{"gene":"KIF2B","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"KIF2B (kinesin-13 family) localizes predominantly to centrosomes and midbodies, but also to spindle microtubules and transiently to kinetochores. KIF2B-deficient cells assemble monopolar or disorganized spindles and show ~80% reduction in chromosome movement velocity. Bipolar spindle assembly can be restored by simultaneous depletion of MCAK, Nuf2, or treatment with low-dose nocodazole, or by perturbing NuMA/HSET pole-focusing activities, placing KIF2B function in spindle assembly and chromosome movement.","method":"siRNA knockdown, GFP-KIF2B live-cell imaging, immunofluorescence, epistasis by double-knockdown","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal KD epistasis with multiple genetic backgrounds, direct localization by live imaging, defined cellular phenotypes with velocity measurements","pmids":["17538014"],"is_preprint":false},{"year":2008,"finding":"KIF2B stimulates kinetochore-microtubule (kMT) dynamics specifically during early mitosis to correct mal-oriented attachments, while MCAK acts in a distinct, later phase. Few-fold reductions in kMT turnover, particularly in early mitosis, induce severe chromosome segregation defects. Overexpression of KIF2B restores kMT dynamics and chromosome segregation fidelity in chromosomally unstable tumor cell lines.","method":"siRNA knockdown, kMT turnover assay (fluorescence dissipation after photoactivation), overexpression rescue in CIN tumor lines","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (kMT turnover, siRNA, OE rescue), replicated across cell lines","pmids":["19060894"],"is_preprint":false},{"year":2010,"finding":"In early mitosis, KIF2B forms a complex with CLASP1 at kinetochores to promote kMT turnover, correction of attachment errors, and maintenance of spindle assembly checkpoint (SAC) signalling. During metaphase, this KIF2B-CLASP1 complex is replaced by an astrin-CLASP1 complex that promotes kMT stability and SAC silencing. The two complexes are mutually exclusive at kinetochores. KIF18A affects kMT attachments and chromosome movement through these proteins.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, kMT turnover assay, epistasis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating complex, functional epistasis, turnover assays, temporal resolution of two distinct complexes","pmids":["20852589"],"is_preprint":false},{"year":2012,"finding":"Plk1 directly phosphorylates KIF2B at threonine 125 (T125) and serine 204 (S204). Phosphorylation of S204 is required for KIF2B kinetochore localization and activity in prometaphase; phosphorylation of T125 is required for KIF2B activity in correcting kMT attachment errors. These sites were identified by mass spectrometry and validated by mutagenesis.","method":"Mass spectrometry phosphoproteomics, in vitro kinase assay with Plk1, phosphomimetic/phosphodeficient mutagenesis, immunofluorescence, Plk1 inhibitor (BI2536)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay + mutagenesis + MS identification, multiple phosphorylation sites with distinct functional readouts","pmids":["22535524"],"is_preprint":false},{"year":2012,"finding":"The C-terminus of KIF2B mediates specific protein-protein interactions that distinguish it from other kinesin-13 paralogs. Cep170 and Cep170R (KIAA0284) specifically associate with KIF2B (not Kif2a or MCAK). Cep170 binds microtubules in vitro and provides KIF2B with a second microtubule-binding site to target it to the mitotic spindle. The N-terminus is the primary determinant of kinesin-13 localization.","method":"Co-immunoprecipitation, in vitro microtubule-binding assay, domain-swap mutants, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro microtubule binding reconstitution, Co-IP, domain mapping, single lab with multiple orthogonal methods","pmids":["23087211"],"is_preprint":false},{"year":2013,"finding":"Chk1 activity is required for stable localization of KIF2B (and MCAK) to centromeres/kinetochores. Decreased Chk1 activity leads to hyperstable kMTs and unstable binding of KIF2B to centromeres/kinetochores. Chk1 phosphorylates Aurora-B at Ser331, and this phosphorylation is required for optimal KIF2B localization. Mps1 inhibition also diminishes initial recruitment of KIF2B to centromeres/kinetochores, and Chk1 and Mps1 jointly regulate KIF2B localization.","method":"Chk1 inhibitor/siRNA, Mps1 inhibitor, immunofluorescence for KIF2B localization, phospho-specific antibodies, Aurora-B mutagenesis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization with inhibitor treatment and functional readout, multiple kinases tested, single lab","pmids":["23321637"],"is_preprint":false},{"year":2015,"finding":"TBK1 is necessary for CEP170 centrosomal localization and for CEP170 binding to KIF2B. Disruption of the TBK1-CEP170 complex augments microtubule stability and triggers mitotic defects, placing TBK1 upstream of the CEP170-KIF2B interaction in regulating microtubule dynamics.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, TBK1 inhibitor","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for TBK1-CEP170-KIF2B, KD with functional readout, single lab","pmids":["26656453"],"is_preprint":false},{"year":2016,"finding":"GSK3β phosphorylates SKAP, and this phosphorylation promotes SKAP binding to KIF2B to regulate its microtubule depolymerase activity at microtubule plus-ends. SKAP competes with KIF2B for microtubule plus-end binding, thereby temporally inhibiting KIF2B depolymerase activity to ensure accurate kinetochore-microtubule attachment.","method":"In vitro kinase assay (GSK3β phosphorylating SKAP), mass spectrometry phosphosite mapping, co-immunoprecipitation, phosphomimetic rescue assay, microtubule plus-end binding competition assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay and MS mapping combined with Co-IP and cell-based rescue, single lab","pmids":["27982129"],"is_preprint":false},{"year":2019,"finding":"Modest overexpression of KIF2B in transgenic mice reduces chromosome segregation defects in K-Ras G12D-driven lung tumors but does not reduce tumor incidence; instead, tumors are significantly larger with elevated Ki-67 in KIF2B-overexpressing animals. This establishes that KIF2B-mediated reduction of CIN suppresses tumor growth in the context of K-Ras-driven lung cancer.","method":"Transgenic mouse overexpression (Kif2b), K-Ras G12D lung cancer model, chromosome segregation scoring, Ki-67 immunostaining","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with defined chromosome segregation readout, single lab","pmids":["31179849"],"is_preprint":false},{"year":2020,"finding":"Plk1 phosphorylation of KIF2B at Ser/Thr sites controls chromosome alignment. Using a Ser/Thr toggle chemical-genetic system, toggling Plk1-phosphorylated Ser residues on KIF2B to Thr (placing them under orthogonal kinase control) caused sharp increases in misaligned chromosomes and prometaphase arrest upon chemical inhibition, confirming that Plk1-mediated phosphorylation of KIF2B is required for chromosome alignment.","method":"Chemical-genetic Plk1 Ser/Thr toggle system, phosphoproteomics, live-cell imaging, chromosome alignment scoring","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — chemical-genetic reconstitution with phosphoproteomic validation, functional chromosomal phenotype, single lab","pmids":["32017920"],"is_preprint":false},{"year":2021,"finding":"SCFFbxw5 ubiquitin E3 ligase polyubiquitylates KIF2B (along with Kif2a and MCAK) in vitro via Cdc34, without requiring preceding modifications on KIF2B. Concomitant knockdown of KIF2B, Kif2a, or MCAK rescues ciliogenesis defects caused by Fbxw5 loss, indicating SCFFbxw5-mediated degradation of KIF2B contributes to regulation of ciliogenesis.","method":"In vitro ubiquitylation reconstitution assay (protein microarray screen + neddylated SCFFbxw5 + Cdc34), siRNA knockdown rescue of ciliogenesis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ubiquitylation is Tier 1, but KIF2B-specific ciliogenesis rescue is single lab","pmids":["34368969"],"is_preprint":false},{"year":2025,"finding":"KIF2B interacts with KASH5 (a LINC complex component) in mouse spermatocytes, as identified by co-immunoprecipitation and yeast two-hybrid assays using KASH5 as bait, suggesting KIF2B participates in force transmission to telomeres during meiotic prophase chromosome movements.","method":"Co-immunoprecipitation, yeast two-hybrid (KASH5 bait), proteomic screen of microtubule-associated motor proteins in mouse spermatocytes","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and Y2H identify interaction but functional role of KIF2B specifically (vs KIF5B) is not directly tested; preprint, single lab","pmids":["40501626"],"is_preprint":true}],"current_model":"KIF2B is a kinesin-13 microtubule depolymerase that acts specifically in early mitosis at kinetochores—where it forms a complex with CLASP1—to promote kinetochore-microtubule turnover and correction of erroneous attachments; its kinetochore localization and depolymerase activity are regulated by direct Plk1 phosphorylation (at S204 for localization and T125 for error-correction activity), by Chk1/Aurora-B and Mps1 signaling, and by competitive binding of GSK3β-phosphorylated SKAP at microtubule plus-ends, while its spindle targeting is facilitated by association with Cep170 (which provides a second microtubule-binding site) and its abundance is controlled by SCFFbxw5-mediated ubiquitylation and proteasomal degradation."},"narrative":{"mechanistic_narrative":"KIF2B is a kinesin-13 family microtubule depolymerase that drives chromosome segregation fidelity by stimulating kinetochore-microtubule (kMT) turnover specifically during early mitosis, where it corrects mal-oriented attachments before MCAK acts in a later phase [PMID:17538014, PMID:19060894]. It localizes to centrosomes, midbodies, spindle microtubules, and transiently to kinetochores, and its loss produces monopolar or disorganized spindles and severely slowed chromosome movement [PMID:17538014]. At kinetochores in early mitosis KIF2B forms a complex with CLASP1 that promotes kMT turnover, error correction, and spindle assembly checkpoint signalling; this complex is replaced at metaphase by an astrin-CLASP1 complex that stabilizes kMTs and silences the checkpoint [PMID:20852589]. KIF2B activity and targeting are governed by phosphoregulation: Plk1 directly phosphorylates S204 (required for kinetochore localization) and T125 (required for attachment-error correction), and Plk1 phosphorylation is required for chromosome alignment [PMID:22535524, PMID:32017920], while Chk1—acting in part through Aurora-B Ser331 phosphorylation—and Mps1 control its centromere/kinetochore recruitment [PMID:23321637]. Its spindle targeting is provided by a C-terminus-specific association with Cep170, which contributes a second microtubule-binding site and is itself dependent on TBK1 [PMID:23087211, PMID:26656453], and its depolymerase activity at microtubule plus-ends is temporally restrained by competitive binding of GSK3β-phosphorylated SKAP [PMID:27982129]. KIF2B abundance is limited by SCF-Fbxw5-mediated polyubiquitylation, linking its turnover to ciliogenesis control [PMID:34368969]. Functionally, restoring KIF2B-mediated kMT dynamics suppresses chromosomal instability, and modest overexpression in K-Ras-driven mouse lung tumors reduces segregation defects [PMID:19060894, PMID:31179849].","teleology":[{"year":2007,"claim":"Established that KIF2B is a kinesin-13 protein required for bipolar spindle assembly and normal chromosome movement, placing it within the mitotic microtubule-dynamics machinery.","evidence":"siRNA knockdown, GFP-KIF2B live imaging, and double-knockdown epistasis with MCAK/Nuf2/NuMA/HSET in human cells","pmids":["17538014"],"confidence":"High","gaps":["Did not resolve whether KIF2B acts at kinetochores versus poles for its primary function","Depolymerase biochemistry not directly reconstituted here"]},{"year":2008,"claim":"Resolved the temporal niche of KIF2B by showing it stimulates kMT turnover specifically in early mitosis to correct errors, distinct from MCAK, and that boosting this activity rescues chromosomal instability.","evidence":"kMT turnover by fluorescence dissipation after photoactivation, siRNA, and overexpression rescue in CIN tumor lines","pmids":["19060894"],"confidence":"High","gaps":["Molecular partners conferring early-mitotic specificity not yet identified","Did not define how turnover defects translate to missegregation mechanistically"]},{"year":2010,"claim":"Identified the CLASP1-KIF2B complex as the early-mitotic kinetochore module for error correction and SAC maintenance, and showed a temporal switch to astrin-CLASP1 at metaphase.","evidence":"Co-immunoprecipitation, siRNA, immunofluorescence, and kMT turnover assays with temporal resolution","pmids":["20852589"],"confidence":"High","gaps":["Mechanism of the complex switch (what displaces KIF2B) not defined here","Direct vs indirect KIF2B-CLASP1 binding not established"]},{"year":2012,"claim":"Defined how KIF2B activity is switched on by establishing Plk1 as a direct kinase phosphorylating distinct residues controlling localization (S204) and error-correction activity (T125).","evidence":"Phosphoproteomics, in vitro Plk1 kinase assay, phosphomutant rescue, and Plk1 inhibition (BI2536)","pmids":["22535524"],"confidence":"High","gaps":["How S204 phosphorylation mechanistically drives kinetochore targeting unresolved","Structural basis of T125-dependent activity unknown"]},{"year":2012,"claim":"Explained paralog-specific spindle targeting by showing KIF2B's C-terminus binds Cep170, which provides a second microtubule-binding site absent in Kif2a/MCAK.","evidence":"Co-IP, in vitro microtubule-binding assay, and domain-swap mutants","pmids":["23087211"],"confidence":"High","gaps":["Quantitative contribution of the second MT-binding site to depolymerase processivity not measured","Whether Cep170 modulates activity or only localization unclear"]},{"year":2013,"claim":"Placed KIF2B kinetochore recruitment downstream of mitotic checkpoint kinases by showing Chk1 (via Aurora-B Ser331) and Mps1 jointly control its centromere localization.","evidence":"Chk1/Mps1 inhibition and siRNA, phospho-specific antibodies, Aurora-B mutagenesis, and immunofluorescence","pmids":["23321637"],"confidence":"Medium","gaps":["Single-lab study","Direct vs indirect role of Aurora-B Ser331 phosphorylation on KIF2B not biochemically isolated"]},{"year":2015,"claim":"Identified TBK1 as an upstream regulator required for CEP170 centrosomal localization and CEP170-KIF2B binding, linking a kinase to KIF2B's spindle-targeting interaction.","evidence":"Co-IP, siRNA, immunofluorescence, and TBK1 inhibition","pmids":["26656453"],"confidence":"Medium","gaps":["Whether TBK1 acts directly on CEP170 or KIF2B not established","Single-lab study"]},{"year":2016,"claim":"Revealed a negative-regulation mechanism in which GSK3β-phosphorylated SKAP competes with KIF2B for microtubule plus-ends to temporally restrain its depolymerase activity.","evidence":"In vitro GSK3β kinase assay, MS phosphosite mapping, Co-IP, phosphomimetic rescue, and plus-end binding competition","pmids":["27982129"],"confidence":"Medium","gaps":["Single-lab study","In vivo timing of SKAP-mediated inhibition relative to Plk1 activation not integrated"]},{"year":2019,"claim":"Tested the tumor-relevance of KIF2B in vivo, showing that modest overexpression reduces segregation defects in K-Ras-driven lung tumors but increases tumor size rather than suppressing incidence.","evidence":"Transgenic Kif2b overexpression in K-Ras G12D mouse lung cancer with segregation scoring and Ki-67 staining","pmids":["31179849"],"confidence":"Medium","gaps":["Mechanism linking reduced CIN to larger tumors not resolved","Single-lab study, overexpression rather than physiological levels"]},{"year":2020,"claim":"Confirmed via orthogonal chemical-genetic control that Plk1-mediated phosphorylation of KIF2B is required for chromosome alignment.","evidence":"Plk1 Ser/Thr toggle chemical-genetic system, phosphoproteomics, and live-cell chromosome alignment scoring","pmids":["32017920"],"confidence":"Medium","gaps":["Single-lab study","Did not separate KIF2B's contribution from other Plk1 substrates in the alignment phenotype"]},{"year":2021,"claim":"Established that KIF2B abundance is controlled by SCF-Fbxw5-mediated polyubiquitylation, connecting its degradation to ciliogenesis.","evidence":"In vitro ubiquitylation reconstitution with neddylated SCF-Fbxw5/Cdc34 and siRNA rescue of ciliogenesis","pmids":["34368969"],"confidence":"Medium","gaps":["KIF2B-specific (vs Kif2a/MCAK) contribution to ciliogenesis rescue is single-lab","In vivo timing of degradation across the cell cycle not defined"]},{"year":2025,"claim":"Extended KIF2B's role to meiosis by identifying an interaction with the LINC component KASH5 in spermatocytes, implicating it in telomere force transmission during meiotic prophase.","evidence":"Co-IP and yeast two-hybrid with KASH5 bait, proteomic screen in mouse spermatocytes (preprint)","pmids":["40501626"],"confidence":"Low","gaps":["Functional role of KIF2B specifically (vs KIF5B) not tested","Preprint, single lab, interaction not validated reciprocally in vivo"]},{"year":null,"claim":"How the multiple regulatory inputs (Plk1, Chk1/Aurora-B/Mps1, SKAP competition, Cep170/TBK1 targeting, Fbxw5 degradation) are integrated in space and time to switch KIF2B activity on and off at individual kinetochores remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of KIF2B or its regulated complexes","Quantitative hierarchy among regulators undefined","Physiological meiotic and ciliary roles not mechanistically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,2,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,2,5]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2,3]}],"complexes":["KIF2B-CLASP1 kinetochore complex","CEP170-KIF2B complex"],"partners":["CLASP1","CEP170","SKAP","TBK1","PLK1","KASH5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N4N8","full_name":"Kinesin-like protein KIF2B","aliases":[],"length_aa":673,"mass_kda":76.3,"function":"Plus end-directed microtubule-dependent motor required for spindle assembly and chromosome movement. Has microtubule depolymerization activity (PubMed:17538014). Plays a role in chromosome congression (PubMed:23891108)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle; Chromosome, centromere, kinetochore","url":"https://www.uniprot.org/uniprotkb/Q8N4N8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIF2B","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIF2B","total_profiled":1310},"omim":[{"mim_id":"620251","title":"CENTROSOMAL PROTEIN 170B; CEP170B","url":"https://www.omim.org/entry/620251"},{"mim_id":"615142","title":"KINESIN FAMILY MEMBER 2B; KIF2B","url":"https://www.omim.org/entry/615142"},{"mim_id":"613023","title":"CENTROSOMAL PROTEIN, 170-KD; CEP170","url":"https://www.omim.org/entry/613023"},{"mim_id":"604538","title":"KINESIN FAMILY MEMBER 2C; KIF2C","url":"https://www.omim.org/entry/604538"},{"mim_id":"602591","title":"KINESIN FAMILY MEMBER 2A; KIF2A","url":"https://www.omim.org/entry/602591"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Microtubules","reliability":"Uncertain"},{"location":"Cytokinetic bridge","reliability":"Uncertain"},{"location":"Mitotic spindle","reliability":"Uncertain"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":70.5}],"url":"https://www.proteinatlas.org/search/KIF2B"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8N4N8","domains":[{"cath_id":"2.30.30","chopping":"29-82","consensus_level":"high","plddt":88.1452,"start":29,"end":82},{"cath_id":"3.40.850.10","chopping":"291-519_535-541","consensus_level":"high","plddt":87.76,"start":291,"end":541}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N4N8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N4N8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N4N8-F1-predicted_aligned_error_v6.png","plddt_mean":72.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIF2B","jax_strain_url":"https://www.jax.org/strain/search?query=KIF2B"},"sequence":{"accession":"Q8N4N8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N4N8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N4N8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N4N8"}},"corpus_meta":[{"pmid":"19060894","id":"PMC_19060894","title":"Genome 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Activity of Certain Key Microtubule Kinesins.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34067543","citation_count":1,"is_preprint":false},{"pmid":"40213390","id":"PMC_40213390","title":"KIF2C is essential for meiosis and manchette dynamics in male mice.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/40213390","citation_count":1,"is_preprint":false},{"pmid":"40501626","id":"PMC_40501626","title":"Kinesin drive meiotic chromosome dynamics via interaction with the KASH5-LINC complex.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40501626","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12766,"output_tokens":3398,"usd":0.044634,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10899,"output_tokens":4083,"usd":0.078285,"stage2_stop_reason":"end_turn"},"total_usd":0.122919,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"KIF2B (kinesin-13 family) localizes predominantly to centrosomes and midbodies, but also to spindle microtubules and transiently to kinetochores. KIF2B-deficient cells assemble monopolar or disorganized spindles and show ~80% reduction in chromosome movement velocity. Bipolar spindle assembly can be restored by simultaneous depletion of MCAK, Nuf2, or treatment with low-dose nocodazole, or by perturbing NuMA/HSET pole-focusing activities, placing KIF2B function in spindle assembly and chromosome movement.\",\n      \"method\": \"siRNA knockdown, GFP-KIF2B live-cell imaging, immunofluorescence, epistasis by double-knockdown\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal KD epistasis with multiple genetic backgrounds, direct localization by live imaging, defined cellular phenotypes with velocity measurements\",\n      \"pmids\": [\"17538014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIF2B stimulates kinetochore-microtubule (kMT) dynamics specifically during early mitosis to correct mal-oriented attachments, while MCAK acts in a distinct, later phase. Few-fold reductions in kMT turnover, particularly in early mitosis, induce severe chromosome segregation defects. Overexpression of KIF2B restores kMT dynamics and chromosome segregation fidelity in chromosomally unstable tumor cell lines.\",\n      \"method\": \"siRNA knockdown, kMT turnover assay (fluorescence dissipation after photoactivation), overexpression rescue in CIN tumor lines\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (kMT turnover, siRNA, OE rescue), replicated across cell lines\",\n      \"pmids\": [\"19060894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In early mitosis, KIF2B forms a complex with CLASP1 at kinetochores to promote kMT turnover, correction of attachment errors, and maintenance of spindle assembly checkpoint (SAC) signalling. During metaphase, this KIF2B-CLASP1 complex is replaced by an astrin-CLASP1 complex that promotes kMT stability and SAC silencing. The two complexes are mutually exclusive at kinetochores. KIF18A affects kMT attachments and chromosome movement through these proteins.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, kMT turnover assay, epistasis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating complex, functional epistasis, turnover assays, temporal resolution of two distinct complexes\",\n      \"pmids\": [\"20852589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Plk1 directly phosphorylates KIF2B at threonine 125 (T125) and serine 204 (S204). Phosphorylation of S204 is required for KIF2B kinetochore localization and activity in prometaphase; phosphorylation of T125 is required for KIF2B activity in correcting kMT attachment errors. These sites were identified by mass spectrometry and validated by mutagenesis.\",\n      \"method\": \"Mass spectrometry phosphoproteomics, in vitro kinase assay with Plk1, phosphomimetic/phosphodeficient mutagenesis, immunofluorescence, Plk1 inhibitor (BI2536)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay + mutagenesis + MS identification, multiple phosphorylation sites with distinct functional readouts\",\n      \"pmids\": [\"22535524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The C-terminus of KIF2B mediates specific protein-protein interactions that distinguish it from other kinesin-13 paralogs. Cep170 and Cep170R (KIAA0284) specifically associate with KIF2B (not Kif2a or MCAK). Cep170 binds microtubules in vitro and provides KIF2B with a second microtubule-binding site to target it to the mitotic spindle. The N-terminus is the primary determinant of kinesin-13 localization.\",\n      \"method\": \"Co-immunoprecipitation, in vitro microtubule-binding assay, domain-swap mutants, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro microtubule binding reconstitution, Co-IP, domain mapping, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23087211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Chk1 activity is required for stable localization of KIF2B (and MCAK) to centromeres/kinetochores. Decreased Chk1 activity leads to hyperstable kMTs and unstable binding of KIF2B to centromeres/kinetochores. Chk1 phosphorylates Aurora-B at Ser331, and this phosphorylation is required for optimal KIF2B localization. Mps1 inhibition also diminishes initial recruitment of KIF2B to centromeres/kinetochores, and Chk1 and Mps1 jointly regulate KIF2B localization.\",\n      \"method\": \"Chk1 inhibitor/siRNA, Mps1 inhibitor, immunofluorescence for KIF2B localization, phospho-specific antibodies, Aurora-B mutagenesis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization with inhibitor treatment and functional readout, multiple kinases tested, single lab\",\n      \"pmids\": [\"23321637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TBK1 is necessary for CEP170 centrosomal localization and for CEP170 binding to KIF2B. Disruption of the TBK1-CEP170 complex augments microtubule stability and triggers mitotic defects, placing TBK1 upstream of the CEP170-KIF2B interaction in regulating microtubule dynamics.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, TBK1 inhibitor\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for TBK1-CEP170-KIF2B, KD with functional readout, single lab\",\n      \"pmids\": [\"26656453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GSK3β phosphorylates SKAP, and this phosphorylation promotes SKAP binding to KIF2B to regulate its microtubule depolymerase activity at microtubule plus-ends. SKAP competes with KIF2B for microtubule plus-end binding, thereby temporally inhibiting KIF2B depolymerase activity to ensure accurate kinetochore-microtubule attachment.\",\n      \"method\": \"In vitro kinase assay (GSK3β phosphorylating SKAP), mass spectrometry phosphosite mapping, co-immunoprecipitation, phosphomimetic rescue assay, microtubule plus-end binding competition assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay and MS mapping combined with Co-IP and cell-based rescue, single lab\",\n      \"pmids\": [\"27982129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Modest overexpression of KIF2B in transgenic mice reduces chromosome segregation defects in K-Ras G12D-driven lung tumors but does not reduce tumor incidence; instead, tumors are significantly larger with elevated Ki-67 in KIF2B-overexpressing animals. This establishes that KIF2B-mediated reduction of CIN suppresses tumor growth in the context of K-Ras-driven lung cancer.\",\n      \"method\": \"Transgenic mouse overexpression (Kif2b), K-Ras G12D lung cancer model, chromosome segregation scoring, Ki-67 immunostaining\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with defined chromosome segregation readout, single lab\",\n      \"pmids\": [\"31179849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Plk1 phosphorylation of KIF2B at Ser/Thr sites controls chromosome alignment. Using a Ser/Thr toggle chemical-genetic system, toggling Plk1-phosphorylated Ser residues on KIF2B to Thr (placing them under orthogonal kinase control) caused sharp increases in misaligned chromosomes and prometaphase arrest upon chemical inhibition, confirming that Plk1-mediated phosphorylation of KIF2B is required for chromosome alignment.\",\n      \"method\": \"Chemical-genetic Plk1 Ser/Thr toggle system, phosphoproteomics, live-cell imaging, chromosome alignment scoring\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — chemical-genetic reconstitution with phosphoproteomic validation, functional chromosomal phenotype, single lab\",\n      \"pmids\": [\"32017920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SCFFbxw5 ubiquitin E3 ligase polyubiquitylates KIF2B (along with Kif2a and MCAK) in vitro via Cdc34, without requiring preceding modifications on KIF2B. Concomitant knockdown of KIF2B, Kif2a, or MCAK rescues ciliogenesis defects caused by Fbxw5 loss, indicating SCFFbxw5-mediated degradation of KIF2B contributes to regulation of ciliogenesis.\",\n      \"method\": \"In vitro ubiquitylation reconstitution assay (protein microarray screen + neddylated SCFFbxw5 + Cdc34), siRNA knockdown rescue of ciliogenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ubiquitylation is Tier 1, but KIF2B-specific ciliogenesis rescue is single lab\",\n      \"pmids\": [\"34368969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIF2B interacts with KASH5 (a LINC complex component) in mouse spermatocytes, as identified by co-immunoprecipitation and yeast two-hybrid assays using KASH5 as bait, suggesting KIF2B participates in force transmission to telomeres during meiotic prophase chromosome movements.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid (KASH5 bait), proteomic screen of microtubule-associated motor proteins in mouse spermatocytes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and Y2H identify interaction but functional role of KIF2B specifically (vs KIF5B) is not directly tested; preprint, single lab\",\n      \"pmids\": [\"40501626\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KIF2B is a kinesin-13 microtubule depolymerase that acts specifically in early mitosis at kinetochores—where it forms a complex with CLASP1—to promote kinetochore-microtubule turnover and correction of erroneous attachments; its kinetochore localization and depolymerase activity are regulated by direct Plk1 phosphorylation (at S204 for localization and T125 for error-correction activity), by Chk1/Aurora-B and Mps1 signaling, and by competitive binding of GSK3β-phosphorylated SKAP at microtubule plus-ends, while its spindle targeting is facilitated by association with Cep170 (which provides a second microtubule-binding site) and its abundance is controlled by SCFFbxw5-mediated ubiquitylation and proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF2B is a kinesin-13 family microtubule depolymerase that drives chromosome segregation fidelity by stimulating kinetochore-microtubule (kMT) turnover specifically during early mitosis, where it corrects mal-oriented attachments before MCAK acts in a later phase [#0, #1]. It localizes to centrosomes, midbodies, spindle microtubules, and transiently to kinetochores, and its loss produces monopolar or disorganized spindles and severely slowed chromosome movement [#0]. At kinetochores in early mitosis KIF2B forms a complex with CLASP1 that promotes kMT turnover, error correction, and spindle assembly checkpoint signalling; this complex is replaced at metaphase by an astrin-CLASP1 complex that stabilizes kMTs and silences the checkpoint [#2]. KIF2B activity and targeting are governed by phosphoregulation: Plk1 directly phosphorylates S204 (required for kinetochore localization) and T125 (required for attachment-error correction), and Plk1 phosphorylation is required for chromosome alignment [#3, #9], while Chk1\\u2014acting in part through Aurora-B Ser331 phosphorylation\\u2014and Mps1 control its centromere/kinetochore recruitment [#5]. Its spindle targeting is provided by a C-terminus-specific association with Cep170, which contributes a second microtubule-binding site and is itself dependent on TBK1 [#4, #6], and its depolymerase activity at microtubule plus-ends is temporally restrained by competitive binding of GSK3\\u03b2-phosphorylated SKAP [#7]. KIF2B abundance is limited by SCF-Fbxw5-mediated polyubiquitylation, linking its turnover to ciliogenesis control [#10]. Functionally, restoring KIF2B-mediated kMT dynamics suppresses chromosomal instability, and modest overexpression in K-Ras-driven mouse lung tumors reduces segregation defects [#1, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that KIF2B is a kinesin-13 protein required for bipolar spindle assembly and normal chromosome movement, placing it within the mitotic microtubule-dynamics machinery.\",\n      \"evidence\": \"siRNA knockdown, GFP-KIF2B live imaging, and double-knockdown epistasis with MCAK/Nuf2/NuMA/HSET in human cells\",\n      \"pmids\": [\"17538014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether KIF2B acts at kinetochores versus poles for its primary function\", \"Depolymerase biochemistry not directly reconstituted here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the temporal niche of KIF2B by showing it stimulates kMT turnover specifically in early mitosis to correct errors, distinct from MCAK, and that boosting this activity rescues chromosomal instability.\",\n      \"evidence\": \"kMT turnover by fluorescence dissipation after photoactivation, siRNA, and overexpression rescue in CIN tumor lines\",\n      \"pmids\": [\"19060894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners conferring early-mitotic specificity not yet identified\", \"Did not define how turnover defects translate to missegregation mechanistically\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the CLASP1-KIF2B complex as the early-mitotic kinetochore module for error correction and SAC maintenance, and showed a temporal switch to astrin-CLASP1 at metaphase.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA, immunofluorescence, and kMT turnover assays with temporal resolution\",\n      \"pmids\": [\"20852589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of the complex switch (what displaces KIF2B) not defined here\", \"Direct vs indirect KIF2B-CLASP1 binding not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined how KIF2B activity is switched on by establishing Plk1 as a direct kinase phosphorylating distinct residues controlling localization (S204) and error-correction activity (T125).\",\n      \"evidence\": \"Phosphoproteomics, in vitro Plk1 kinase assay, phosphomutant rescue, and Plk1 inhibition (BI2536)\",\n      \"pmids\": [\"22535524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How S204 phosphorylation mechanistically drives kinetochore targeting unresolved\", \"Structural basis of T125-dependent activity unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Explained paralog-specific spindle targeting by showing KIF2B's C-terminus binds Cep170, which provides a second microtubule-binding site absent in Kif2a/MCAK.\",\n      \"evidence\": \"Co-IP, in vitro microtubule-binding assay, and domain-swap mutants\",\n      \"pmids\": [\"23087211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of the second MT-binding site to depolymerase processivity not measured\", \"Whether Cep170 modulates activity or only localization unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed KIF2B kinetochore recruitment downstream of mitotic checkpoint kinases by showing Chk1 (via Aurora-B Ser331) and Mps1 jointly control its centromere localization.\",\n      \"evidence\": \"Chk1/Mps1 inhibition and siRNA, phospho-specific antibodies, Aurora-B mutagenesis, and immunofluorescence\",\n      \"pmids\": [\"23321637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct vs indirect role of Aurora-B Ser331 phosphorylation on KIF2B not biochemically isolated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified TBK1 as an upstream regulator required for CEP170 centrosomal localization and CEP170-KIF2B binding, linking a kinase to KIF2B's spindle-targeting interaction.\",\n      \"evidence\": \"Co-IP, siRNA, immunofluorescence, and TBK1 inhibition\",\n      \"pmids\": [\"26656453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TBK1 acts directly on CEP170 or KIF2B not established\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a negative-regulation mechanism in which GSK3\\u03b2-phosphorylated SKAP competes with KIF2B for microtubule plus-ends to temporally restrain its depolymerase activity.\",\n      \"evidence\": \"In vitro GSK3\\u03b2 kinase assay, MS phosphosite mapping, Co-IP, phosphomimetic rescue, and plus-end binding competition\",\n      \"pmids\": [\"27982129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"In vivo timing of SKAP-mediated inhibition relative to Plk1 activation not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tested the tumor-relevance of KIF2B in vivo, showing that modest overexpression reduces segregation defects in K-Ras-driven lung tumors but increases tumor size rather than suppressing incidence.\",\n      \"evidence\": \"Transgenic Kif2b overexpression in K-Ras G12D mouse lung cancer with segregation scoring and Ki-67 staining\",\n      \"pmids\": [\"31179849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking reduced CIN to larger tumors not resolved\", \"Single-lab study, overexpression rather than physiological levels\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed via orthogonal chemical-genetic control that Plk1-mediated phosphorylation of KIF2B is required for chromosome alignment.\",\n      \"evidence\": \"Plk1 Ser/Thr toggle chemical-genetic system, phosphoproteomics, and live-cell chromosome alignment scoring\",\n      \"pmids\": [\"32017920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Did not separate KIF2B's contribution from other Plk1 substrates in the alignment phenotype\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that KIF2B abundance is controlled by SCF-Fbxw5-mediated polyubiquitylation, connecting its degradation to ciliogenesis.\",\n      \"evidence\": \"In vitro ubiquitylation reconstitution with neddylated SCF-Fbxw5/Cdc34 and siRNA rescue of ciliogenesis\",\n      \"pmids\": [\"34368969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KIF2B-specific (vs Kif2a/MCAK) contribution to ciliogenesis rescue is single-lab\", \"In vivo timing of degradation across the cell cycle not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended KIF2B's role to meiosis by identifying an interaction with the LINC component KASH5 in spermatocytes, implicating it in telomere force transmission during meiotic prophase.\",\n      \"evidence\": \"Co-IP and yeast two-hybrid with KASH5 bait, proteomic screen in mouse spermatocytes (preprint)\",\n      \"pmids\": [\"40501626\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional role of KIF2B specifically (vs KIF5B) not tested\", \"Preprint, single lab, interaction not validated reciprocally in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory inputs (Plk1, Chk1/Aurora-B/Mps1, SKAP competition, Cep170/TBK1 targeting, Fbxw5 degradation) are integrated in space and time to switch KIF2B activity on and off at individual kinetochores remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of KIF2B or its regulated complexes\", \"Quantitative hierarchy among regulators undefined\", \"Physiological meiotic and ciliary roles not mechanistically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"complexes\": [\"KIF2B-CLASP1 kinetochore complex\", \"CEP170-KIF2B complex\"],\n    \"partners\": [\"CLASP1\", \"CEP170\", \"SKAP\", \"TBK1\", \"PLK1\", \"KASH5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}