{"gene":"KIF22","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1996,"finding":"KIF22 (Kid) is a kinesin family protein with an N-terminal microtubule-binding motor domain and a C-terminal DNA-binding domain containing a putative nuclear localization signal; it colocalizes with mitotic chromosomes and is enriched at the kinetochore at anaphase, suggesting a role in chromosomal movement along microtubules during mitosis.","method":"Molecular cloning, nucleotide sequencing, microtubule-binding assay, indirect immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical binding assay for microtubules combined with immunolocalization; foundational characterization paper replicated by subsequent studies","pmids":["8599929"],"is_preprint":false},{"year":2001,"finding":"KIF22 (Kid) generates the polar ejection force that pushes chromosome arms away from spindle poles in vertebrate cells; loss of Kid function via antibody microinjection abolishes chromosome oscillation and causes atypical chromosome arm orientation toward spindle poles, but does not prevent chromosome congression in the majority of cells.","method":"Antibody microinjection, time-lapse differential interference contrast microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell imaging with function-blocking antibodies, multiple quantitative readouts, replicated concept in subsequent studies","pmids":["11564754"],"is_preprint":false},{"year":2000,"finding":"SIAH-1 E3 ubiquitin ligase interacts with KIF22 (Kid) and mediates its degradation via the ubiquitin-proteasome pathway during mitosis; this interaction requires the N-terminal RING finger domain of SIAH-1.","method":"Yeast two-hybrid, co-immunoprecipitation, proteasome inhibitor experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identification plus functional degradation assay in cells, single lab","pmids":["11146551"],"is_preprint":false},{"year":2003,"finding":"KIF22 (Kid) is a plus end-directed microtubule motor with an average velocity of ~160 nm/s, demonstrated by optical trapping microscopy using bacterially expressed truncated Kid fragments (amino acids 1-388 or 1-439); no processive movement was detected.","method":"Optical trapping microscopy, in vitro motility assay with recombinant protein","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro motor assay with optical trap, rigorous biophysical characterization, single lab","pmids":["12606572"],"is_preprint":false},{"year":2003,"finding":"Cdc2 (CDK1)-cyclin B phosphorylates KIF22 (Kid) at Thr463 during M phase; this phosphorylation reduces Kid's affinity for microtubules by weakening stalk-region microtubule interaction, ensuring reversible spindle association and allowing Kid to bind chromosomes and generate polar ejection force. A T463A mutation causes Kid to remain on spindles and fail to localize to chromosomes.","method":"M phase-specific phosphorylation site mapping, in vitro kinase assay, site-directed mutagenesis, live-cell localization of mutant constructs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay identifying the kinase, mutagenesis validating functional consequence on localization and microtubule binding, single lab with multiple orthogonal methods","pmids":["12727876"],"is_preprint":false},{"year":2003,"finding":"KIF22 (Kid) is monomeric (confirmed in both mammalian and E. coli expression systems) and possesses a second microtubule-binding site outside the motor domain that cross-links microtubules in an ATP-sensitive manner and enhances microtubule affinity without affecting motor velocity.","method":"Sedimentation equilibrium, microtubule co-sedimentation, ATPase assay, in vitro motility assay with deletion constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple in vitro biochemical methods (ATPase, binding, sedimentation), deletion constructs to map second site, single lab","pmids":["12692123"],"is_preprint":false},{"year":2003,"finding":"Ran GTPase modulates Kid activity through importin-beta: binding of nuclear transport receptors to Kid's N-terminal microtubule-binding domain inhibits its microtubule-binding activity but not its DNA-binding activity; RanGTP releases importin-beta, restoring microtubule binding.","method":"Domain mapping of nuclear targeting sequences, in vitro binding assay with importin-beta and Kid fragments","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays with defined domains and functional readouts, single lab","pmids":["14600264"],"is_preprint":false},{"year":2003,"finding":"Kid and NuMA have a functional relationship: simultaneous perturbation of Kid and NuMA leads to short bipolar spindles with organized poles (contrasting with splayed poles from NuMA perturbation alone), and chromosomes fail to align efficiently despite normal kinetochore-microtubule interactions and chromosome velocities; HSET is sufficient for spindle organization in the absence of both Kid and NuMA.","method":"Antibody microinjection epistasis, time-lapse microscopy, chromosome velocity measurement","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by sequential perturbation with multiple combinations, single lab","pmids":["12972545"],"is_preprint":false},{"year":2005,"finding":"KIF22 (Kid) is required for proper metaphase spindle length maintenance; RNAi depletion of Kid in HeLa cells causes a ~20% reduction in spindle pole-to-pole distance and less robust spindle microtubule bundles, in addition to chromosome arm misalignment. Kid exhibits microtubule bundling activity in vitro, and the shortened spindle phenotype requires neither the DNA-binding domain nor ATPase activity but does require a coiled-coil domain.","method":"RNA interference, spindle length measurement, in vitro microtubule bundling assay, rescue experiments with domain deletion mutants","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — RNAi phenotypic analysis combined with in vitro bundling assay and structure-function rescue experiments with defined mutants, single lab","pmids":["16176979"],"is_preprint":false},{"year":2007,"finding":"KIF22 (Kid) is degraded specifically by the APC/C(Cdh1) ubiquitin ligase complex (not by APC/C(Cdc20)) in late mitosis/G1, via a KENxP motif; this degradation is not required for mitotic progression but likely contributes to KIF22 inactivation in G1.","method":"Ubiquitin-mediated degradation assays, identification of KEN box motif, cell cycle timing experiments","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional degradation assays distinguishing APC/C substrate specificity, single lab","pmids":["17726374"],"is_preprint":false},{"year":2008,"finding":"KIF22 (Kid) localizes to the boundaries of anaphase and telophase chromosomes and contributes to shortening of the anaphase chromosome mass along the spindle axis; loss of Kid causes failure of chromosome compaction, leading to multinucleated cell formation, particularly during oocyte meiosis II and the first mitotic divisions of the embryo, resulting in embryonic death.","method":"Kid knockout mice, cultured cells lacking Kid expression, live-cell imaging, electron microscopy","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in mouse with specific cellular and developmental phenotypic readouts, replicated in cultured cells","pmids":["18329364"],"is_preprint":false},{"year":2008,"finding":"CHICA (a novel spindle protein) co-immunoprecipitates with KIF22 (Kid) and is required for Kid's localization to the mitotic spindle without affecting its chromosome association; CHICA-depleted cells phenocopy Kid depletion with shorter spindles and chromosome congression failure.","method":"Co-immunoprecipitation, RNAi depletion, immunofluorescence localization, monopolar spindle assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal functional interaction demonstrated by co-IP and epistasis experiments with depletion of both proteins, single lab","pmids":["18485706"],"is_preprint":false},{"year":2008,"finding":"KIF22 (hKid) is an import cargo of the importin-alpha/beta transport pathway; importin-alpha/beta association with hKid is required for its initial targeting to mitotic chromosomes, and local Ran-GTP generation at chromosomes promotes importin-beta-mediated cargo release and hKid accumulation on chromosomes. Loss of functional NLSs reduces hKid chromosome association.","method":"NLS mapping by mutagenesis, digitonin-permeabilized cell transport assay, Ran-GDP/GTP manipulation, live-cell imaging of NLS mutants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection with NLS mutants, in vitro transport reconstitution in permeabilized cells, Ran-GTP functional manipulation, single lab with multiple orthogonal methods","pmids":["18268099"],"is_preprint":false},{"year":2009,"finding":"Chfr E3 ubiquitin ligase interacts with KIF22 (Kif22) and ubiquitylates it; Chfr-mediated Kif22 downregulation is required for maintenance of chromosome stability during the early mitotic checkpoint response.","method":"Co-immunoprecipitation, ubiquitylation assay, siRNA knockdown with chromosome stability readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional ubiquitylation assay and chromosome stability phenotype, single lab","pmids":["19321445"],"is_preprint":false},{"year":2011,"finding":"Dominant missense mutations in KIF22 affecting Pro148 and Arg149 in the motor domain (ATP-binding region) cause spondyloepimetaphyseal dysplasia with joint laxity (lepto-SEMDJL), an autosomal dominant skeletal dysplasia; in silico analysis indicates these residues maintain hydrogen bonds in the ATP-binding and motor domains.","method":"Whole-exome sequencing, Sanger sequencing, co-segregation analysis, in silico structural analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — identified causative variants by exome sequencing replicated across multiple families and confirmed by segregation, but functional mechanism relies on in silico prediction; independently replicated in a concurrent paper","pmids":["22152677","22152678"],"is_preprint":false},{"year":2014,"finding":"Inhibition of KIF22 delays mitotic exit by upregulating CDC25C expression at the transcriptional level; phosphorylation of KIF22 is required for its transcriptional regulatory function and for reduction of CDK1 activity. KIF22 knockdown increases CDC25C expression and CDK1 activity, resulting in G2/M accumulation.","method":"siRNA knockdown, flow cytometry, ChIP/reporter assay to identify CDC25C as direct transcriptional target, CDK1 activity assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional target identified by ChIP, functional rescue experiment, single lab","pmids":["24626146"],"is_preprint":false},{"year":2015,"finding":"KIF22 (Kid) contributes to chromosome congression independently of end-on kinetochore-microtubule attachment: in cells depleted of Hec1 (essential for end-on attachment), co-depletion of Kid further perturbs the partial transient chromosome congression, demonstrating Kid's role in lateral-attachment-based congression.","method":"siRNA co-depletion, live-cell imaging, kinetochore-microtubule attachment analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by double depletion with defined attachment readout, single lab","pmids":["25743205"],"is_preprint":false},{"year":2016,"finding":"Cdk1-mediated phosphorylation of KIF22 Thr463 is required to generate polar ejection force (PEF-ON mode) during prometaphase/metaphase; dephosphorylation of Thr463 at the metaphase-to-anaphase transition turns off polar ejection force (PEF-OFF mode). The coiled-coil domain, together with the second microtubule-binding domain, is required to prevent re-congression of separated chromosomes during anaphase.","method":"Expression of phospho-mimetic and phospho-null Thr463 Kid mutants in Kid-deficient cells, live-cell imaging, rescue experiments with domain deletion mutants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — structure-function analysis with phospho-mutants in knockout background, multiple domain deletion constructs, live-cell imaging readout, single lab","pmids":["27550518"],"is_preprint":false},{"year":2016,"finding":"NuSAP microtubule-associated protein regulates the polar ejection force generated by KIF22 (Kid); NuSAP depletion suppresses amplitude and velocity of chromosome oscillation, and epistasis experiments in monopolar and bipolar spindles reveal NuSAP acts upstream of or in concert with Kid to generate the polar ejection force.","method":"NuSAP depletion, 3D time-lapse live-cell imaging of chromosome oscillation, monopolar spindle assay, double depletion epistasis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with multiple depletion conditions, single lab","pmids":["26839278"],"is_preprint":false},{"year":2018,"finding":"KIF22 interacts with the coxsackievirus and adenovirus receptor (CAR) following EGF stimulation; KIF22-dependent regulation of microtubule dynamics leads to delayed EGFR internalization and enhanced EGFR signaling, coordinating CAR dynamics at cell-cell junctions to promote cancer cell proliferation.","method":"Co-immunoprecipitation, siRNA depletion, EGFR internalization assay, live-cell imaging of receptor dynamics","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating interaction, functional depletion experiments with defined signaling readouts, single lab","pmids":["29382784"],"is_preprint":false},{"year":2022,"finding":"Pathogenic KIF22 mutations (in the α2 helix of the motor domain and in the tail) do not impair early mitotic functions (chromosome congression/alignment) but instead prevent KIF22 inactivation at the metaphase-to-anaphase transition, resulting in disrupted anaphase chromosome segregation, abnormal daughter cell nuclear morphology, reduced proliferation, and cytokinesis failure. Constitutive activation via phospho-mimicry at the tail (known phosphoregulatory site) phenocopies pathogenic mutations. Phospho-mimicry at α2 helix residue T158 also prevents KIF22 anaphase inactivation.","method":"Patient variant identification, expression of disease-causing and phospho-mimetic mutants, live-cell imaging of chromosome dynamics, nuclear morphology quantification, cytokinesis assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — structure-function dissection with patient mutations and engineered phospho-mimetic/null variants, multiple cellular readouts establishing mechanism of anaphase regulation, single lab with orthogonal methods","pmids":["35730929"],"is_preprint":false},{"year":2022,"finding":"GBP2 directly interacts with KIF22 and regulates glioma cell proliferation and migration through a KIF22/EGFR signaling axis; depletion of GBP2 impairs KIF22-mediated EGFR signaling.","method":"Co-immunoprecipitation, siRNA/overexpression, in vitro and in vivo proliferation/migration assays","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying interaction, functional knockdown with proliferation readout but limited mechanistic depth, single lab","pmids":["35436989"],"is_preprint":false}],"current_model":"KIF22 (Kid/kinesin-10) is a monomeric, plus end-directed chromokinesin that uses its N-terminal motor domain and a second microtubule-binding site in the stalk to generate polar ejection forces that push chromosome arms away from spindle poles during prometaphase and metaphase; its chromosome localization is governed by importin-alpha/beta-mediated targeting and local Ran-GTP release, its microtubule affinity is regulated by CDK1/Cdc2-mediated phosphorylation of Thr463 (phosphorylation reduces spindle association to allow chromosome binding during metaphase and is reversed at anaphase onset to turn off polar ejection force), it is ubiquitylated and degraded by APC/C(Cdh1) in G1 and by SIAH-1 during mitosis, and it interacts with the spindle adaptor CHICA for spindle localization, with NuSAP for chromosome oscillation, and with membrane receptors CAR/EGFR to regulate receptor dynamics; pathogenic mutations in the motor domain α2 helix or tail prevent proper KIF22 inactivation at anaphase onset, disrupting chromosome segregation and causing the skeletal dysplasia lepto-SEMDJL."},"narrative":{"mechanistic_narrative":"KIF22 (Kid/kinesin-10) is a monomeric, plus end-directed chromokinesin that generates the polar ejection force pushing chromosome arms away from spindle poles during prometaphase and metaphase [PMID:11564754, PMID:12606572]. It combines an N-terminal microtubule-binding motor domain with a C-terminal DNA-binding domain bearing a nuclear localization signal, and a second, ATP-sensitive microtubule-binding site in the stalk that cross-links and bundles microtubules and contributes to spindle length maintenance [PMID:8599929, PMID:12692123, PMID:16176979]. Targeting of KIF22 to mitotic chromosomes is achieved through the importin-alpha/beta transport pathway, with local Ran-GTP generation at chromosomes releasing importin-beta to permit chromosome accumulation while inhibiting microtubule binding away from chromatin [PMID:14600264, PMID:18268099]. Its activity is gated by Cdk1/cyclin B phosphorylation of Thr463, which weakens stalk-microtubule affinity to permit chromosome loading; this phosphorylation switches polar ejection force ON during prometaphase/metaphase and is reversed at the metaphase-to-anaphase transition to switch the force OFF, while the coiled-coil and second microtubule-binding domain prevent re-congression of separated chromosomes [PMID:12727876, PMID:27550518]. KIF22 contributes to chromosome congression via lateral attachments independently of end-on kinetochore-microtubule attachment, and to anaphase chromosome compaction, with loss causing multinucleation and embryonic death in knockout mice [PMID:18329364, PMID:25743205]. KIF22 abundance is controlled by ubiquitin-dependent degradation through APC/C(Cdh1) in late mitosis/G1 via a KEN motif and through SIAH-1 and Chfr E3 ligases [PMID:11146551, PMID:17726374, PMID:19321445]. Spindle localization and chromosome oscillation are further governed by the partners CHICA and NuSAP, respectively [PMID:18485706, PMID:26839278]. Dominant missense mutations in the motor domain (Pro148/Arg149 and the α2 helix) and tail cause the skeletal dysplasia lepto-SEMDJL by preventing KIF22 inactivation at anaphase onset rather than impairing early mitotic functions, disrupting chromosome segregation [PMID:22152677, PMID:22152678, PMID:35730929]. Beyond mitosis, KIF22 interacts with the receptor CAR to modulate EGFR internalization and signaling in cancer cells [PMID:29382784].","teleology":[{"year":1996,"claim":"Established KIF22 as a kinesin with a dual architecture—a microtubule-binding motor domain and a DNA-binding domain—that localizes to mitotic chromosomes, defining it as a candidate motor for chromosome movement.","evidence":"Molecular cloning, microtubule-binding assay, and immunofluorescence","pmids":["8599929"],"confidence":"High","gaps":["Directionality and force generation not yet determined","DNA-binding domain function in chromosome transport not tested"]},{"year":2000,"claim":"Identified SIAH-1 as an E3 ligase that targets KIF22 for proteasomal degradation during mitosis, opening the question of how KIF22 levels are temporally controlled.","evidence":"Yeast two-hybrid, co-IP, and proteasome inhibitor experiments","pmids":["11146551"],"confidence":"Medium","gaps":["Cell-cycle window of SIAH-1 action not precisely defined","Degron on KIF22 not mapped"]},{"year":2001,"claim":"Defined the cellular function of KIF22 as the source of polar ejection force, showing it drives chromosome oscillation and arm orientation without being essential for congression.","evidence":"Function-blocking antibody microinjection with live DIC imaging in vertebrate cells","pmids":["11564754"],"confidence":"High","gaps":["Molecular basis of force generation not resolved","Did not establish motor velocity or processivity in vitro"]},{"year":2003,"claim":"Provided the biophysical and regulatory mechanism: KIF22 is a monomeric plus end-directed motor with a second microtubule-binding site, its microtubule affinity is gated by Cdk1 phosphorylation at Thr463, and its activity is spatially controlled by importin-beta/Ran.","evidence":"Optical-trap motility, sedimentation/ATPase/co-sedimentation assays, in vitro kinase mapping and mutagenesis, and importin-beta binding assays","pmids":["12606572","12692123","12727876","14600264"],"confidence":"High","gaps":["Phosphatase reversing Thr463 not identified","How the second site and motor coordinate during force generation unresolved"]},{"year":2003,"claim":"Placed KIF22 in a functional relationship with NuMA in spindle organization, showing it cooperates in chromosome alignment while HSET can substitute for spindle pole organization.","evidence":"Antibody microinjection epistasis with time-lapse imaging and chromosome velocity measurement","pmids":["12972545"],"confidence":"Medium","gaps":["No direct physical interaction with NuMA demonstrated","Mechanism of cooperative alignment unclear"]},{"year":2005,"claim":"Extended KIF22 function beyond chromosome arms to spindle length maintenance via microtubule bundling, dissecting which domains are required for the phenotype.","evidence":"RNAi with spindle length measurement, in vitro bundling assay, and domain-deletion rescue","pmids":["16176979"],"confidence":"High","gaps":["How bundling is regulated in cells not established","Relationship of coiled-coil bundling to motor activity unresolved"]},{"year":2007,"claim":"Showed KIF22 is a specific APC/C(Cdh1) substrate degraded via a KEN motif in late mitosis/G1, refining the cell-cycle logic of its turnover.","evidence":"Ubiquitin-mediated degradation assays and KEN-box identification with cell-cycle timing","pmids":["17726374"],"confidence":"Medium","gaps":["Functional consequence of failed degradation not fully defined","Relationship to SIAH-1 pathway not integrated"]},{"year":2008,"claim":"Established the in vivo requirement for KIF22 in anaphase chromosome compaction and development, with chromosome-targeting governed by importin-alpha/beta and local Ran-GTP, and spindle localization governed by the partner CHICA.","evidence":"Knockout mice and cultured cells, EM and live imaging; NLS-mutant transport assays; CHICA co-IP and reciprocal depletion","pmids":["18329364","18268099","18485706"],"confidence":"High","gaps":["How CHICA bridges KIF22 to the spindle structurally unknown","Mechanism of chromosome-mass compaction not molecularly defined"]},{"year":2009,"claim":"Added Chfr as an additional E3 ligase ubiquitylating KIF22, linking its downregulation to chromosome stability during the early mitotic checkpoint.","evidence":"Co-IP, ubiquitylation assay, and siRNA with chromosome-stability readout","pmids":["19321445"],"confidence":"Medium","gaps":["Redundancy among SIAH-1, APC/C, and Chfr not resolved","Checkpoint trigger for Chfr targeting unclear"]},{"year":2014,"claim":"Uncovered a non-canonical role in which KIF22 transcriptionally regulates CDC25C to control CDK1 activity and mitotic exit timing.","evidence":"siRNA, flow cytometry, ChIP/reporter assay, and CDK1 activity assay","pmids":["24626146"],"confidence":"Medium","gaps":["How a motor protein acts on transcription mechanistically unexplained","Generality across cell types not tested"]},{"year":2015,"claim":"Defined a specific contribution of KIF22 to lateral-attachment-based chromosome congression independent of end-on kinetochore-microtubule attachment.","evidence":"siRNA co-depletion with Hec1, live imaging, and attachment analysis","pmids":["25743205"],"confidence":"Medium","gaps":["Molecular basis of lateral congression contribution not detailed","Quantitative force contribution unmeasured"]},{"year":2016,"claim":"Resolved the temporal switch logic: Thr463 phosphorylation turns polar ejection force ON in prometaphase/metaphase and its dephosphorylation turns it OFF at anaphase, with NuSAP regulating the oscillation, defining how the force is timed and modulated.","evidence":"Phospho-mimetic/null Thr463 mutants in Kid-deficient cells with domain deletions and live imaging; NuSAP depletion with 3D oscillation imaging and epistasis","pmids":["27550518","26839278"],"confidence":"High","gaps":["Phosphatase executing anaphase Thr463 dephosphorylation not identified","Mechanism of NuSAP–KIF22 cooperation unresolved"]},{"year":2018,"claim":"Extended KIF22 function to interphase signaling, showing it interacts with CAR and regulates EGFR internalization and signaling to promote cancer cell proliferation.","evidence":"Co-IP, siRNA, EGFR internalization assay, and live imaging of receptor dynamics","pmids":["29382784"],"confidence":"Medium","gaps":["Whether motor activity is required for receptor regulation unclear","Direct vs indirect CAR interaction not fully resolved"]},{"year":2022,"claim":"Established the disease mechanism of lepto-SEMDJL: pathogenic motor-domain and tail mutations do not impair early mitosis but prevent KIF22 inactivation at the metaphase-to-anaphase transition, disrupting segregation, with phospho-mimicry phenocopying the defect.","evidence":"Patient-variant and phospho-mimetic expression with live imaging, nuclear morphology and cytokinesis assays; earlier exome sequencing and segregation across families","pmids":["35730929","22152677","22152678"],"confidence":"High","gaps":["Tissue specificity of skeletal phenotype not explained","Structural basis of failed inactivation not solved"]},{"year":2022,"claim":"Implicated GBP2 as a KIF22 partner acting through a KIF22/EGFR axis in glioma proliferation and migration.","evidence":"Co-IP, knockdown/overexpression, and proliferation/migration assays in vitro and in vivo","pmids":["35436989"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation of direct binding","Mechanistic link to EGFR signaling not dissected"]},{"year":null,"claim":"The phosphatase that dephosphorylates Thr463 to switch off polar ejection force at anaphase, and the structural basis by which disease mutations block this inactivation, remain unidentified.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No anaphase Thr463 phosphatase identified","No high-resolution structure of KIF22 motor/tail in active vs inactive states","Integration of multiple E3 ligase pathways not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[1,3,5]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,12]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,5,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,4,10,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,9,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,20]}],"complexes":[],"partners":["SIAH1","CHICA","NUSAP1","CHFR","CXADR","EGFR","GBP2","KPNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14807","full_name":"Kinesin-like protein KIF22","aliases":["Kinesin-like DNA-binding protein","Kinesin-like protein 4"],"length_aa":665,"mass_kda":73.3,"function":"Kinesin family member that is involved in spindle formation and the movements of chromosomes during mitosis and meiosis. 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epithelia.","date":"1998","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9843910","citation_count":15,"is_preprint":false},{"pmid":"26831144","id":"PMC_26831144","title":"Altered cellular localization and hemichannel activities of KID syndrome associated connexin26 I30N and D50Y mutations.","date":"2016","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26831144","citation_count":15,"is_preprint":false},{"pmid":"33608974","id":"PMC_33608974","title":"The new kid on the block: a dominant-negative mutation of phototropin1 enhances carotenoid content in tomato fruits.","date":"2021","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33608974","citation_count":15,"is_preprint":false},{"pmid":"12932738","id":"PMC_12932738","title":"Non-cytotoxic variants of the Kid protein that retain their auto-regulatory 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A Series of Six Patients With Inherited Actin-Related Protein 2/3 Complex Subunit 1B Deficiency and Review of the Literature.","date":"2023","source":"The journal of allergy and clinical immunology. In practice","url":"https://pubmed.ncbi.nlm.nih.gov/36708766","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43317,"output_tokens":5243,"usd":0.104298,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13785,"output_tokens":4880,"usd":0.095463,"stage2_stop_reason":"end_turn"},"total_usd":0.199761,"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\": 1996,\n      \"finding\": \"KIF22 (Kid) is a kinesin family protein with an N-terminal microtubule-binding motor domain and a C-terminal DNA-binding domain containing a putative nuclear localization signal; it colocalizes with mitotic chromosomes and is enriched at the kinetochore at anaphase, suggesting a role in chromosomal movement along microtubules during mitosis.\",\n      \"method\": \"Molecular cloning, nucleotide sequencing, microtubule-binding assay, indirect immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical binding assay for microtubules combined with immunolocalization; foundational characterization paper replicated by subsequent studies\",\n      \"pmids\": [\"8599929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"KIF22 (Kid) generates the polar ejection force that pushes chromosome arms away from spindle poles in vertebrate cells; loss of Kid function via antibody microinjection abolishes chromosome oscillation and causes atypical chromosome arm orientation toward spindle poles, but does not prevent chromosome congression in the majority of cells.\",\n      \"method\": \"Antibody microinjection, time-lapse differential interference contrast microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell imaging with function-blocking antibodies, multiple quantitative readouts, replicated concept in subsequent studies\",\n      \"pmids\": [\"11564754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SIAH-1 E3 ubiquitin ligase interacts with KIF22 (Kid) and mediates its degradation via the ubiquitin-proteasome pathway during mitosis; this interaction requires the N-terminal RING finger domain of SIAH-1.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, proteasome inhibitor experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identification plus functional degradation assay in cells, single lab\",\n      \"pmids\": [\"11146551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KIF22 (Kid) is a plus end-directed microtubule motor with an average velocity of ~160 nm/s, demonstrated by optical trapping microscopy using bacterially expressed truncated Kid fragments (amino acids 1-388 or 1-439); no processive movement was detected.\",\n      \"method\": \"Optical trapping microscopy, in vitro motility assay with recombinant protein\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro motor assay with optical trap, rigorous biophysical characterization, single lab\",\n      \"pmids\": [\"12606572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cdc2 (CDK1)-cyclin B phosphorylates KIF22 (Kid) at Thr463 during M phase; this phosphorylation reduces Kid's affinity for microtubules by weakening stalk-region microtubule interaction, ensuring reversible spindle association and allowing Kid to bind chromosomes and generate polar ejection force. A T463A mutation causes Kid to remain on spindles and fail to localize to chromosomes.\",\n      \"method\": \"M phase-specific phosphorylation site mapping, in vitro kinase assay, site-directed mutagenesis, live-cell localization of mutant constructs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay identifying the kinase, mutagenesis validating functional consequence on localization and microtubule binding, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12727876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KIF22 (Kid) is monomeric (confirmed in both mammalian and E. coli expression systems) and possesses a second microtubule-binding site outside the motor domain that cross-links microtubules in an ATP-sensitive manner and enhances microtubule affinity without affecting motor velocity.\",\n      \"method\": \"Sedimentation equilibrium, microtubule co-sedimentation, ATPase assay, in vitro motility assay with deletion constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple in vitro biochemical methods (ATPase, binding, sedimentation), deletion constructs to map second site, single lab\",\n      \"pmids\": [\"12692123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Ran GTPase modulates Kid activity through importin-beta: binding of nuclear transport receptors to Kid's N-terminal microtubule-binding domain inhibits its microtubule-binding activity but not its DNA-binding activity; RanGTP releases importin-beta, restoring microtubule binding.\",\n      \"method\": \"Domain mapping of nuclear targeting sequences, in vitro binding assay with importin-beta and Kid fragments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays with defined domains and functional readouts, single lab\",\n      \"pmids\": [\"14600264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Kid and NuMA have a functional relationship: simultaneous perturbation of Kid and NuMA leads to short bipolar spindles with organized poles (contrasting with splayed poles from NuMA perturbation alone), and chromosomes fail to align efficiently despite normal kinetochore-microtubule interactions and chromosome velocities; HSET is sufficient for spindle organization in the absence of both Kid and NuMA.\",\n      \"method\": \"Antibody microinjection epistasis, time-lapse microscopy, chromosome velocity measurement\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by sequential perturbation with multiple combinations, single lab\",\n      \"pmids\": [\"12972545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KIF22 (Kid) is required for proper metaphase spindle length maintenance; RNAi depletion of Kid in HeLa cells causes a ~20% reduction in spindle pole-to-pole distance and less robust spindle microtubule bundles, in addition to chromosome arm misalignment. Kid exhibits microtubule bundling activity in vitro, and the shortened spindle phenotype requires neither the DNA-binding domain nor ATPase activity but does require a coiled-coil domain.\",\n      \"method\": \"RNA interference, spindle length measurement, in vitro microtubule bundling assay, rescue experiments with domain deletion mutants\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — RNAi phenotypic analysis combined with in vitro bundling assay and structure-function rescue experiments with defined mutants, single lab\",\n      \"pmids\": [\"16176979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KIF22 (Kid) is degraded specifically by the APC/C(Cdh1) ubiquitin ligase complex (not by APC/C(Cdc20)) in late mitosis/G1, via a KENxP motif; this degradation is not required for mitotic progression but likely contributes to KIF22 inactivation in G1.\",\n      \"method\": \"Ubiquitin-mediated degradation assays, identification of KEN box motif, cell cycle timing experiments\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional degradation assays distinguishing APC/C substrate specificity, single lab\",\n      \"pmids\": [\"17726374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIF22 (Kid) localizes to the boundaries of anaphase and telophase chromosomes and contributes to shortening of the anaphase chromosome mass along the spindle axis; loss of Kid causes failure of chromosome compaction, leading to multinucleated cell formation, particularly during oocyte meiosis II and the first mitotic divisions of the embryo, resulting in embryonic death.\",\n      \"method\": \"Kid knockout mice, cultured cells lacking Kid expression, live-cell imaging, electron microscopy\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in mouse with specific cellular and developmental phenotypic readouts, replicated in cultured cells\",\n      \"pmids\": [\"18329364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CHICA (a novel spindle protein) co-immunoprecipitates with KIF22 (Kid) and is required for Kid's localization to the mitotic spindle without affecting its chromosome association; CHICA-depleted cells phenocopy Kid depletion with shorter spindles and chromosome congression failure.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion, immunofluorescence localization, monopolar spindle assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional interaction demonstrated by co-IP and epistasis experiments with depletion of both proteins, single lab\",\n      \"pmids\": [\"18485706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIF22 (hKid) is an import cargo of the importin-alpha/beta transport pathway; importin-alpha/beta association with hKid is required for its initial targeting to mitotic chromosomes, and local Ran-GTP generation at chromosomes promotes importin-beta-mediated cargo release and hKid accumulation on chromosomes. Loss of functional NLSs reduces hKid chromosome association.\",\n      \"method\": \"NLS mapping by mutagenesis, digitonin-permeabilized cell transport assay, Ran-GDP/GTP manipulation, live-cell imaging of NLS mutants\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection with NLS mutants, in vitro transport reconstitution in permeabilized cells, Ran-GTP functional manipulation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18268099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Chfr E3 ubiquitin ligase interacts with KIF22 (Kif22) and ubiquitylates it; Chfr-mediated Kif22 downregulation is required for maintenance of chromosome stability during the early mitotic checkpoint response.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, siRNA knockdown with chromosome stability readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional ubiquitylation assay and chromosome stability phenotype, single lab\",\n      \"pmids\": [\"19321445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Dominant missense mutations in KIF22 affecting Pro148 and Arg149 in the motor domain (ATP-binding region) cause spondyloepimetaphyseal dysplasia with joint laxity (lepto-SEMDJL), an autosomal dominant skeletal dysplasia; in silico analysis indicates these residues maintain hydrogen bonds in the ATP-binding and motor domains.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, co-segregation analysis, in silico structural analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — identified causative variants by exome sequencing replicated across multiple families and confirmed by segregation, but functional mechanism relies on in silico prediction; independently replicated in a concurrent paper\",\n      \"pmids\": [\"22152677\", \"22152678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Inhibition of KIF22 delays mitotic exit by upregulating CDC25C expression at the transcriptional level; phosphorylation of KIF22 is required for its transcriptional regulatory function and for reduction of CDK1 activity. KIF22 knockdown increases CDC25C expression and CDK1 activity, resulting in G2/M accumulation.\",\n      \"method\": \"siRNA knockdown, flow cytometry, ChIP/reporter assay to identify CDC25C as direct transcriptional target, CDK1 activity assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional target identified by ChIP, functional rescue experiment, single lab\",\n      \"pmids\": [\"24626146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIF22 (Kid) contributes to chromosome congression independently of end-on kinetochore-microtubule attachment: in cells depleted of Hec1 (essential for end-on attachment), co-depletion of Kid further perturbs the partial transient chromosome congression, demonstrating Kid's role in lateral-attachment-based congression.\",\n      \"method\": \"siRNA co-depletion, live-cell imaging, kinetochore-microtubule attachment analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by double depletion with defined attachment readout, single lab\",\n      \"pmids\": [\"25743205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cdk1-mediated phosphorylation of KIF22 Thr463 is required to generate polar ejection force (PEF-ON mode) during prometaphase/metaphase; dephosphorylation of Thr463 at the metaphase-to-anaphase transition turns off polar ejection force (PEF-OFF mode). The coiled-coil domain, together with the second microtubule-binding domain, is required to prevent re-congression of separated chromosomes during anaphase.\",\n      \"method\": \"Expression of phospho-mimetic and phospho-null Thr463 Kid mutants in Kid-deficient cells, live-cell imaging, rescue experiments with domain deletion mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structure-function analysis with phospho-mutants in knockout background, multiple domain deletion constructs, live-cell imaging readout, single lab\",\n      \"pmids\": [\"27550518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NuSAP microtubule-associated protein regulates the polar ejection force generated by KIF22 (Kid); NuSAP depletion suppresses amplitude and velocity of chromosome oscillation, and epistasis experiments in monopolar and bipolar spindles reveal NuSAP acts upstream of or in concert with Kid to generate the polar ejection force.\",\n      \"method\": \"NuSAP depletion, 3D time-lapse live-cell imaging of chromosome oscillation, monopolar spindle assay, double depletion epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with multiple depletion conditions, single lab\",\n      \"pmids\": [\"26839278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIF22 interacts with the coxsackievirus and adenovirus receptor (CAR) following EGF stimulation; KIF22-dependent regulation of microtubule dynamics leads to delayed EGFR internalization and enhanced EGFR signaling, coordinating CAR dynamics at cell-cell junctions to promote cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, EGFR internalization assay, live-cell imaging of receptor dynamics\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating interaction, functional depletion experiments with defined signaling readouts, single lab\",\n      \"pmids\": [\"29382784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pathogenic KIF22 mutations (in the α2 helix of the motor domain and in the tail) do not impair early mitotic functions (chromosome congression/alignment) but instead prevent KIF22 inactivation at the metaphase-to-anaphase transition, resulting in disrupted anaphase chromosome segregation, abnormal daughter cell nuclear morphology, reduced proliferation, and cytokinesis failure. Constitutive activation via phospho-mimicry at the tail (known phosphoregulatory site) phenocopies pathogenic mutations. Phospho-mimicry at α2 helix residue T158 also prevents KIF22 anaphase inactivation.\",\n      \"method\": \"Patient variant identification, expression of disease-causing and phospho-mimetic mutants, live-cell imaging of chromosome dynamics, nuclear morphology quantification, cytokinesis assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structure-function dissection with patient mutations and engineered phospho-mimetic/null variants, multiple cellular readouts establishing mechanism of anaphase regulation, single lab with orthogonal methods\",\n      \"pmids\": [\"35730929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GBP2 directly interacts with KIF22 and regulates glioma cell proliferation and migration through a KIF22/EGFR signaling axis; depletion of GBP2 impairs KIF22-mediated EGFR signaling.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/overexpression, in vitro and in vivo proliferation/migration assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying interaction, functional knockdown with proliferation readout but limited mechanistic depth, single lab\",\n      \"pmids\": [\"35436989\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIF22 (Kid/kinesin-10) is a monomeric, plus end-directed chromokinesin that uses its N-terminal motor domain and a second microtubule-binding site in the stalk to generate polar ejection forces that push chromosome arms away from spindle poles during prometaphase and metaphase; its chromosome localization is governed by importin-alpha/beta-mediated targeting and local Ran-GTP release, its microtubule affinity is regulated by CDK1/Cdc2-mediated phosphorylation of Thr463 (phosphorylation reduces spindle association to allow chromosome binding during metaphase and is reversed at anaphase onset to turn off polar ejection force), it is ubiquitylated and degraded by APC/C(Cdh1) in G1 and by SIAH-1 during mitosis, and it interacts with the spindle adaptor CHICA for spindle localization, with NuSAP for chromosome oscillation, and with membrane receptors CAR/EGFR to regulate receptor dynamics; pathogenic mutations in the motor domain α2 helix or tail prevent proper KIF22 inactivation at anaphase onset, disrupting chromosome segregation and causing the skeletal dysplasia lepto-SEMDJL.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF22 (Kid/kinesin-10) is a monomeric, plus end-directed chromokinesin that generates the polar ejection force pushing chromosome arms away from spindle poles during prometaphase and metaphase [#1, #3]. It combines an N-terminal microtubule-binding motor domain with a C-terminal DNA-binding domain bearing a nuclear localization signal, and a second, ATP-sensitive microtubule-binding site in the stalk that cross-links and bundles microtubules and contributes to spindle length maintenance [#0, #5, #8]. Targeting of KIF22 to mitotic chromosomes is achieved through the importin-alpha/beta transport pathway, with local Ran-GTP generation at chromosomes releasing importin-beta to permit chromosome accumulation while inhibiting microtubule binding away from chromatin [#6, #12]. Its activity is gated by Cdk1/cyclin B phosphorylation of Thr463, which weakens stalk-microtubule affinity to permit chromosome loading; this phosphorylation switches polar ejection force ON during prometaphase/metaphase and is reversed at the metaphase-to-anaphase transition to switch the force OFF, while the coiled-coil and second microtubule-binding domain prevent re-congression of separated chromosomes [#4, #17]. KIF22 contributes to chromosome congression via lateral attachments independently of end-on kinetochore-microtubule attachment, and to anaphase chromosome compaction, with loss causing multinucleation and embryonic death in knockout mice [#10, #16]. KIF22 abundance is controlled by ubiquitin-dependent degradation through APC/C(Cdh1) in late mitosis/G1 via a KEN motif and through SIAH-1 and Chfr E3 ligases [#2, #9, #13]. Spindle localization and chromosome oscillation are further governed by the partners CHICA and NuSAP, respectively [#11, #18]. Dominant missense mutations in the motor domain (Pro148/Arg149 and the α2 helix) and tail cause the skeletal dysplasia lepto-SEMDJL by preventing KIF22 inactivation at anaphase onset rather than impairing early mitotic functions, disrupting chromosome segregation [#14, #20]. Beyond mitosis, KIF22 interacts with the receptor CAR to modulate EGFR internalization and signaling in cancer cells [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established KIF22 as a kinesin with a dual architecture—a microtubule-binding motor domain and a DNA-binding domain—that localizes to mitotic chromosomes, defining it as a candidate motor for chromosome movement.\",\n      \"evidence\": \"Molecular cloning, microtubule-binding assay, and immunofluorescence\",\n      \"pmids\": [\"8599929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Directionality and force generation not yet determined\", \"DNA-binding domain function in chromosome transport not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified SIAH-1 as an E3 ligase that targets KIF22 for proteasomal degradation during mitosis, opening the question of how KIF22 levels are temporally controlled.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and proteasome inhibitor experiments\",\n      \"pmids\": [\"11146551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-cycle window of SIAH-1 action not precisely defined\", \"Degron on KIF22 not mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the cellular function of KIF22 as the source of polar ejection force, showing it drives chromosome oscillation and arm orientation without being essential for congression.\",\n      \"evidence\": \"Function-blocking antibody microinjection with live DIC imaging in vertebrate cells\",\n      \"pmids\": [\"11564754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of force generation not resolved\", \"Did not establish motor velocity or processivity in vitro\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the biophysical and regulatory mechanism: KIF22 is a monomeric plus end-directed motor with a second microtubule-binding site, its microtubule affinity is gated by Cdk1 phosphorylation at Thr463, and its activity is spatially controlled by importin-beta/Ran.\",\n      \"evidence\": \"Optical-trap motility, sedimentation/ATPase/co-sedimentation assays, in vitro kinase mapping and mutagenesis, and importin-beta binding assays\",\n      \"pmids\": [\"12606572\", \"12692123\", \"12727876\", \"14600264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase reversing Thr463 not identified\", \"How the second site and motor coordinate during force generation unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed KIF22 in a functional relationship with NuMA in spindle organization, showing it cooperates in chromosome alignment while HSET can substitute for spindle pole organization.\",\n      \"evidence\": \"Antibody microinjection epistasis with time-lapse imaging and chromosome velocity measurement\",\n      \"pmids\": [\"12972545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct physical interaction with NuMA demonstrated\", \"Mechanism of cooperative alignment unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended KIF22 function beyond chromosome arms to spindle length maintenance via microtubule bundling, dissecting which domains are required for the phenotype.\",\n      \"evidence\": \"RNAi with spindle length measurement, in vitro bundling assay, and domain-deletion rescue\",\n      \"pmids\": [\"16176979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How bundling is regulated in cells not established\", \"Relationship of coiled-coil bundling to motor activity unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed KIF22 is a specific APC/C(Cdh1) substrate degraded via a KEN motif in late mitosis/G1, refining the cell-cycle logic of its turnover.\",\n      \"evidence\": \"Ubiquitin-mediated degradation assays and KEN-box identification with cell-cycle timing\",\n      \"pmids\": [\"17726374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of failed degradation not fully defined\", \"Relationship to SIAH-1 pathway not integrated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the in vivo requirement for KIF22 in anaphase chromosome compaction and development, with chromosome-targeting governed by importin-alpha/beta and local Ran-GTP, and spindle localization governed by the partner CHICA.\",\n      \"evidence\": \"Knockout mice and cultured cells, EM and live imaging; NLS-mutant transport assays; CHICA co-IP and reciprocal depletion\",\n      \"pmids\": [\"18329364\", \"18268099\", \"18485706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CHICA bridges KIF22 to the spindle structurally unknown\", \"Mechanism of chromosome-mass compaction not molecularly defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Added Chfr as an additional E3 ligase ubiquitylating KIF22, linking its downregulation to chromosome stability during the early mitotic checkpoint.\",\n      \"evidence\": \"Co-IP, ubiquitylation assay, and siRNA with chromosome-stability readout\",\n      \"pmids\": [\"19321445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy among SIAH-1, APC/C, and Chfr not resolved\", \"Checkpoint trigger for Chfr targeting unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Uncovered a non-canonical role in which KIF22 transcriptionally regulates CDC25C to control CDK1 activity and mitotic exit timing.\",\n      \"evidence\": \"siRNA, flow cytometry, ChIP/reporter assay, and CDK1 activity assay\",\n      \"pmids\": [\"24626146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a motor protein acts on transcription mechanistically unexplained\", \"Generality across cell types not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a specific contribution of KIF22 to lateral-attachment-based chromosome congression independent of end-on kinetochore-microtubule attachment.\",\n      \"evidence\": \"siRNA co-depletion with Hec1, live imaging, and attachment analysis\",\n      \"pmids\": [\"25743205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of lateral congression contribution not detailed\", \"Quantitative force contribution unmeasured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the temporal switch logic: Thr463 phosphorylation turns polar ejection force ON in prometaphase/metaphase and its dephosphorylation turns it OFF at anaphase, with NuSAP regulating the oscillation, defining how the force is timed and modulated.\",\n      \"evidence\": \"Phospho-mimetic/null Thr463 mutants in Kid-deficient cells with domain deletions and live imaging; NuSAP depletion with 3D oscillation imaging and epistasis\",\n      \"pmids\": [\"27550518\", \"26839278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase executing anaphase Thr463 dephosphorylation not identified\", \"Mechanism of NuSAP–KIF22 cooperation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended KIF22 function to interphase signaling, showing it interacts with CAR and regulates EGFR internalization and signaling to promote cancer cell proliferation.\",\n      \"evidence\": \"Co-IP, siRNA, EGFR internalization assay, and live imaging of receptor dynamics\",\n      \"pmids\": [\"29382784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether motor activity is required for receptor regulation unclear\", \"Direct vs indirect CAR interaction not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the disease mechanism of lepto-SEMDJL: pathogenic motor-domain and tail mutations do not impair early mitosis but prevent KIF22 inactivation at the metaphase-to-anaphase transition, disrupting segregation, with phospho-mimicry phenocopying the defect.\",\n      \"evidence\": \"Patient-variant and phospho-mimetic expression with live imaging, nuclear morphology and cytokinesis assays; earlier exome sequencing and segregation across families\",\n      \"pmids\": [\"35730929\", \"22152677\", \"22152678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue specificity of skeletal phenotype not explained\", \"Structural basis of failed inactivation not solved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated GBP2 as a KIF22 partner acting through a KIF22/EGFR axis in glioma proliferation and migration.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, and proliferation/migration assays in vitro and in vivo\",\n      \"pmids\": [\"35436989\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation of direct binding\", \"Mechanistic link to EGFR signaling not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The phosphatase that dephosphorylates Thr463 to switch off polar ejection force at anaphase, and the structural basis by which disease mutations block this inactivation, remain unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No anaphase Thr463 phosphatase identified\", \"No high-resolution structure of KIF22 motor/tail in active vs inactive states\", \"Integration of multiple E3 ligase pathways not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 5, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 4, 10, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 9, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SIAH1\", \"CHICA\", \"NUSAP1\", \"CHFR\", \"CXADR\", \"EGFR\", \"GBP2\", \"KPNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":9,"faith_pct":88.88888888888889}}