR and prevents EGFR protein degradation in a Cdc42-dependent manner in castration-resistant prostate cancer, thereby enhancing EGFR signaling including MAPK and PI3K/AKT pathways. Increased KIF15 expression is positively correlated with EGFR protein level in CRPC tumors.","method":"Co-immunoprecipitation, protein stability assay, Cdc42 inhibition, western blot, knockdown/overexpression","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus Cdc42-dependent epistasis plus protein stability assay, single lab","pmids":["34804913"],"is_preprint":false},{"year":2022,"finding":"KIF15 depletion in mouse oocyte meiosis does not affect spindle morphology but causes chromosome misalignment due to reduced K-fiber stability, which leads to loss of kinetochore-microtubule attachment and activates the spindle assembly checkpoint (SAC), evidenced by failed release of Bub3 and BubR1. Mass spectrometry and Co-IP showed KIF15 recruits HDAC6, NAT10, and SIRT2 to maintain tubulin acetylation levels, which affects microtubule stability.","method":"siRNA knockdown, mass spectrometry, Co-immunoprecipitation, immunofluorescence, SAC marker analysis","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mass spectrometry plus functional loss-of-function with SAC readout, single lab, multiple methods","pmids":["35835966"],"is_preprint":false},{"year":2022,"finding":"SIRT1-mediated acetylation of KIF15 is essential for KIF15 phosphorylation (the key activation event for motor protein function). KIF15 recruits PI3K-C2α via its C-terminal tail domain to promote integrin β1/FAK signaling and focal adhesion disassembly in a RAB11A-dependent manner, promoting pancreatic cancer cell migration.","method":"siRNA kinesin library screen, Co-IP, integrin recycling assay, SIRT1 inhibition, acetylation/phosphorylation analysis, in vivo migration model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen plus Co-IP plus post-translational modification analysis plus RAB11A epistasis, single lab, multiple orthogonal methods","pmids":["36280663"],"is_preprint":false},{"year":2023,"finding":"KIF15 promotes PGK1 protein stability and glycolytic capacity in pancreatic cancer by recruiting USP10 deubiquitinase to PGK1, thereby reducing PGK1 ubiquitination. The KIF15 coil2 domain mediates binding to both PGK1 and USP10. Co-IP and ubiquitination assays confirm the KIF15/USP10/PGK1 axis.","method":"Mass spectrometry, Co-immunoprecipitation, ubiquitination assay, KIF15 truncation/domain analysis, ECAR/OCR metabolic measurements, siRNA knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mass spectrometry plus ubiquitination assay plus domain mapping, single lab, multiple orthogonal methods","pmids":["36807568"],"is_preprint":false},{"year":2023,"finding":"KIF15 interacts with STAT3, retaining it in the cytoplasm. KIF15 knockdown decreases STAT3's inhibitory effect on ATG7, thereby upregulating autophagy, and METTL3-mediated m6A methylation increases KIF15 mRNA stability to promote radioresistance in NPC. Overexpression of STAT3 reverses the inhibitory effects of KIF15 knockdown on autophagy.","method":"Co-immunoprecipitation, m6A RNA immunoprecipitation, STAT3 localization assay, autophagy flux analysis, overexpression/knockdown epistasis","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus m6A-RIP plus STAT3 localization plus autophagy pathway epistasis, single lab, multiple methods","pmids":["39504712"],"is_preprint":false},{"year":2023,"finding":"KIF15 interacts with PSD95 protein (demonstrated by endogenous and exogenous Co-IP). In Kif15-/- mice, PSD95 is distributed around neuronal nuclei rather than at cell membranes, demonstrating KIF15 is required for proper PSD95 transport/localization. Kif15 deficiency reduces excitatory postsynaptic scaffolding (PSD95, NMDAR) and dendritic spine density while increasing inhibitory scaffolding (Gephyrin, GABRB1), contributing to bipolar disorder-like behavior.","method":"CRISPR/Cas9 knockout mice, endogenous and exogenous Co-IP, immunofluorescence, electrophysiology (mEPSC), behavioral assays, zebrafish rescue experiments","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP (endogenous + exogenous) plus KO mouse phenotype plus zebrafish rescue, single lab, multiple orthogonal methods","pmids":["40892874"],"is_preprint":false},{"year":2023,"finding":"KIF15 knockdown reduces NRAS protein stability by increasing ubiquitination of NRAS. KIF15 interacts with the E3 ubiquitin ligase MDM2 (by Co-IP), and this interaction reduces ubiquitination modification of NRAS, stabilizing NRAS protein and activating the Rac signaling pathway to promote colorectal cancer proliferation and migration.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, siRNA knockdown, xenograft model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus loss-of-function phenotype, single lab","pmids":["37970344"],"is_preprint":false},{"year":2024,"finding":"KIF15 modulates HDAC6 to affect tubulin acetylation and maintain microtubule stability in porcine oocytes; KIF15 localization depends on microtubule dynamics. KIF15 deficiency causes spindle morphology defects, chromosome misalignment due to microtubule instability (shown by cold treatment depolymerization), and blocks polar body extrusion during aging.","method":"Morpholino/siRNA knockdown, immunofluorescence, cold-induced MT depolymerization assay, tubulin acetylation analysis","journal":"Theriogenology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with microtubule stability assay and HDAC6 pathway connection, single lab","pmids":["38838614"],"is_preprint":false},{"year":2024,"finding":"PRC1-mediated antiparallel microtubule bundling supports KIF15-driven mitotic spindle assembly in Eg5-inhibitor-resistant cells (KIRCs). Loss of PRC1 in KIRCs decreases spindle bipolarity; PRC1 overexpression increases spindle formation efficiency and protects naïve cells against Eg5 inhibitors; PRC1 overexpression promotes establishment of Eg5-inhibitor resistance. These effects are not fully reproduced by TPX2 (a non-orientation-selective MT bundler).","method":"siRNA knockdown, overexpression, spindle bipolarity assays, drug resistance assays, comparison with TPX2 overexpression controls","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in drug-resistant cells plus comparative overexpression controls, single lab, multiple functional readouts","pmids":["38598297"],"is_preprint":false},{"year":2024,"finding":"KIF15 deficiency in dorsal root ganglion neurons leads to reduced Annexin A2 function at the cell membrane and increased TRPA1 channel membrane localization, contributing to cold hypersensitivity. KIF15 physically interacts with Annexin A2 in peripheral sensory neurons. In oxaliplatin-induced peripheral neuropathy, KIF15 expression is markedly reduced, coinciding with increased TRPA1 membrane localization.","method":"KIF15 knockout mice, Co-immunoprecipitation, immunofluorescence/membrane fractionation, behavioral cold sensitivity assay, oxaliplatin neuropathy model","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus KO mouse model plus TRPA1 membrane localization analysis, single lab, multiple methods","pmids":["39914618"],"is_preprint":false},{"year":2024,"finding":"KIF15 inhibitor treatment increases migration and phagocytosis of macrophages in vitro, associated with increased activation of Cdc42 and RhoA. In zebrafish kif15 morphants with spinal cord injury, Coro1a+ immune cells show increased recruitment then rapid decline, with enhanced phagocytic capacity.","method":"Zebrafish morpholino knockdown, Kif15 pharmacological inhibition, phagocytosis assay, Cdc42/RhoA activation assay, live imaging","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo zebrafish morphant model plus in vitro inhibitor assays plus Rho GTPase activation, single lab","pmids":["39709909"],"is_preprint":false},{"year":2021,"finding":"KIF15 upregulation in leiomyosarcoma promotes cell proliferation by preventing DEK protein degradation via increasing USP15-mediated deubiquitylation of DEK. Co-IP confirms mutual interaction between KIF15 and DEK, and between USP15 and both DEK and KIF15. USP15 knockdown decreases DEK stability and cancels KIF15-mediated DEK stabilization.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, protein stability assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus genetic epistasis, single lab, multiple orthogonal approaches","pmids":["34280614"],"is_preprint":false},{"year":2023,"finding":"FoxO6 transcription factor directly activates Kif15 expression as a downstream molecule; Kif15 inhibition attenuates the aggravating effect of FoxO6 overexpression on cardiac hypertrophy. KIF15 promotes TGF-β1 release from cardiomyocytes, which induces fibroblast proliferation and differentiation, establishing the FoxO6/Kif15/TGF-β1 axis in cardiac pathological remodeling.","method":"FoxO6 knockout/overexpression mice, Ang-II cardiac hypertrophy model, Kif15 inhibition, cardiomyocyte-fibroblast co-culture, TGF-β1 measurement","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and overexpression mouse model plus in vitro epistasis, single lab, multiple cellular/molecular readouts","pmids":["37799807"],"is_preprint":false},{"year":2024,"finding":"REST transcription factor binds to the KIF15 promoter and transactivates KIF15 expression; REST interacts with the histone acetyltransferase P300 and depends on P300's HAT activity to co-regulate KIF15 expression. Both REST and P300 promote GBM progression via KIF15.","method":"Chromatin immunoprecipitation, promoter reporter assay, co-immunoprecipitation (REST-P300 interaction), overexpression/knockdown, P300 HAT inhibitor treatment, xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP plus functional inhibitor epistasis in vitro and in vivo, single lab","pmids":["39430242"],"is_preprint":false},{"year":2026,"finding":"KIF15 interacts with peroxiredoxin 1 (PRDX1) to stabilize PRDX1 protein, reducing intracellular hydroperoxides and maintaining mitochondrial function. Depletion of PRDX1 reverses KIF15-mediated oncogenic effects. YY1 transcription factor directly binds the KIF15 promoter to activate KIF15 expression, and YY1 also directly transcriptionally regulates PRDX1.","method":"Co-immunoprecipitation, protein stability assay, PRDX1 knockdown rescue, YY1 ChIP, promoter binding assay, ROS measurement, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus protein stability assay plus in vivo model, single lab, multiple orthogonal methods","pmids":["41912772"],"is_preprint":false},{"year":2026,"finding":"Kif15 facilitates the expression and localization of neuronal CX3CL1 (fractalkine); in Kif15 KO mice, CX3CL1-CX3CR1 signaling between neurons and microglia is downregulated. Kif15 knockout mice show accelerated functional recovery after sciatic nerve injury, associated with a repair-promoting microglial profile and neuroprotective neuronal gene expression changes.","method":"CRISPR/Cas9 Kif15 KO mice, single-nucleus RNA sequencing, CX3CL1 localization assay, sciatic nerve injury model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model plus snRNA-seq plus CX3CL1 localization analysis, single lab","pmids":["42055325"],"is_preprint":false}],"current_model":"KIF15 (Kinesin-12/Hklp2) is a plus-end-directed, processive homotetrameric microtubule motor that cooperates with Eg5 to drive bipolar mitotic spindle assembly by crosslinking and sliding antiparallel microtubules; it is self-repressed by its C-terminus and activated by simultaneous binding to two microtubules, targets kinetochore fibers to reinforce their mechanical integrity as a crosslinker, and is regulated by TPX2 (which inhibits stepping when MT-bound) and PRC1-mediated antiparallel MT bundling; beyond mitosis, KIF15 participates in integrin endocytic trafficking via Dab2, stabilizes AR/EGFR/NRAS/PRDX1/DEK/PGK1 proteins by recruiting specific deubiquitinases (USP14, USP15, USP10), activates MEK-ERK and PI3K-AKT signaling in multiple cancer contexts, regulates axonal microtubule dynamics and PSD95/TRPA1 localization in neurons, and undergoes SIRT1-mediated acetylation required for its own phosphorylation and motor activation."},"narrative":{"mechanistic_narrative":"KIF15 (Hklp2/Kinesin-12) is a plus-end-directed processive homotetrameric microtubule motor that drives bipolar mitotic spindle assembly in cooperation with Eg5/KIF11, becoming essential when Eg5 is partially inhibited and able to reconstitute bipolarity in the complete absence of Eg5 activity [PMID:19818618]. Single-molecule reconstitution established KIF15 as a processive motor that steps against loads up to 3.5 pN and uniquely switches microtubule tracks at intersections; its tetramers crosslink microtubules and slide antiparallel filaments apart through a non-motor tail domain that binds the tubulin E-hook with a rupture force exceeding the motor stall force, while parallel bundles remain stationary [PMID:24668168, PMID:28918951]. KIF15 is self-repressed by its C-terminus and activated by simultaneous binding to two microtubules, which targets it to kinetochore-fiber bundles where it acts principally as a crosslinker to fortify and repair K-fibers rather than through motor activity [PMID:25264249, PMID:34668719]. Its activity is tuned by associated factors: TPX2 inhibits stepping when KIF15 is microtubule-bound yet contributes to spindle localization [PMID:24668168, PMID:27852894], kinesin-binding protein (KBP) directly blocks microtubule binding to regulate chromosome alignment and K-fiber length [PMID:28445502, PMID:30709852], and PRC1-mediated antiparallel bundling supports KIF15-driven assembly in Eg5-inhibitor-resistant cells [PMID:38598297]. KIF15 upregulation mediates resistance to Eg5 inhibitors, a vulnerability reversible by Aurora A inhibition or direct KIF15 inhibitors [PMID:24950801, PMID:29703754]. Beyond mitosis, KIF15 restrains axonal outgrowth and regeneration [PMID:30411440], directs PSD95 and TRPA1 channel localization in neurons [PMID:40892874, PMID:39914618], and in numerous cancers stabilizes client proteins (AR, EGFR, NRAS, DEK, PGK1, PRDX1) by recruiting deubiquitinases or modulating E3 ligase activity, thereby activating MEK-ERK, PI3K-AKT and related growth pathways [PMID:28595260, PMID:33277366, PMID:34804913, PMID:36807568, PMID:37970344, PMID:34280614, PMID:41912772].","teleology":[{"year":2000,"claim":"Established the first molecular partner of KIF15/Hklp2, linking it to mitotic chromosome periphery via a mitosis-specific phosphorylated interaction domain.","evidence":"Yeast two-hybrid, in vitro phosphorylation with cell extracts, and immunofluorescence in HeLa cells","pmids":["10878014"],"confidence":"Medium","gaps":["Functional consequence of the Ki-67 interaction unresolved","Identity of the mitotic kinase not determined"]},{"year":2003,"claim":"Mapped KIF15 subcellular distribution across mitotic, interphase and neuronal contexts, hinting at roles in microtubule bundling beyond mitosis.","evidence":"Immunofluorescence and localization across multiple cell types including neurons","pmids":["14618103"],"confidence":"Medium","gaps":["Mechanistic basis for actin vs microtubule association unclear","Neuronal function not functionally tested here"]},{"year":2009,"claim":"Defined KIF15's central role as an Eg5-cooperating motor that drives bipolar spindle assembly and can substitute for Eg5 when overexpressed.","evidence":"RNAi, Eg5 inhibitors, overexpression rescue, live imaging and epistasis in cells","pmids":["19818618"],"confidence":"High","gaps":["Whether TPX2 is strictly required for crosslinking debated by later in vitro work","Direct biochemical demonstration of antiparallel sliding not yet shown"]},{"year":2011,"claim":"Showed KIF15-driven bipolarization in Eg5-inhibited cells proceeds via altered microtubule dynamics and acentrosomal pole formation.","evidence":"Live imaging, siRNA, and pharmacological inhibition in cells","pmids":["22024925"],"confidence":"Medium","gaps":["Molecular determinants linking MT dynamics to KIF15 activity unresolved"]},{"year":2013,"claim":"Provided the structural and kinetic basis distinguishing KIF15's motor mechanism from Eg5.","evidence":"X-ray crystallography of the motor domain plus kinetic and co-sedimentation assays","pmids":["24419385"],"confidence":"High","gaps":["No full-length or tail-domain structure","Mechanistic link between structure and crosslinking not defined"]},{"year":2014,"claim":"Reconstitution of full-length KIF15 defined it as a processive, load-bearing tetramer that crosslinks microtubules independently of TPX2 and switches tracks at intersections, reframing the KIF15-TPX2 relationship.","evidence":"In vitro reconstitution with purified hKif15/hTpx2, single-molecule optical trapping and TIRF","pmids":["24668168"],"confidence":"High","gaps":["In vivo relevance of track-switching not established","How tetramerization is regulated unclear"]},{"year":2014,"claim":"Revealed the autoregulatory two-step activation: C-terminal self-repression relieved by two-microtubule binding drives K-fiber targeting without TPX2 loading.","evidence":"In vitro MT-binding/motility assays, truncations, TIRF and co-pelleting","pmids":["25264249"],"confidence":"High","gaps":["Structural mechanism of C-terminal autoinhibition not solved","In vivo trigger for two-MT engagement unclear"]},{"year":2014,"claim":"Identified KIF15 upregulation as a mechanism of Eg5-inhibitor resistance overridable by Aurora A inhibition, establishing therapeutic relevance.","evidence":"Drug-resistance cell model, live imaging, synergy analysis and siRNA","pmids":["24950801"],"confidence":"Medium","gaps":["Mechanism connecting Aurora A to KIF15 dependence not defined"]},{"year":2014,"claim":"Extended KIF15 function beyond mitosis to membrane trafficking by controlling Dab2-dependent integrin internalization.","evidence":"Quantitative RNAi screen with siRNA validation and integrin trafficking assays","pmids":["24659801"],"confidence":"Medium","gaps":["Direct KIF15-Dab2 interaction not demonstrated","Cargo specificity unresolved"]},{"year":2017,"claim":"Demonstrated KIF15 generates antiparallel sliding force through its non-motor tail domain binding the tubulin E-hook, clarifying the biophysical basis of crosslinking.","evidence":"Single-molecule optical tweezers, gliding/trapping assays and stochastic simulation","pmids":["28918951"],"confidence":"High","gaps":["Tail-E-hook interaction not structurally resolved","Regulation of parallel vs antiparallel selectivity unclear"]},{"year":2017,"claim":"Identified KBP as a mitotic KIF15 partner required for chromosome alignment and stable K-fiber assembly.","evidence":"Co-IP, immunofluorescence, siRNA and live imaging","pmids":["28445502"],"confidence":"Medium","gaps":["Direct vs indirect interaction not distinguished in this study"]},{"year":2019,"claim":"Showed KBP directly inhibits KIF15 (and KIF18A) motor activity by blocking microtubule binding, defining a negative regulatory mechanism for spindle motors.","evidence":"Gliding filament and co-pelleting assays plus overexpression/knockdown live imaging","pmids":["30709852"],"confidence":"High","gaps":["Structural basis of KBP-motor inhibition not resolved"]},{"year":2016,"claim":"Refined the TPX2 contribution: its C-terminal domain suppresses KIF15 walking in vitro yet supports spindle localization and dynamic-MT-coupled motility in cells.","evidence":"In vitro motility, TIRF, live imaging, TPX2 truncations and paclitaxel treatment","pmids":["27852894"],"confidence":"Medium","gaps":["Reconciliation of inhibitory vs localization roles incomplete"]},{"year":2018,"claim":"Provided selective KIF15 chemical inhibitors and validated combination with Eg5 inhibition as an anticancer strategy.","evidence":"Single-molecule trapping, MT-gliding, viability and drug-combination assays (KIF15-IN-1); ATPase/motility screen (GW108X)","pmids":["29703754","30528696"],"confidence":"High","gaps":["In vivo efficacy and selectivity of inhibitors not established here"]},{"year":2018,"claim":"Established a neuronal role: KIF15 restrains axonal outgrowth, branching and regenerative velocity in vivo.","evidence":"CRISPR/Cas9 knockout in zebrafish with live imaging and laser axotomy","pmids":["30411440"],"confidence":"Medium","gaps":["Molecular cargo or microtubule substrate in neurons not identified"]},{"year":2021,"claim":"Demonstrated KIF15 fortifies K-fibers mechanically via its crosslinking (MT-binding) function rather than motor activity.","evidence":"Laser ablation with rigor vs MT-binding inhibitors and live imaging","pmids":["34668719"],"confidence":"Medium","gaps":["Quantitative contribution relative to other K-fiber crosslinkers unclear"]},{"year":2021,"claim":"Extended KIF15 spindle function to meiosis (oocytes) and to Sertoli-cell cytoskeletal organization and blood-testis barrier integrity.","evidence":"RNAi knockdown with cytoskeletal immunofluorescence and barrier assays in Sertoli cells","pmids":["33453102"],"confidence":"Medium","gaps":["Direct molecular targets in Sertoli cytoskeleton unresolved"]},{"year":2024,"claim":"Defined how K-fiber/spindle stability is maintained via KIF15-dependent control of tubulin acetylation in oocyte meiosis.","evidence":"siRNA/morpholino knockdown, Co-IP, mass spectrometry, cold-depolymerization and SAC marker analysis in mouse and porcine oocytes","pmids":["35835966","38838614"],"confidence":"Medium","gaps":["Whether KIF15 directly regulates HDAC6/NAT10/SIRT2 enzymatic activity unresolved","Generalizability to mitotic spindle unclear"]},{"year":2024,"claim":"Showed PRC1-mediated antiparallel bundling specifically supports KIF15-driven assembly in Eg5-inhibitor-resistant cells, distinguishing it from non-selective TPX2 bundling.","evidence":"siRNA, overexpression and drug-resistance assays with TPX2 comparison controls","pmids":["38598297"],"confidence":"Medium","gaps":["Direct PRC1-KIF15 physical relationship not established"]},{"year":2026,"claim":"Mapped KIF15-dependent transport and localization functions in neurons (PSD95, TRPA1, CX3CL1) linking it to synaptic scaffolding, cold sensation and neuroimmune signaling.","evidence":"CRISPR/Cas9 KO mice, Co-IP, membrane fractionation, electrophysiology, snRNA-seq and injury/behavior models","pmids":["40892874","39914618","42055325"],"confidence":"Medium","gaps":["Whether KIF15 directly motors these cargoes vs acts indirectly not resolved","Microtubule-track dependence of neuronal cargo delivery untested"]},{"year":2023,"claim":"Established a recurrent oncogenic paradigm whereby KIF15 stabilizes client proteins by recruiting deubiquitinases or modulating E3 ligases to activate growth and metabolic pathways.","evidence":"Co-IP, ubiquitination/protein-stability assays, domain mapping and xenografts across AR, EGFR, 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activating crosstalk of multiple pathways in ovarian cancer: bioinformatic and experimental analysis.","date":"2021","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33564360","citation_count":4,"is_preprint":false},{"pmid":"39709909","id":"PMC_39709909","title":"Kif15 regulates Coro1a+ cell migration and phagocytosis in zebrafish after spinal cord injury.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39709909","citation_count":3,"is_preprint":false},{"pmid":"37970344","id":"PMC_37970344","title":"KIF15 knockdown inhibits colorectal cancer proliferation and migration through affecting the ubiquitination modification of NRAS.","date":"2023","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/37970344","citation_count":3,"is_preprint":false},{"pmid":"38598297","id":"PMC_38598297","title":"Antiparallel microtubule bundling supports KIF15-driven mitotic spindle assembly.","date":"2024","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/38598297","citation_count":3,"is_preprint":false},{"pmid":"40087774","id":"PMC_40087774","title":"Atractylenolide I ameliorated the growth and enzalutamide resistance of castration-resistant prostate cancer by targeting KIF15.","date":"2025","source":"Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40087774","citation_count":3,"is_preprint":false},{"pmid":"39914618","id":"PMC_39914618","title":"Deficiency of KIF15 contributes to oxaliplatin-induced cold hypersensitivity by limiting annexin A2 and enhancing TRPA1 localization in DRG neuronal membrane.","date":"2025","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39914618","citation_count":2,"is_preprint":false},{"pmid":"40892874","id":"PMC_40892874","title":"Deficiency of Kif15 impairing synaptic development leads to mood disorder in mice.","date":"2025","source":"PLoS 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The interaction is strongest in mitotic extract, and immunofluorescence shows co-localization at the periphery of mitotic chromosomes near centromeres.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro phosphorylation assay with mitotic/interphase cell extracts, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus in vitro phosphorylation plus immunofluorescence, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10878014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In mitotic cells, Kif15 localizes to spindle poles and microtubules during prometaphase to early anaphase, then relocates to the actin-based cleavage furrow during cytokinesis. In interphase fibroblasts, Kif15 localizes to actin bundles but not microtubules. In cultured neurons, Kif15 localizes specifically to bundled microtubules and is enriched in stalled growth cones and dendrites. Migratory neurons show pronounced Kif15 enrichment, suggesting a role in limiting independent microtubule movements.\",\n      \"method\": \"Immunofluorescence microscopy, subcellular fractionation/localization in multiple cell types\",\n      \"journal\": \"Journal of neurocytology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunofluorescence localization across multiple cell types and developmental contexts, single lab\",\n      \"pmids\": [\"14618103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Kif15/Hklp2 cooperates with Eg5 to promote bipolar spindle assembly. While dispensable when Eg5 is fully active, Kif15 becomes essential when Eg5 is partially inhibited. Ectopic overexpression of Kif15 can fully reconstitute bipolar spindle assembly in the complete absence of Eg5 activity. This activity depends on Kif15's interaction with the microtubule-associated protein TPX2, and requires both its motor domain and its TPX2-binding capability, suggesting the Kif15-TPX2 complex crosslinks and slides antiparallel microtubules to drive centrosome separation.\",\n      \"method\": \"RNAi knockdown, Eg5 inhibitor (monastrol/STLC), ectopic overexpression, live-cell imaging, epistasis analysis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, drug inhibition, overexpression rescue, live imaging), replicated across conditions, clear epistasis\",\n      \"pmids\": [\"19818618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hklp2/Kif15 drives bipolar spindle assembly in Eg5-inhibited cells through a mechanism involving altered microtubule dynamics. Depletion of TOGp or low-dose nocodazole enables Hklp2/Kif15-dependent bipolarization through formation of acentrosomal poles, a mechanism reminiscent of meiosis. Once bipolar spindles form via Kif15, they no longer require altered microtubule dynamics to maintain bipolarity.\",\n      \"method\": \"Live cell imaging, siRNA depletion, pharmacological inhibition (Eg5 inhibitors, nocodazole)\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging plus RNAi plus drug epistasis, single lab\",\n      \"pmids\": [\"22024925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of the Kif15 motor domain was solved; the motor domain contains ADP in the catalytic site but is captured in an 'ATP-like' configuration with the neck linker docked to the catalytic core. Biochemical and kinetic characterization revealed differences in microtubule interaction mode between Kif15 and Eg5, indicating profound differences in their mechanism of action consistent with distinct microtubule cross-linking and sliding.\",\n      \"method\": \"X-ray crystallography, biochemical/kinetic characterization, microtubule co-sedimentation assay\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical validation, single lab but multiple orthogonal methods including structural and kinetic data\",\n      \"pmids\": [\"24419385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Full-length hKif15 is a plus-end-directed processive homotetramer that steps against loads up to 3.5 pN. hKif15 is the first kinesin shown to switch microtubule tracks at intersections, enabling navigation through microtubule networks. hKif15 tetramers crosslink microtubules independently of hTpx2; instead, hTpx2 inhibits hKif15 stepping when microtubule-bound.\",\n      \"method\": \"In vitro reconstitution of full-length hKif15 and hTpx2, single-molecule optical trapping, TIRF microscopy, motility assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified full-length proteins, single-molecule optical trapping and fluorescence microscopy, multiple orthogonal assays\",\n      \"pmids\": [\"24668168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Kif15 accumulates specifically on kinetochore fiber (K-fiber) microtubule bundles via an intrinsic two-step mechanism: (1) Kif15 is self-repressed by its C-terminus, and (2) a non-motor MT-binding site enables dimeric Kif15 to crosslink and slide MTs, with two-MT binding activating Kif15 and driving its accumulation and motility on MT bundles but not individual MTs. This demonstrates that Kif15 K-fiber targeting does not require TPX2 loading as previously proposed.\",\n      \"method\": \"In vitro MT-binding and motility assays, deletion/truncation analysis, TIRF microscopy, MT co-pelleting\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with truncations/mutagenesis, TIRF imaging, pelleting assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25264249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIF15-dependent resistance to Eg5/KIF11 inhibitor SB743921 can be overcome by Aurora A kinase inhibitors, which synergistically promote monoastral spindle formation and mitotic catastrophe. A KIF15-dependent resistance cell model was developed, demonstrating that KIF15 upregulation mediates Eg5-inhibitor resistance and that Aurora A inhibition overrides this resistance.\",\n      \"method\": \"Drug resistance cell model, live-cell imaging, isobologram synergy analysis, siRNA knockdown\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging plus pharmacological epistasis plus resistance model, single lab, multiple methods\",\n      \"pmids\": [\"24950801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIF15 functions as a significant inhibitor of endocytic trafficking of α2 integrin. KIF15 mediates plasma membrane localization of the alternative clathrin adaptor Dab2, thereby impinging on pathways regulating α2 integrin internalization.\",\n      \"method\": \"Quantitative fluorescence-microscopy-based RNAi screen (386 genes), siRNA validation, integrin trafficking assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi screen with validation, integrin trafficking functional readout, Dab2 localization assay, single lab\",\n      \"pmids\": [\"24659801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The C-terminal domain of TPX2 contributes to localization of Kif15 to spindle microtubules in cells and suppresses motor walking in vitro. Kif15-dependent bipolar spindle formation in vivo requires the C-terminal domain of TPX2. GFP-Kif15 fluorescent puncta move toward the spindle equator at a rate equivalent to microtubule growth; reduction of microtubule growth with paclitaxel suppresses GFP-Kif15 motility, demonstrating that dynamic microtubules contribute to Kif15 behavior.\",\n      \"method\": \"In vitro motility assays, live-cell imaging, TIRF microscopy, TPX2 truncation/domain analysis, paclitaxel treatment\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo complementary approaches, domain deletion analysis, live imaging, single lab\",\n      \"pmids\": [\"27852894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Kif15 dimers generate forces to slide antiparallel microtubules apart via a mechanism dependent on the non-motor microtubule-binding tail domain, which interacts with the microtubule E-hook with a rupture force higher than the motor stall force, enabling productive force generation. Parallel microtubule bundles remain stationary with only a small antagonizing force. Stochastic simulations confirm the essential role of the tail domain for load storage.\",\n      \"method\": \"Single-molecule optical tweezers, in vitro MT gliding and optical trapping fluorescence assay, stochastic simulation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule optical trapping reconstitution with multiple assay formats plus computational modeling, single lab\",\n      \"pmids\": [\"28918951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KBP (kinesin-binding protein) is identified as a specific interaction partner of Kif15 in mitosis. KBP promotes localization of Kif15 to the spindle equator near chromosomes. Both Kif15 and KBP are required for chromosome alignment to the metaphase plate and assembly of stable kinetochore fibers of correct length.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, live-cell imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional knockdown phenotypes plus localization, single lab\",\n      \"pmids\": [\"28445502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIF15 promotes pancreatic cancer cell proliferation via the MEK-ERK signaling pathway; KIF15 upregulation increases cyclin D1, CDK2, and phospho-RB levels, promotes G1/S transition, and elevates p-MEK and p-ERK levels. MEK-ERK inhibitor PD98059 blocks KIF15-mediated proliferation in vivo and in vitro.\",\n      \"method\": \"siRNA knockdown, overexpression, western blot, cell cycle analysis, in vivo xenograft, MEK inhibitor treatment\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with pathway inhibitor epistasis, in vitro and in vivo, single lab\",\n      \"pmids\": [\"28595260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIF15 motility differs significantly from Eg5. KIF15-IN-1 is a potent inhibitor of KIF15 motility. MT gliding powered by KIF15 and Eg5 only ceases when both motors are inhibited. Pairing KIF15-IN-1 with Eg5 inhibitors synergistically reduces cancer cell growth, supporting a combination drug strategy.\",\n      \"method\": \"Single-molecule optical trapping, MT-gliding assay, cancer cell viability assay, drug combination analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule optical trapping plus MT-gliding assay plus cell viability, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29703754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CRISPR/Cas9-mediated kif15 knockout in zebrafish accelerates axonal outgrowth and increases axon length in primary motor neurons and Rohon-Beard sensory neurons, while reducing axon branching. After laser-induced axon injury in R-B sensory neurons, kif15 knockout significantly increases regenerative velocity.\",\n      \"method\": \"CRISPR/Cas9 gene knockout in zebrafish, live imaging of transgenic/labeled neurons, laser axotomy and regeneration assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CRISPR knockout with live imaging and axon regeneration functional readout, comparison of homo/heterozygotes to wildtype\",\n      \"pmids\": [\"30411440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GW108X (an oxindole) inhibits Kif15 in vitro with a mechanism of action distinct from the commercially available Kif15-IN-1 inhibitor, providing a novel chemical probe for Kif15 inhibition.\",\n      \"method\": \"In vitro kinesin ATPase/motility assay, small molecule screen of kinase inhibitor library\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assay demonstrating inhibition, single lab, single method described\",\n      \"pmids\": [\"30528696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kinesin-binding protein (KBP) directly inhibits KIF18A and KIF15 motor activity by preventing microtubule binding, as demonstrated by gliding filament and microtubule co-pelleting assays. KBP overexpression disrupts chromosome movement/alignment and decreases spindle length (phenotypes matching KIF18A and KIF15 deficiency). KBP depletion causes lagging chromosomes in anaphase, recapitulated by KIF15 and KIF18A overexpression.\",\n      \"method\": \"Gliding filament assay, MT co-pelleting assay, overexpression, siRNA knockdown, live-cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro inhibition of motor-microtubule binding demonstrated by two biochemical assays plus functional cell biology, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30709852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KIF15 directly binds the N-terminus of AR and AR-V7, and prevents AR/AR-V7 protein degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7, thereby stabilizing AR protein and promoting enzalutamide resistance. In turn, transcriptionally active AR stimulates KIF15 expression, forming a reciprocal feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, AR protein stability assay, xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo model, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33277366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"B7-H3 regulates KIF15 expression (via NF-κB-independent pathway); KIF15 in turn activates ERK1/2 signaling to confer radioresistance in colorectal cancer. siRNA-mediated KIF15 silencing or KIF15 inhibitor (SB743921) abolishes B7-H3-mediated radioresistance both in vitro and in vivo.\",\n      \"method\": \"RNA sequencing, siRNA knockdown, pharmacological inhibition, clonogenic survival assay, in vivo tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis analysis with RNAseq identification plus siRNA and inhibitor validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"33011740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIF15 is essential for spermatid transport in Sertoli cells; KIF15 knockdown by RNAi impedes blood-testis barrier function through disruption of microtubule, actin, vimentin, and septin cytoskeletal organization in Sertoli cells.\",\n      \"method\": \"RNAi knockdown in primary Sertoli cells, immunofluorescence for cytoskeletal proteins, tight junction barrier function assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with functional barrier readout and multi-cytoskeletal phenotype assessment, single lab\",\n      \"pmids\": [\"33453102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pharmacological inhibition of Kif15-microtubule binding (not its motor activity) reduces the mechanical integrity of k-fibers (kinetochore fiber bundles), demonstrating that Kif15 acts as a microtubule cross-linker to fortify and repair k-fibers rather than primarily through its motor activity.\",\n      \"method\": \"Laser ablation of k-fibers, pharmacological inhibition with motor-null (rigor) vs. MT-binding inhibitors, live-cell imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — laser ablation plus differential pharmacological inhibition (rigor vs MT-binding), live imaging, single lab\",\n      \"pmids\": [\"34668719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIF15 binds to EGFR and prevents EGFR protein degradation in a Cdc42-dependent manner in castration-resistant prostate cancer, thereby enhancing EGFR signaling including MAPK and PI3K/AKT pathways. Increased KIF15 expression is positively correlated with EGFR protein level in CRPC tumors.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, Cdc42 inhibition, western blot, knockdown/overexpression\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus Cdc42-dependent epistasis plus protein stability assay, single lab\",\n      \"pmids\": [\"34804913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KIF15 depletion in mouse oocyte meiosis does not affect spindle morphology but causes chromosome misalignment due to reduced K-fiber stability, which leads to loss of kinetochore-microtubule attachment and activates the spindle assembly checkpoint (SAC), evidenced by failed release of Bub3 and BubR1. Mass spectrometry and Co-IP showed KIF15 recruits HDAC6, NAT10, and SIRT2 to maintain tubulin acetylation levels, which affects microtubule stability.\",\n      \"method\": \"siRNA knockdown, mass spectrometry, Co-immunoprecipitation, immunofluorescence, SAC marker analysis\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mass spectrometry plus functional loss-of-function with SAC readout, single lab, multiple methods\",\n      \"pmids\": [\"35835966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT1-mediated acetylation of KIF15 is essential for KIF15 phosphorylation (the key activation event for motor protein function). KIF15 recruits PI3K-C2α via its C-terminal tail domain to promote integrin β1/FAK signaling and focal adhesion disassembly in a RAB11A-dependent manner, promoting pancreatic cancer cell migration.\",\n      \"method\": \"siRNA kinesin library screen, Co-IP, integrin recycling assay, SIRT1 inhibition, acetylation/phosphorylation analysis, in vivo migration model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen plus Co-IP plus post-translational modification analysis plus RAB11A epistasis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36280663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIF15 promotes PGK1 protein stability and glycolytic capacity in pancreatic cancer by recruiting USP10 deubiquitinase to PGK1, thereby reducing PGK1 ubiquitination. The KIF15 coil2 domain mediates binding to both PGK1 and USP10. Co-IP and ubiquitination assays confirm the KIF15/USP10/PGK1 axis.\",\n      \"method\": \"Mass spectrometry, Co-immunoprecipitation, ubiquitination assay, KIF15 truncation/domain analysis, ECAR/OCR metabolic measurements, siRNA knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mass spectrometry plus ubiquitination assay plus domain mapping, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36807568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIF15 interacts with STAT3, retaining it in the cytoplasm. KIF15 knockdown decreases STAT3's inhibitory effect on ATG7, thereby upregulating autophagy, and METTL3-mediated m6A methylation increases KIF15 mRNA stability to promote radioresistance in NPC. Overexpression of STAT3 reverses the inhibitory effects of KIF15 knockdown on autophagy.\",\n      \"method\": \"Co-immunoprecipitation, m6A RNA immunoprecipitation, STAT3 localization assay, autophagy flux analysis, overexpression/knockdown epistasis\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus m6A-RIP plus STAT3 localization plus autophagy pathway epistasis, single lab, multiple methods\",\n      \"pmids\": [\"39504712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIF15 interacts with PSD95 protein (demonstrated by endogenous and exogenous Co-IP). In Kif15-/- mice, PSD95 is distributed around neuronal nuclei rather than at cell membranes, demonstrating KIF15 is required for proper PSD95 transport/localization. Kif15 deficiency reduces excitatory postsynaptic scaffolding (PSD95, NMDAR) and dendritic spine density while increasing inhibitory scaffolding (Gephyrin, GABRB1), contributing to bipolar disorder-like behavior.\",\n      \"method\": \"CRISPR/Cas9 knockout mice, endogenous and exogenous Co-IP, immunofluorescence, electrophysiology (mEPSC), behavioral assays, zebrafish rescue experiments\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP (endogenous + exogenous) plus KO mouse phenotype plus zebrafish rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40892874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIF15 knockdown reduces NRAS protein stability by increasing ubiquitination of NRAS. KIF15 interacts with the E3 ubiquitin ligase MDM2 (by Co-IP), and this interaction reduces ubiquitination modification of NRAS, stabilizing NRAS protein and activating the Rac signaling pathway to promote colorectal cancer proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, siRNA knockdown, xenograft model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus loss-of-function phenotype, single lab\",\n      \"pmids\": [\"37970344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF15 modulates HDAC6 to affect tubulin acetylation and maintain microtubule stability in porcine oocytes; KIF15 localization depends on microtubule dynamics. KIF15 deficiency causes spindle morphology defects, chromosome misalignment due to microtubule instability (shown by cold treatment depolymerization), and blocks polar body extrusion during aging.\",\n      \"method\": \"Morpholino/siRNA knockdown, immunofluorescence, cold-induced MT depolymerization assay, tubulin acetylation analysis\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with microtubule stability assay and HDAC6 pathway connection, single lab\",\n      \"pmids\": [\"38838614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRC1-mediated antiparallel microtubule bundling supports KIF15-driven mitotic spindle assembly in Eg5-inhibitor-resistant cells (KIRCs). Loss of PRC1 in KIRCs decreases spindle bipolarity; PRC1 overexpression increases spindle formation efficiency and protects naïve cells against Eg5 inhibitors; PRC1 overexpression promotes establishment of Eg5-inhibitor resistance. These effects are not fully reproduced by TPX2 (a non-orientation-selective MT bundler).\",\n      \"method\": \"siRNA knockdown, overexpression, spindle bipolarity assays, drug resistance assays, comparison with TPX2 overexpression controls\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in drug-resistant cells plus comparative overexpression controls, single lab, multiple functional readouts\",\n      \"pmids\": [\"38598297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF15 deficiency in dorsal root ganglion neurons leads to reduced Annexin A2 function at the cell membrane and increased TRPA1 channel membrane localization, contributing to cold hypersensitivity. KIF15 physically interacts with Annexin A2 in peripheral sensory neurons. In oxaliplatin-induced peripheral neuropathy, KIF15 expression is markedly reduced, coinciding with increased TRPA1 membrane localization.\",\n      \"method\": \"KIF15 knockout mice, Co-immunoprecipitation, immunofluorescence/membrane fractionation, behavioral cold sensitivity assay, oxaliplatin neuropathy model\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus KO mouse model plus TRPA1 membrane localization analysis, single lab, multiple methods\",\n      \"pmids\": [\"39914618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIF15 inhibitor treatment increases migration and phagocytosis of macrophages in vitro, associated with increased activation of Cdc42 and RhoA. In zebrafish kif15 morphants with spinal cord injury, Coro1a+ immune cells show increased recruitment then rapid decline, with enhanced phagocytic capacity.\",\n      \"method\": \"Zebrafish morpholino knockdown, Kif15 pharmacological inhibition, phagocytosis assay, Cdc42/RhoA activation assay, live imaging\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo zebrafish morphant model plus in vitro inhibitor assays plus Rho GTPase activation, single lab\",\n      \"pmids\": [\"39709909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIF15 upregulation in leiomyosarcoma promotes cell proliferation by preventing DEK protein degradation via increasing USP15-mediated deubiquitylation of DEK. Co-IP confirms mutual interaction between KIF15 and DEK, and between USP15 and both DEK and KIF15. USP15 knockdown decreases DEK stability and cancels KIF15-mediated DEK stabilization.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, protein stability assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus genetic epistasis, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"34280614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FoxO6 transcription factor directly activates Kif15 expression as a downstream molecule; Kif15 inhibition attenuates the aggravating effect of FoxO6 overexpression on cardiac hypertrophy. KIF15 promotes TGF-β1 release from cardiomyocytes, which induces fibroblast proliferation and differentiation, establishing the FoxO6/Kif15/TGF-β1 axis in cardiac pathological remodeling.\",\n      \"method\": \"FoxO6 knockout/overexpression mice, Ang-II cardiac hypertrophy model, Kif15 inhibition, cardiomyocyte-fibroblast co-culture, TGF-β1 measurement\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and overexpression mouse model plus in vitro epistasis, single lab, multiple cellular/molecular readouts\",\n      \"pmids\": [\"37799807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"REST transcription factor binds to the KIF15 promoter and transactivates KIF15 expression; REST interacts with the histone acetyltransferase P300 and depends on P300's HAT activity to co-regulate KIF15 expression. Both REST and P300 promote GBM progression via KIF15.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter reporter assay, co-immunoprecipitation (REST-P300 interaction), overexpression/knockdown, P300 HAT inhibitor treatment, xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP plus functional inhibitor epistasis in vitro and in vivo, single lab\",\n      \"pmids\": [\"39430242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KIF15 interacts with peroxiredoxin 1 (PRDX1) to stabilize PRDX1 protein, reducing intracellular hydroperoxides and maintaining mitochondrial function. Depletion of PRDX1 reverses KIF15-mediated oncogenic effects. YY1 transcription factor directly binds the KIF15 promoter to activate KIF15 expression, and YY1 also directly transcriptionally regulates PRDX1.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, PRDX1 knockdown rescue, YY1 ChIP, promoter binding assay, ROS measurement, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus protein stability assay plus in vivo model, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41912772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Kif15 facilitates the expression and localization of neuronal CX3CL1 (fractalkine); in Kif15 KO mice, CX3CL1-CX3CR1 signaling between neurons and microglia is downregulated. Kif15 knockout mice show accelerated functional recovery after sciatic nerve injury, associated with a repair-promoting microglial profile and neuroprotective neuronal gene expression changes.\",\n      \"method\": \"CRISPR/Cas9 Kif15 KO mice, single-nucleus RNA sequencing, CX3CL1 localization assay, sciatic nerve injury model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model plus snRNA-seq plus CX3CL1 localization analysis, single lab\",\n      \"pmids\": [\"42055325\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIF15 (Kinesin-12/Hklp2) is a plus-end-directed, processive homotetrameric microtubule motor that cooperates with Eg5 to drive bipolar mitotic spindle assembly by crosslinking and sliding antiparallel microtubules; it is self-repressed by its C-terminus and activated by simultaneous binding to two microtubules, targets kinetochore fibers to reinforce their mechanical integrity as a crosslinker, and is regulated by TPX2 (which inhibits stepping when MT-bound) and PRC1-mediated antiparallel MT bundling; beyond mitosis, KIF15 participates in integrin endocytic trafficking via Dab2, stabilizes AR/EGFR/NRAS/PRDX1/DEK/PGK1 proteins by recruiting specific deubiquitinases (USP14, USP15, USP10), activates MEK-ERK and PI3K-AKT signaling in multiple cancer contexts, regulates axonal microtubule dynamics and PSD95/TRPA1 localization in neurons, and undergoes SIRT1-mediated acetylation required for its own phosphorylation and motor activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF15 (Hklp2/Kinesin-12) is a plus-end-directed processive homotetrameric microtubule motor that drives bipolar mitotic spindle assembly in cooperation with Eg5/KIF11, becoming essential when Eg5 is partially inhibited and able to reconstitute bipolarity in the complete absence of Eg5 activity [#2]. Single-molecule reconstitution established KIF15 as a processive motor that steps against loads up to 3.5 pN and uniquely switches microtubule tracks at intersections; its tetramers crosslink microtubules and slide antiparallel filaments apart through a non-motor tail domain that binds the tubulin E-hook with a rupture force exceeding the motor stall force, while parallel bundles remain stationary [#5, #10]. KIF15 is self-repressed by its C-terminus and activated by simultaneous binding to two microtubules, which targets it to kinetochore-fiber bundles where it acts principally as a crosslinker to fortify and repair K-fibers rather than through motor activity [#6, #20]. Its activity is tuned by associated factors: TPX2 inhibits stepping when KIF15 is microtubule-bound yet contributes to spindle localization [#5, #9], kinesin-binding protein (KBP) directly blocks microtubule binding to regulate chromosome alignment and K-fiber length [#11, #16], and PRC1-mediated antiparallel bundling supports KIF15-driven assembly in Eg5-inhibitor-resistant cells [#29]. KIF15 upregulation mediates resistance to Eg5 inhibitors, a vulnerability reversible by Aurora A inhibition or direct KIF15 inhibitors [#7, #13]. Beyond mitosis, KIF15 restrains axonal outgrowth and regeneration [#14], directs PSD95 and TRPA1 channel localization in neurons [#26, #30], and in numerous cancers stabilizes client proteins (AR, EGFR, NRAS, DEK, PGK1, PRDX1) by recruiting deubiquitinases or modulating E3 ligase activity, thereby activating MEK-ERK, PI3K-AKT and related growth pathways [#12, #17, #21, #24, #27, #32, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the first molecular partner of KIF15/Hklp2, linking it to mitotic chromosome periphery via a mitosis-specific phosphorylated interaction domain.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro phosphorylation with cell extracts, and immunofluorescence in HeLa cells\",\n      \"pmids\": [\"10878014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the Ki-67 interaction unresolved\", \"Identity of the mitotic kinase not determined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped KIF15 subcellular distribution across mitotic, interphase and neuronal contexts, hinting at roles in microtubule bundling beyond mitosis.\",\n      \"evidence\": \"Immunofluorescence and localization across multiple cell types including neurons\",\n      \"pmids\": [\"14618103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis for actin vs microtubule association unclear\", \"Neuronal function not functionally tested here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined KIF15's central role as an Eg5-cooperating motor that drives bipolar spindle assembly and can substitute for Eg5 when overexpressed.\",\n      \"evidence\": \"RNAi, Eg5 inhibitors, overexpression rescue, live imaging and epistasis in cells\",\n      \"pmids\": [\"19818618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TPX2 is strictly required for crosslinking debated by later in vitro work\", \"Direct biochemical demonstration of antiparallel sliding not yet shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed KIF15-driven bipolarization in Eg5-inhibited cells proceeds via altered microtubule dynamics and acentrosomal pole formation.\",\n      \"evidence\": \"Live imaging, siRNA, and pharmacological inhibition in cells\",\n      \"pmids\": [\"22024925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular determinants linking MT dynamics to KIF15 activity unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural and kinetic basis distinguishing KIF15's motor mechanism from Eg5.\",\n      \"evidence\": \"X-ray crystallography of the motor domain plus kinetic and co-sedimentation assays\",\n      \"pmids\": [\"24419385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length or tail-domain structure\", \"Mechanistic link between structure and crosslinking not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reconstitution of full-length KIF15 defined it as a processive, load-bearing tetramer that crosslinks microtubules independently of TPX2 and switches tracks at intersections, reframing the KIF15-TPX2 relationship.\",\n      \"evidence\": \"In vitro reconstitution with purified hKif15/hTpx2, single-molecule optical trapping and TIRF\",\n      \"pmids\": [\"24668168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of track-switching not established\", \"How tetramerization is regulated unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed the autoregulatory two-step activation: C-terminal self-repression relieved by two-microtubule binding drives K-fiber targeting without TPX2 loading.\",\n      \"evidence\": \"In vitro MT-binding/motility assays, truncations, TIRF and co-pelleting\",\n      \"pmids\": [\"25264249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of C-terminal autoinhibition not solved\", \"In vivo trigger for two-MT engagement unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified KIF15 upregulation as a mechanism of Eg5-inhibitor resistance overridable by Aurora A inhibition, establishing therapeutic relevance.\",\n      \"evidence\": \"Drug-resistance cell model, live imaging, synergy analysis and siRNA\",\n      \"pmids\": [\"24950801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting Aurora A to KIF15 dependence not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended KIF15 function beyond mitosis to membrane trafficking by controlling Dab2-dependent integrin internalization.\",\n      \"evidence\": \"Quantitative RNAi screen with siRNA validation and integrin trafficking assays\",\n      \"pmids\": [\"24659801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KIF15-Dab2 interaction not demonstrated\", \"Cargo specificity unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated KIF15 generates antiparallel sliding force through its non-motor tail domain binding the tubulin E-hook, clarifying the biophysical basis of crosslinking.\",\n      \"evidence\": \"Single-molecule optical tweezers, gliding/trapping assays and stochastic simulation\",\n      \"pmids\": [\"28918951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tail-E-hook interaction not structurally resolved\", \"Regulation of parallel vs antiparallel selectivity unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified KBP as a mitotic KIF15 partner required for chromosome alignment and stable K-fiber assembly.\",\n      \"evidence\": \"Co-IP, immunofluorescence, siRNA and live imaging\",\n      \"pmids\": [\"28445502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect interaction not distinguished in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed KBP directly inhibits KIF15 (and KIF18A) motor activity by blocking microtubule binding, defining a negative regulatory mechanism for spindle motors.\",\n      \"evidence\": \"Gliding filament and co-pelleting assays plus overexpression/knockdown live imaging\",\n      \"pmids\": [\"30709852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of KBP-motor inhibition not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined the TPX2 contribution: its C-terminal domain suppresses KIF15 walking in vitro yet supports spindle localization and dynamic-MT-coupled motility in cells.\",\n      \"evidence\": \"In vitro motility, TIRF, live imaging, TPX2 truncations and paclitaxel treatment\",\n      \"pmids\": [\"27852894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of inhibitory vs localization roles incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided selective KIF15 chemical inhibitors and validated combination with Eg5 inhibition as an anticancer strategy.\",\n      \"evidence\": \"Single-molecule trapping, MT-gliding, viability and drug-combination assays (KIF15-IN-1); ATPase/motility screen (GW108X)\",\n      \"pmids\": [\"29703754\", \"30528696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy and selectivity of inhibitors not established here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a neuronal role: KIF15 restrains axonal outgrowth, branching and regenerative velocity in vivo.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in zebrafish with live imaging and laser axotomy\",\n      \"pmids\": [\"30411440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cargo or microtubule substrate in neurons not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated KIF15 fortifies K-fibers mechanically via its crosslinking (MT-binding) function rather than motor activity.\",\n      \"evidence\": \"Laser ablation with rigor vs MT-binding inhibitors and live imaging\",\n      \"pmids\": [\"34668719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution relative to other K-fiber crosslinkers unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended KIF15 spindle function to meiosis (oocytes) and to Sertoli-cell cytoskeletal organization and blood-testis barrier integrity.\",\n      \"evidence\": \"RNAi knockdown with cytoskeletal immunofluorescence and barrier assays in Sertoli cells\",\n      \"pmids\": [\"33453102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets in Sertoli cytoskeleton unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined how K-fiber/spindle stability is maintained via KIF15-dependent control of tubulin acetylation in oocyte meiosis.\",\n      \"evidence\": \"siRNA/morpholino knockdown, Co-IP, mass spectrometry, cold-depolymerization and SAC marker analysis in mouse and porcine oocytes\",\n      \"pmids\": [\"35835966\", \"38838614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KIF15 directly regulates HDAC6/NAT10/SIRT2 enzymatic activity unresolved\", \"Generalizability to mitotic spindle unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed PRC1-mediated antiparallel bundling specifically supports KIF15-driven assembly in Eg5-inhibitor-resistant cells, distinguishing it from non-selective TPX2 bundling.\",\n      \"evidence\": \"siRNA, overexpression and drug-resistance assays with TPX2 comparison controls\",\n      \"pmids\": [\"38598297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PRC1-KIF15 physical relationship not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapped KIF15-dependent transport and localization functions in neurons (PSD95, TRPA1, CX3CL1) linking it to synaptic scaffolding, cold sensation and neuroimmune signaling.\",\n      \"evidence\": \"CRISPR/Cas9 KO mice, Co-IP, membrane fractionation, electrophysiology, snRNA-seq and injury/behavior models\",\n      \"pmids\": [\"40892874\", \"39914618\", \"42055325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KIF15 directly motors these cargoes vs acts indirectly not resolved\", \"Microtubule-track dependence of neuronal cargo delivery untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a recurrent oncogenic paradigm whereby KIF15 stabilizes client proteins by recruiting deubiquitinases or modulating E3 ligases to activate growth and metabolic pathways.\",\n      \"evidence\": \"Co-IP, ubiquitination/protein-stability assays, domain mapping and xenografts across AR, EGFR, NRAS, DEK, PGK1, PRDX1 in multiple cancers\",\n      \"pmids\": [\"33277366\", \"34804913\", \"37970344\", \"34280614\", \"36807568\", \"41912772\", \"28595260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a microtubule motor scaffolds DUB-substrate complexes mechanistically unclear\", \"Whether these functions require motor/MT-binding activity untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked KIF15 activation to post-translational regulation, with SIRT1-mediated acetylation required for its phosphorylation and motor activation, coupling it to integrin/FAK signaling and cell migration.\",\n      \"evidence\": \"siRNA kinesin screen, Co-IP, acetylation/phosphorylation analysis, integrin recycling and RAB11A epistasis with in vivo migration model\",\n      \"pmids\": [\"36280663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetylation and phosphorylation sites not mapped\", \"Direct enzyme-KIF15 contacts not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single autoinhibited microtubule motor is repurposed across mitotic crosslinking, neuronal cargo localization, and DUB-mediated protein stabilization in cancer—and whether the non-mitotic functions depend on its motor/MT-binding activity—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of full-length autoinhibition and activation\", \"Whether cancer scaffolding functions require microtubule binding untested\", \"Direct cargo motoring vs indirect localization effects in neurons undistinguished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [2, 4, 5, 10]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 6, 10, 20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [17, 24, 27, 32]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17, 24, 27, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [1, 2, 6, 20]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 5, 10, 19]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 3, 6, 11, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 17, 21, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 13, 17, 18]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 23]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TPX2\", \"KBP\", \"USP14\", \"USP10\", \"USP15\", \"MDM2\", \"PRDX1\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}