{"gene":"KNSTRN","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2010,"finding":"KNSTRN (SKAP) forms a complex with Astrin and dynein light chain LC8 at kinetochores. Localization of this complex to bioriented kinetochores is antagonized by Aurora B kinase, restricting it to tension-bearing (bioriented) kinetochores. Astrin and SKAP bind directly to microtubules and are required for CLASP localization to kinetochores.","method":"Co-immunoprecipitation, RNAi depletion, live-cell imaging, in vitro microtubule binding assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro microtubule binding, functional KD phenotype, replicated by multiple subsequent labs","pmids":["20937697"],"is_preprint":false},{"year":2011,"finding":"KNSTRN (kinastrin/SKAP) is the major astrin-interacting protein in mitotic cells and is required for astrin targeting to microtubule plus ends proximal to the plus-tip tracking protein EB1. Depletion or overexpression of kinastrin mislocalizes astrin and disrupts spindle architecture and chromosome alignment.","method":"Co-immunoprecipitation, RNAi depletion, fluorescence live-cell imaging, overexpression studies","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional KD and OE with defined phenotypes, consistent with independent lab (PMID 20937697)","pmids":["21402792"],"is_preprint":false},{"year":2009,"finding":"KNSTRN (SKAP) localizes to spindle microtubules and kinetochores in mitosis. Depletion of SKAP does not activate the spindle assembly checkpoint but increases duration of metaphase, delays separase activation, and decreases fidelity of chromosome segregation.","method":"RNAi depletion, live-cell imaging, immunofluorescence, separase activity assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with defined cellular phenotype, single lab, multiple readouts","pmids":["19667759"],"is_preprint":false},{"year":2011,"finding":"KNSTRN (SKAP) physically interacts with the C-terminal tail of CENP-E in vitro and cooperates with CENP-E to regulate kinetochore-microtubule interactions. SKAP is a constituent of kinetochore corona fibers. SKAP binds microtubules in vitro, and this interaction is synergized by CENP-E. Depletion of SKAP reduces inter-kinetochore tension and causes chromosome mis-segregation.","method":"In vitro binding/pulldown, immunoelectron microscopy, RNAi, in vitro microtubule binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of binding, immunoelectron microscopy for localization, functional RNAi phenotype, single lab but multiple orthogonal methods","pmids":["22110139"],"is_preprint":false},{"year":2012,"finding":"KNSTRN (SKAP) physically interacts with MIS13 (a component of the MIS12/KMN complex), which specifies kinetochore localization of SKAP. SKAP exhibits EB1-dependent microtubule plus-end loading and tracking in vitro (TIRF assay) and is essential for kinetochore oscillations and microtubule plus-end dynamics during mitosis.","method":"Co-immunoprecipitation, siRNA, TIRF microscopy in vitro, live-cell imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with TIRF, reciprocal Co-IP, functional siRNA phenotype, single lab but multiple orthogonal methods","pmids":["23035123"],"is_preprint":false},{"year":2014,"finding":"Cancer-associated KNSTRN mutations, most notably p.Ser24Phe, disrupt sister chromatid cohesion in normal cells and correlate with increased aneuploidy in primary tumors, implicating KNSTRN in maintenance of chromatid cohesion.","method":"Mutant expression in normal cells (cohesion assay), in vivo tumorigenesis model, sequencing of primary tumors","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional expression of cancer mutant with cohesion phenotype, in vivo tumorigenesis, single lab","pmids":["25194279"],"is_preprint":false},{"year":2016,"finding":"SKAP is expressed as two distinct isoforms in mammals: a shorter mitotic isoform and a longer testis-specific isoform. Only the short mitotic isoform rescues SKAP depletion in mitosis and displays robust microtubule plus-end tracking including localization to astral microtubules. SKAP microtubule binding mutants that abolish plus-end tracking cause spindle positioning defects and reduce Clasp1 localization at microtubule plus ends, leading to increased lateral microtubule contacts with the cell cortex.","method":"Isoform expression, rescue assays, live-cell imaging, mutant analysis, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific rescue, multiple separation-of-function mutants, live imaging with multiple orthogonal readouts","pmids":["27138257"],"is_preprint":false},{"year":2016,"finding":"KNSTRN (SKAP) contains a microtubule-binding domain distinct from the SXIP motif that mediates EB protein binding and plus-end tracking. This microtubule-binding domain stimulates the growth rate of microtubules possibly through direct interaction with tubulin. Mutations targeting this domain impair plus-end tracking but not kinetochore targeting and recapitulate SKAP depletion phenotypes.","method":"In vitro microtubule binding assay, mutagenesis, cross-linking mass spectrometry, biochemical reconstitution","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, cross-linking MS, separation-of-function mutants, single lab with multiple orthogonal methods","pmids":["27095104"],"is_preprint":false},{"year":2017,"finding":"Biochemical reconstitution of the 4-subunit Astrin-SKAP complex reveals it contains a novel MYCBP subunit. The complex has separable kinetochore localization and microtubule binding domains. Cross-linking analysis and biochemical reconstitution show the Astrin-SKAP complex binds synergistically to microtubules together with the Ndc80 complex to form an integrated interface.","method":"Complex reconstitution, cross-linking mass spectrometry, in vitro microtubule binding, biochemical domain mapping","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — full complex reconstitution in vitro, cross-linking MS, synergistic microtubule binding assay; multiple orthogonal methods in one study","pmids":["28841134"],"is_preprint":false},{"year":2016,"finding":"GSK3β phosphorylates KNSTRN (SKAP) in vitro; phosphorylation sites mapped by mass spectrometry. GSK3β-mediated phosphorylation of SKAP promotes SKAP binding to the Kif2b microtubule depolymerase, thereby competing with Kif2b for microtubule plus-end binding and regulating Kif2b depolymerase activity. Phosphomimetic SKAP rescues chromosome mis-segregation phenotype.","method":"In vitro kinase assay, mass spectrometry phosphosite mapping, Co-IP, rescue with phosphomimetic mutant, live-cell imaging","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with phosphosite mapping, phosphomimetic rescue, Co-IP; single lab","pmids":["27982129"],"is_preprint":false},{"year":2021,"finding":"Src-family kinases phosphorylate KNSTRN (kinastrin) at Tyr-87 on the mitotic spindle. Phosphomimetic kinastrin at Tyr-87 impairs its ability to bind microtubules, suggesting that SFK-mediated phosphorylation promotes kinastrin delocalization from microtubules during mitosis.","method":"Mass spectrometry of mitotic spindle preparations, phosphomimetic mutant analysis, microtubule binding assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — MS-identified phosphosite, phosphomimetic functional assay, single lab; microtubule binding assay","pmids":["33510346"],"is_preprint":false},{"year":2022,"finding":"KNSTRN (SKAP) physically interacts with Aurora B and spontaneously phase-separates in vitro via weak multivalent interactions into droplets. SKAP and Aurora B form heterogeneous coacervates in vitro that recapitulate in vivo SKAP comet dynamics. This SKAP-Aurora B interaction via phase separation is required for accurate chromosome segregation and the lateral-to-end-on conversion of kinetochore-microtubule attachments.","method":"In vitro phase separation assay, Co-IP, live-cell imaging, functional mutant analysis","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro phase separation reconstitution, Co-IP, functional mutant phenotype; single lab","pmids":["34554241"],"is_preprint":false},{"year":2022,"finding":"The Astrin-SKAP complex reduces friction at the kinetochore-microtubule interface. SKAP depletion dampens movement and decreases coordination of metaphase sister kinetochores, increases inter-kinetochore tension, and slows kinetochore movement on both polymerizing and depolymerizing microtubules. More force is needed to rescue microtubules to polymerize without SKAP, indicating Astrin-SKAP acts as a 'lubricant' reducing grip on bioriented attachments.","method":"Live imaging, laser ablation, SKAP RNAi depletion, kinetochore force measurements","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — laser ablation force measurements combined with live imaging and functional depletion, replicated in follow-up study (PMID 40154475)","pmids":["35580605"],"is_preprint":false},{"year":2021,"finding":"Plk1 directly interacts with Astrin in the Astrin-SKAP complex, and Plk1 phosphorylates astrin at four sites. This Plk1-mediated regulation is dispensable for bipolar spindle formation and bulk chromosome congression but promotes stable microtubule-kinetochore attachments and metaphase plate maintenance.","method":"Co-IP (direct astrin-Plk1 interaction), phosphosite mapping, separation-of-function mutants, live-cell imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction Co-IP, phosphomutant functional analysis; single lab, note this is astrin (SPAG5) as the direct Plk1 substrate within complex containing SKAP","pmids":["33288550"],"is_preprint":false},{"year":2025,"finding":"SKAP's direct microtubule binding is essential for sister kinetochore coordination, force dissipation at the kinetochore-microtubule interface, attachment responsiveness to force changes, and prevention of chromosome detachment under spindle forces and microneedle-generated forces.","method":"SKAP microtubule-binding mutants, live imaging, laser ablation, microneedle force application","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — separation-of-function mutants, multiple force measurement approaches, confirms prior mechanistic finding with mechanistic extension","pmids":["40154475"],"is_preprint":false},{"year":2021,"finding":"KNSTRN physically interacts with AKT at the cell membrane via AKT's PH domain, competing with PTEN. KNSTRN promotes AKT movement to PIP3 and alleviates PTEN suppression of AKT, thereby activating AKT phosphorylation at Thr308 and Ser473, which promotes bladder cancer metastasis and gemcitabine resistance.","method":"Co-IP, PIP3 pulldown assay, AKT phosphorylation assays, AKT inhibitor rescue, in vitro and in vivo tumorigenesis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, PIP3 pulldown, pharmacological rescue with AKT inhibitor; single lab, multiple methods","pmids":["33452459"],"is_preprint":false},{"year":2017,"finding":"Loss of KNSTRN (SKAP) expression in patients with Roifman-Chitayat syndrome leads to aberrant T-cell spreading, cell-cell interaction, and migration. A novel SKAP-binding partner, microtubule-associated protein 4 (MAP4), was identified; MAP4 undergoes relocalization in patient T cells with associated areas of microtubule hyperstabilization.","method":"Patient genetic analysis, protein expression studies, Co-IP/pulldown (MAP4 interaction), cellular functional assays in patient T cells","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel binding partner identified with functional consequence in patient cells; single study, human genetics + cellular assays","pmids":["29180244"],"is_preprint":false},{"year":2014,"finding":"KNSTRN (SKAP) interacts with Pre-mRNA processing Factor 19 (Prp19) and negatively regulates Prp19 protein levels. Overexpression or knockdown of SKAP both sensitize cells to UV-induced apoptosis, and this pro-apoptotic effect of SKAP is executed through Prp19.","method":"Co-IP, knockdown, overexpression, rescue experiments, UV-induced apoptosis assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, rescue experiment establishing epistasis, functional KD/OE; single lab","pmids":["24718257"],"is_preprint":false},{"year":2015,"finding":"KNSTRN (SKAP) interacts with IQGAP1; binding interfaces map to the WWIQ motif of IQGAP1 and the C-terminus of SKAP. The N-terminus of SKAP binds EB1 while the C-terminus binds IQGAP1. Disruption of the IQGAP1-SKAP interaction inhibits EGF-directed cell migration.","method":"Co-IP, domain mapping, TAT-WWIQ peptide perturbation, directional migration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, peptide perturbation with functional migration readout; single lab","pmids":["26242911"],"is_preprint":false},{"year":2016,"finding":"KNSTRN (SKAP/kinastrin) exists in two isoforms in human and mouse: ubiquitously expressed SKAP16 and testis/sperm-specific SKAP1. The testis-specific isoform SKAP1 interacts with Pontin, and SKAP1 and Pontin co-localize in the flagellar region of human sperm, suggesting a role in sperm motility.","method":"RT-PCR, Western blotting, immunocytochemistry, Co-IP (Pontin interaction), co-localization","journal":"Human molecular genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying Pontin interaction, co-localization; no functional assay confirming sperm motility role","pmids":["27170314"],"is_preprint":false},{"year":2026,"finding":"KNSTRN knockdown causes intracellular ROS accumulation and lysosomal dysfunction, impairing autophagosome-lysosome fusion and blocking autophagic flux in bladder cancer cells. Restoring lysosomal function (clioquinol) or scavenging ROS (NAC) rescues autophagy flux; autophagy activator rapamycin counteracts KNSTRN knockdown-induced cell death.","method":"siRNA knockdown, ROS assays, lysosomal pH measurement, autophagic flux assays, pharmacological rescue (clioquinol, NAC, rapamycin), in vitro and in vivo","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with mechanistic pathway placement via multiple pharmacological rescues; single lab","pmids":["41704764"],"is_preprint":false}],"current_model":"KNSTRN (also called SKAP/kinastrin) is a kinetochore and microtubule plus-end tracking protein that forms a 4-subunit complex with Astrin, DYNLL1, and MYCBP; this complex localizes preferentially to bioriented kinetochores (antagonized by Aurora B), directly binds microtubules via a domain distinct from its EB1-interacting SXIP motif, synergizes with the Ndc80 complex to stabilize kinetochore-microtubule attachments, and reduces rather than increases friction at the kinetochore-microtubule interface to maintain force-responsive, dynamic attachments; KNSTRN is regulated by post-translational modifications (Aurora B-dependent localization, GSK3β phosphorylation controlling Kif2b depolymerase activity, and Src-mediated Tyr-87 phosphorylation that impairs microtubule binding), interacts with CENP-E, MIS13/KMN, IQGAP1, MAP4, and Prp19 to coordinate chromosome segregation, cell migration, and apoptosis, and in cancer contexts activates AKT signaling by competing with PTEN at the plasma membrane."},"narrative":{"mechanistic_narrative":"KNSTRN (SKAP/kinastrin) is a microtubule plus-end tracking protein and kinetochore component that, as the major astrin partner, governs the stability and force-responsiveness of kinetochore-microtubule attachments during mitosis [PMID:21402792, PMID:20937697]. It assembles into a reconstituted four-subunit Astrin-SKAP complex containing DYNLL1/LC8 and MYCBP, and this complex binds microtubules synergistically with the Ndc80 complex through a microtubule-binding domain that is distinct and separable from its EB1-dependent SXIP plus-tip-tracking module [PMID:28841134, PMID:27095104, PMID:20937697]. The complex localizes preferentially to bioriented, tension-bearing kinetochores, a restriction imposed by Aurora B, and is recruited there through interaction with MIS13 of the KMN network and cooperation with CENP-E [PMID:20937697, PMID:23035123, PMID:22110139]. Rather than acting as a static clamp, Astrin-SKAP reduces friction at the kinetochore-microtubule interface, acting as a lubricant that coordinates sister-kinetochore movement, dissipates force, and prevents detachment under load; this depends directly on SKAP's microtubule binding [PMID:35580605, PMID:40154475]. KNSTRN function is tuned by post-translational modification: GSK3β phosphorylation directs SKAP binding to the Kif2b depolymerase, while Src-family phosphorylation of Tyr-87 impairs microtubule binding [PMID:27982129, PMID:33510346]. Beyond mitosis, KNSTRN supports EGF-directed and T-cell migration via IQGAP1 and MAP4, modulates UV-induced apoptosis through Prp19, and in cancer activates AKT signaling by competing with PTEN at the plasma membrane [PMID:26242911, PMID:29180244, PMID:24718257, PMID:33452459]. Cancer-associated mutation (p.Ser24Phe) disrupts sister chromatid cohesion and promotes aneuploidy, and loss-of-expression underlies the cellular defects of Roifman-Chitayat syndrome [PMID:25194279, PMID:29180244].","teleology":[{"year":2009,"claim":"Established that KNSTRN is a mitotic spindle and kinetochore protein whose loss compromises segregation fidelity without triggering the spindle assembly checkpoint, distinguishing it from core checkpoint machinery.","evidence":"RNAi depletion with live imaging and separase activity assays","pmids":["19667759"],"confidence":"Medium","gaps":["Molecular partners at the kinetochore not yet defined","Mechanism of segregation delay unresolved"]},{"year":2010,"claim":"Defined KNSTRN as part of an Astrin-SKAP-LC8 complex restricted to bioriented kinetochores by Aurora B, linking it to tension-sensing and CLASP recruitment.","evidence":"Co-IP, RNAi, live imaging, in vitro microtubule binding","pmids":["20937697"],"confidence":"High","gaps":["Full subunit composition incomplete (MYCBP not yet identified)","Direct vs indirect microtubule contacts unresolved"]},{"year":2011,"claim":"Showed KNSTRN/kinastrin is the principal astrin-targeting factor and a CENP-E-cooperating microtubule binder, establishing both its complex hierarchy and contribution to inter-kinetochore tension.","evidence":"Reciprocal Co-IP, in vitro binding, immunoelectron microscopy, RNAi","pmids":["21402792","22110139"],"confidence":"High","gaps":["Kinetochore receptor for SKAP not identified","Quantitative contribution to attachment strength unmeasured"]},{"year":2012,"claim":"Identified MIS13/KMN as the kinetochore receptor specifying SKAP localization and demonstrated EB1-dependent plus-end tracking in vitro, connecting recruitment to plus-end dynamics.","evidence":"Co-IP, siRNA, in vitro TIRF reconstitution, live imaging","pmids":["23035123"],"confidence":"High","gaps":["Separation of kinetochore vs plus-tip functions not yet achieved","Mechanism of dynamics regulation unclear"]},{"year":2014,"claim":"Linked KNSTRN to chromatid cohesion and tumorigenesis, showing the recurrent p.Ser24Phe mutation disrupts cohesion and drives aneuploidy, and tied SKAP to UV-induced apoptosis via Prp19.","evidence":"Cancer mutant expression with cohesion assay, tumorigenesis model, tumor sequencing; Co-IP and rescue for Prp19","pmids":["25194279","24718257"],"confidence":"Medium","gaps":["Molecular basis of cohesion defect not mechanistically resolved","Prp19 regulatory mechanism partly defined"]},{"year":2015,"claim":"Extended KNSTRN function beyond mitosis by mapping an IQGAP1 interaction (C-terminus) distinct from its N-terminal EB1 binding, required for directed cell migration.","evidence":"Co-IP, domain mapping, peptide perturbation, migration assay","pmids":["26242911"],"confidence":"Medium","gaps":["Interplay between mitotic and migratory roles unclear","Structural basis of dual-terminus binding not solved"]},{"year":2016,"claim":"Resolved isoform-specific function and architecture: a short mitotic isoform mediates plus-end tracking via a dedicated microtubule-binding domain separable from the SXIP/EB module, with mutations giving separation-of-function phenotypes.","evidence":"Isoform rescue, in vitro microtubule binding, cross-linking MS, mutagenesis, live imaging","pmids":["27138257","27095104"],"confidence":"High","gaps":["Atomic structure of the microtubule-binding domain undetermined","Testis isoform mitotic relevance excluded but its own role unclear"]},{"year":2016,"claim":"Placed KNSTRN under kinase control, showing GSK3β phosphorylation couples SKAP to the Kif2b depolymerase to regulate plus-end dynamics.","evidence":"In vitro kinase assay, phosphosite mapping, Co-IP, phosphomimetic rescue, live imaging","pmids":["27982129"],"confidence":"Medium","gaps":["In vivo phosphorylation stoichiometry unknown","Single lab; reciprocal Kif2b regulation not fully mapped"]},{"year":2017,"claim":"Completed the complex by reconstituting a four-subunit Astrin-SKAP complex with MYCBP and demonstrated synergistic microtubule binding with the Ndc80 complex, defining an integrated attachment interface; also tied SKAP loss to Roifman-Chitayat syndrome immune-cell defects via MAP4.","evidence":"Complex reconstitution, cross-linking MS, in vitro microtubule binding; patient genetics with MAP4 Co-IP and T-cell assays","pmids":["28841134","29180244"],"confidence":"High","gaps":["Stoichiometry and structure of the Ndc80-Astrin/SKAP interface not solved","MAP4 functional axis single study"]},{"year":2021,"claim":"Added further regulatory and signaling layers: Src phosphorylation at Tyr-87 displaces SKAP from microtubules, Plk1 acts via astrin within the complex to stabilize attachments, and KNSTRN activates AKT by outcompeting PTEN at the membrane in cancer.","evidence":"MS phosphosite mapping with phosphomimetics; Co-IP and phosphomutant analysis; Co-IP, PIP3 pulldown and AKT inhibitor rescue in tumor models","pmids":["33510346","33288550","33452459"],"confidence":"Medium","gaps":["Physiological trigger for Src/Plk1 modification unclear","AKT axis mechanistic detail from single lab"]},{"year":2022,"claim":"Reframed the mechanical role of Astrin-SKAP as a friction-reducing 'lubricant' that coordinates sister kinetochores and dissipates force, and linked a SKAP-Aurora B phase-separation behavior to lateral-to-end-on attachment conversion.","evidence":"Live imaging, laser ablation force measurements, RNAi; in vitro phase separation and Co-IP","pmids":["35580605","34554241"],"confidence":"High","gaps":["Physiological relevance of in vitro coacervates uncertain","Molecular origin of reduced friction not structurally defined"]},{"year":2025,"claim":"Confirmed that SKAP's direct microtubule binding is the basis of force dissipation, attachment force-responsiveness, and prevention of detachment under applied force.","evidence":"Microtubule-binding mutants, live imaging, laser ablation, microneedle force application","pmids":["40154475"],"confidence":"High","gaps":["Quantitative model of grip/slip behavior incomplete","Interplay with Ndc80 under force not directly tested"]},{"year":2026,"claim":"Implicated KNSTRN in cancer cell survival through autophagy, where its loss causes ROS accumulation and lysosomal dysfunction that block autophagic flux.","evidence":"siRNA, ROS and lysosomal assays, autophagic flux measurement, pharmacological rescue, in vivo","pmids":["41704764"],"confidence":"Medium","gaps":["Direct molecular link between KNSTRN and lysosome/ROS biology unidentified","Relationship to its mitotic function unclear"]},{"year":null,"claim":"How KNSTRN's mechanical role at the kinetochore is coordinated with its diverse non-mitotic functions (migration, AKT signaling, autophagy) through a single shared biochemistry remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the microtubule- or Ndc80-binding interfaces","Unclear whether mitotic and non-mitotic roles use overlapping domains","Mechanism linking KNSTRN to lysosomal/ROS homeostasis undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,7,8,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,8]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,6,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,3,4,8,12,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[20]}],"complexes":["Astrin-SKAP complex (Astrin/SPAG5-KNSTRN-DYNLL1-MYCBP)","kinetochore corona"],"partners":["SPAG5","DYNLL1","MYCBP","CENP-E","MIS13","EB1","IQGAP1","MAP4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y448","full_name":"Small kinetochore-associated protein","aliases":["Kinetochore-localized astrin-binding protein","Kinastrin","Kinetochore-localized astrin/SPAG5-binding protein","TRAF4-associated factor 1"],"length_aa":316,"mass_kda":35.4,"function":"Essential component of the mitotic spindle required for faithful chromosome segregation and progression into anaphase (PubMed:19667759). Promotes the metaphase-to-anaphase transition and is required for chromosome alignment, normal timing of sister chromatid segregation, and maintenance of spindle pole architecture (PubMed:19667759, PubMed:22110139). The astrin (SPAG5)-kinastrin (SKAP) complex promotes stable microtubule-kinetochore attachments (PubMed:21402792). Required for kinetochore oscillations and dynamics of microtubule plus-ends during live cell mitosis, possibly by forming a link between spindle microtubule plus-ends and mitotic chromosomes to achieve faithful cell division (PubMed:23035123). May be involved in UV-induced apoptosis via its interaction with PRPF19; however, these results need additional evidences (PubMed:24718257)","subcellular_location":"Nucleus; Chromosome, centromere, kinetochore; Cytoplasm, cytoskeleton, spindle pole; Cytoplasm, cytoskeleton, microtubule organizing center","url":"https://www.uniprot.org/uniprotkb/Q9Y448/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KNSTRN","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"PRPF19","stoichiometry":0.2},{"gene":"PSMD9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KNSTRN","total_profiled":1310},"omim":[{"mim_id":"617997","title":"RCC1 DOMAIN-CONTAINING PROTEIN 1; RCCD1","url":"https://www.omim.org/entry/617997"},{"mim_id":"614718","title":"KINETOCHORE-LOCALIZED ASTRIN/SPAG5-BINDING PROTEIN; KNSTRN","url":"https://www.omim.org/entry/614718"},{"mim_id":"613328","title":"ROIFMAN-CHITAYAT SYNDROME; ROCHIS","url":"https://www.omim.org/entry/613328"},{"mim_id":"602839","title":"PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, DELTA; PIK3CD","url":"https://www.omim.org/entry/602839"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitotic spindle","reliability":"Enhanced"},{"location":"Centriolar satellite","reliability":"Enhanced"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":59.0},{"tissue":"thyroid gland","ntpm":51.2}],"url":"https://www.proteinatlas.org/search/KNSTRN"},"hgnc":{"alias_symbol":["FLJ14502","SKAP","kinastrin","TRAF4AF1"],"prev_symbol":["C15orf23"]},"alphafold":{"accession":"Q9Y448","domains":[{"cath_id":"1.20.5","chopping":"171-228","consensus_level":"medium","plddt":92.9257,"start":171,"end":228}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y448","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y448-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y448-F1-predicted_aligned_error_v6.png","plddt_mean":67.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KNSTRN","jax_strain_url":"https://www.jax.org/strain/search?query=KNSTRN"},"sequence":{"accession":"Q9Y448","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y448.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y448/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y448"}},"corpus_meta":[{"pmid":"25194279","id":"PMC_25194279","title":"Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma.","date":"2014","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25194279","citation_count":124,"is_preprint":false},{"pmid":"20937697","id":"PMC_20937697","title":"Aurora B kinase controls the targeting of the Astrin-SKAP complex to bioriented kinetochores.","date":"2010","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20937697","citation_count":107,"is_preprint":false},{"pmid":"21402792","id":"PMC_21402792","title":"The astrin-kinastrin/SKAP complex localizes to microtubule plus ends and facilitates chromosome alignment.","date":"2011","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21402792","citation_count":96,"is_preprint":false},{"pmid":"17403904","id":"PMC_17403904","title":"RIAM links the ADAP/SKAP-55 signaling module to Rap1, facilitating T-cell-receptor-mediated integrin activation.","date":"2007","source":"Molecular 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progression.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41704764","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18982,"output_tokens":5274,"usd":0.068028,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13618,"output_tokens":4448,"usd":0.089645,"stage2_stop_reason":"end_turn"},"total_usd":0.157673,"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\": 2010,\n      \"finding\": \"KNSTRN (SKAP) forms a complex with Astrin and dynein light chain LC8 at kinetochores. Localization of this complex to bioriented kinetochores is antagonized by Aurora B kinase, restricting it to tension-bearing (bioriented) kinetochores. Astrin and SKAP bind directly to microtubules and are required for CLASP localization to kinetochores.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion, live-cell imaging, in vitro microtubule binding assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro microtubule binding, functional KD phenotype, replicated by multiple subsequent labs\",\n      \"pmids\": [\"20937697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KNSTRN (kinastrin/SKAP) is the major astrin-interacting protein in mitotic cells and is required for astrin targeting to microtubule plus ends proximal to the plus-tip tracking protein EB1. Depletion or overexpression of kinastrin mislocalizes astrin and disrupts spindle architecture and chromosome alignment.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion, fluorescence live-cell imaging, overexpression studies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional KD and OE with defined phenotypes, consistent with independent lab (PMID 20937697)\",\n      \"pmids\": [\"21402792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KNSTRN (SKAP) localizes to spindle microtubules and kinetochores in mitosis. Depletion of SKAP does not activate the spindle assembly checkpoint but increases duration of metaphase, delays separase activation, and decreases fidelity of chromosome segregation.\",\n      \"method\": \"RNAi depletion, live-cell imaging, immunofluorescence, separase activity assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with defined cellular phenotype, single lab, multiple readouts\",\n      \"pmids\": [\"19667759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KNSTRN (SKAP) physically interacts with the C-terminal tail of CENP-E in vitro and cooperates with CENP-E to regulate kinetochore-microtubule interactions. SKAP is a constituent of kinetochore corona fibers. SKAP binds microtubules in vitro, and this interaction is synergized by CENP-E. Depletion of SKAP reduces inter-kinetochore tension and causes chromosome mis-segregation.\",\n      \"method\": \"In vitro binding/pulldown, immunoelectron microscopy, RNAi, in vitro microtubule binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of binding, immunoelectron microscopy for localization, functional RNAi phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22110139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KNSTRN (SKAP) physically interacts with MIS13 (a component of the MIS12/KMN complex), which specifies kinetochore localization of SKAP. SKAP exhibits EB1-dependent microtubule plus-end loading and tracking in vitro (TIRF assay) and is essential for kinetochore oscillations and microtubule plus-end dynamics during mitosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA, TIRF microscopy in vitro, live-cell imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with TIRF, reciprocal Co-IP, functional siRNA phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23035123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cancer-associated KNSTRN mutations, most notably p.Ser24Phe, disrupt sister chromatid cohesion in normal cells and correlate with increased aneuploidy in primary tumors, implicating KNSTRN in maintenance of chromatid cohesion.\",\n      \"method\": \"Mutant expression in normal cells (cohesion assay), in vivo tumorigenesis model, sequencing of primary tumors\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional expression of cancer mutant with cohesion phenotype, in vivo tumorigenesis, single lab\",\n      \"pmids\": [\"25194279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SKAP is expressed as two distinct isoforms in mammals: a shorter mitotic isoform and a longer testis-specific isoform. Only the short mitotic isoform rescues SKAP depletion in mitosis and displays robust microtubule plus-end tracking including localization to astral microtubules. SKAP microtubule binding mutants that abolish plus-end tracking cause spindle positioning defects and reduce Clasp1 localization at microtubule plus ends, leading to increased lateral microtubule contacts with the cell cortex.\",\n      \"method\": \"Isoform expression, rescue assays, live-cell imaging, mutant analysis, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific rescue, multiple separation-of-function mutants, live imaging with multiple orthogonal readouts\",\n      \"pmids\": [\"27138257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KNSTRN (SKAP) contains a microtubule-binding domain distinct from the SXIP motif that mediates EB protein binding and plus-end tracking. This microtubule-binding domain stimulates the growth rate of microtubules possibly through direct interaction with tubulin. Mutations targeting this domain impair plus-end tracking but not kinetochore targeting and recapitulate SKAP depletion phenotypes.\",\n      \"method\": \"In vitro microtubule binding assay, mutagenesis, cross-linking mass spectrometry, biochemical reconstitution\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, cross-linking MS, separation-of-function mutants, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27095104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biochemical reconstitution of the 4-subunit Astrin-SKAP complex reveals it contains a novel MYCBP subunit. The complex has separable kinetochore localization and microtubule binding domains. Cross-linking analysis and biochemical reconstitution show the Astrin-SKAP complex binds synergistically to microtubules together with the Ndc80 complex to form an integrated interface.\",\n      \"method\": \"Complex reconstitution, cross-linking mass spectrometry, in vitro microtubule binding, biochemical domain mapping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full complex reconstitution in vitro, cross-linking MS, synergistic microtubule binding assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"28841134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GSK3β phosphorylates KNSTRN (SKAP) in vitro; phosphorylation sites mapped by mass spectrometry. GSK3β-mediated phosphorylation of SKAP promotes SKAP binding to the Kif2b microtubule depolymerase, thereby competing with Kif2b for microtubule plus-end binding and regulating Kif2b depolymerase activity. Phosphomimetic SKAP rescues chromosome mis-segregation phenotype.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry phosphosite mapping, Co-IP, rescue with phosphomimetic mutant, live-cell imaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with phosphosite mapping, phosphomimetic rescue, Co-IP; single lab\",\n      \"pmids\": [\"27982129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Src-family kinases phosphorylate KNSTRN (kinastrin) at Tyr-87 on the mitotic spindle. Phosphomimetic kinastrin at Tyr-87 impairs its ability to bind microtubules, suggesting that SFK-mediated phosphorylation promotes kinastrin delocalization from microtubules during mitosis.\",\n      \"method\": \"Mass spectrometry of mitotic spindle preparations, phosphomimetic mutant analysis, microtubule binding assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS-identified phosphosite, phosphomimetic functional assay, single lab; microtubule binding assay\",\n      \"pmids\": [\"33510346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KNSTRN (SKAP) physically interacts with Aurora B and spontaneously phase-separates in vitro via weak multivalent interactions into droplets. SKAP and Aurora B form heterogeneous coacervates in vitro that recapitulate in vivo SKAP comet dynamics. This SKAP-Aurora B interaction via phase separation is required for accurate chromosome segregation and the lateral-to-end-on conversion of kinetochore-microtubule attachments.\",\n      \"method\": \"In vitro phase separation assay, Co-IP, live-cell imaging, functional mutant analysis\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phase separation reconstitution, Co-IP, functional mutant phenotype; single lab\",\n      \"pmids\": [\"34554241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The Astrin-SKAP complex reduces friction at the kinetochore-microtubule interface. SKAP depletion dampens movement and decreases coordination of metaphase sister kinetochores, increases inter-kinetochore tension, and slows kinetochore movement on both polymerizing and depolymerizing microtubules. More force is needed to rescue microtubules to polymerize without SKAP, indicating Astrin-SKAP acts as a 'lubricant' reducing grip on bioriented attachments.\",\n      \"method\": \"Live imaging, laser ablation, SKAP RNAi depletion, kinetochore force measurements\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — laser ablation force measurements combined with live imaging and functional depletion, replicated in follow-up study (PMID 40154475)\",\n      \"pmids\": [\"35580605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plk1 directly interacts with Astrin in the Astrin-SKAP complex, and Plk1 phosphorylates astrin at four sites. This Plk1-mediated regulation is dispensable for bipolar spindle formation and bulk chromosome congression but promotes stable microtubule-kinetochore attachments and metaphase plate maintenance.\",\n      \"method\": \"Co-IP (direct astrin-Plk1 interaction), phosphosite mapping, separation-of-function mutants, live-cell imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction Co-IP, phosphomutant functional analysis; single lab, note this is astrin (SPAG5) as the direct Plk1 substrate within complex containing SKAP\",\n      \"pmids\": [\"33288550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SKAP's direct microtubule binding is essential for sister kinetochore coordination, force dissipation at the kinetochore-microtubule interface, attachment responsiveness to force changes, and prevention of chromosome detachment under spindle forces and microneedle-generated forces.\",\n      \"method\": \"SKAP microtubule-binding mutants, live imaging, laser ablation, microneedle force application\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — separation-of-function mutants, multiple force measurement approaches, confirms prior mechanistic finding with mechanistic extension\",\n      \"pmids\": [\"40154475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KNSTRN physically interacts with AKT at the cell membrane via AKT's PH domain, competing with PTEN. KNSTRN promotes AKT movement to PIP3 and alleviates PTEN suppression of AKT, thereby activating AKT phosphorylation at Thr308 and Ser473, which promotes bladder cancer metastasis and gemcitabine resistance.\",\n      \"method\": \"Co-IP, PIP3 pulldown assay, AKT phosphorylation assays, AKT inhibitor rescue, in vitro and in vivo tumorigenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, PIP3 pulldown, pharmacological rescue with AKT inhibitor; single lab, multiple methods\",\n      \"pmids\": [\"33452459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of KNSTRN (SKAP) expression in patients with Roifman-Chitayat syndrome leads to aberrant T-cell spreading, cell-cell interaction, and migration. A novel SKAP-binding partner, microtubule-associated protein 4 (MAP4), was identified; MAP4 undergoes relocalization in patient T cells with associated areas of microtubule hyperstabilization.\",\n      \"method\": \"Patient genetic analysis, protein expression studies, Co-IP/pulldown (MAP4 interaction), cellular functional assays in patient T cells\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel binding partner identified with functional consequence in patient cells; single study, human genetics + cellular assays\",\n      \"pmids\": [\"29180244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KNSTRN (SKAP) interacts with Pre-mRNA processing Factor 19 (Prp19) and negatively regulates Prp19 protein levels. Overexpression or knockdown of SKAP both sensitize cells to UV-induced apoptosis, and this pro-apoptotic effect of SKAP is executed through Prp19.\",\n      \"method\": \"Co-IP, knockdown, overexpression, rescue experiments, UV-induced apoptosis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, rescue experiment establishing epistasis, functional KD/OE; single lab\",\n      \"pmids\": [\"24718257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KNSTRN (SKAP) interacts with IQGAP1; binding interfaces map to the WWIQ motif of IQGAP1 and the C-terminus of SKAP. The N-terminus of SKAP binds EB1 while the C-terminus binds IQGAP1. Disruption of the IQGAP1-SKAP interaction inhibits EGF-directed cell migration.\",\n      \"method\": \"Co-IP, domain mapping, TAT-WWIQ peptide perturbation, directional migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, peptide perturbation with functional migration readout; single lab\",\n      \"pmids\": [\"26242911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KNSTRN (SKAP/kinastrin) exists in two isoforms in human and mouse: ubiquitously expressed SKAP16 and testis/sperm-specific SKAP1. The testis-specific isoform SKAP1 interacts with Pontin, and SKAP1 and Pontin co-localize in the flagellar region of human sperm, suggesting a role in sperm motility.\",\n      \"method\": \"RT-PCR, Western blotting, immunocytochemistry, Co-IP (Pontin interaction), co-localization\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying Pontin interaction, co-localization; no functional assay confirming sperm motility role\",\n      \"pmids\": [\"27170314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KNSTRN knockdown causes intracellular ROS accumulation and lysosomal dysfunction, impairing autophagosome-lysosome fusion and blocking autophagic flux in bladder cancer cells. Restoring lysosomal function (clioquinol) or scavenging ROS (NAC) rescues autophagy flux; autophagy activator rapamycin counteracts KNSTRN knockdown-induced cell death.\",\n      \"method\": \"siRNA knockdown, ROS assays, lysosomal pH measurement, autophagic flux assays, pharmacological rescue (clioquinol, NAC, rapamycin), in vitro and in vivo\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with mechanistic pathway placement via multiple pharmacological rescues; single lab\",\n      \"pmids\": [\"41704764\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KNSTRN (also called SKAP/kinastrin) is a kinetochore and microtubule plus-end tracking protein that forms a 4-subunit complex with Astrin, DYNLL1, and MYCBP; this complex localizes preferentially to bioriented kinetochores (antagonized by Aurora B), directly binds microtubules via a domain distinct from its EB1-interacting SXIP motif, synergizes with the Ndc80 complex to stabilize kinetochore-microtubule attachments, and reduces rather than increases friction at the kinetochore-microtubule interface to maintain force-responsive, dynamic attachments; KNSTRN is regulated by post-translational modifications (Aurora B-dependent localization, GSK3β phosphorylation controlling Kif2b depolymerase activity, and Src-mediated Tyr-87 phosphorylation that impairs microtubule binding), interacts with CENP-E, MIS13/KMN, IQGAP1, MAP4, and Prp19 to coordinate chromosome segregation, cell migration, and apoptosis, and in cancer contexts activates AKT signaling by competing with PTEN at the plasma membrane.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KNSTRN (SKAP/kinastrin) is a microtubule plus-end tracking protein and kinetochore component that, as the major astrin partner, governs the stability and force-responsiveness of kinetochore-microtubule attachments during mitosis [#1, #0]. It assembles into a reconstituted four-subunit Astrin-SKAP complex containing DYNLL1/LC8 and MYCBP, and this complex binds microtubules synergistically with the Ndc80 complex through a microtubule-binding domain that is distinct and separable from its EB1-dependent SXIP plus-tip-tracking module [#8, #7, #0]. The complex localizes preferentially to bioriented, tension-bearing kinetochores, a restriction imposed by Aurora B, and is recruited there through interaction with MIS13 of the KMN network and cooperation with CENP-E [#0, #4, #3]. Rather than acting as a static clamp, Astrin-SKAP reduces friction at the kinetochore-microtubule interface, acting as a lubricant that coordinates sister-kinetochore movement, dissipates force, and prevents detachment under load; this depends directly on SKAP's microtubule binding [#12, #14]. KNSTRN function is tuned by post-translational modification: GSK3\\u03b2 phosphorylation directs SKAP binding to the Kif2b depolymerase, while Src-family phosphorylation of Tyr-87 impairs microtubule binding [#9, #10]. Beyond mitosis, KNSTRN supports EGF-directed and T-cell migration via IQGAP1 and MAP4, modulates UV-induced apoptosis through Prp19, and in cancer activates AKT signaling by competing with PTEN at the plasma membrane [#18, #16, #17, #15]. Cancer-associated mutation (p.Ser24Phe) disrupts sister chromatid cohesion and promotes aneuploidy, and loss-of-expression underlies the cellular defects of Roifman-Chitayat syndrome [#5, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that KNSTRN is a mitotic spindle and kinetochore protein whose loss compromises segregation fidelity without triggering the spindle assembly checkpoint, distinguishing it from core checkpoint machinery.\",\n      \"evidence\": \"RNAi depletion with live imaging and separase activity assays\",\n      \"pmids\": [\"19667759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners at the kinetochore not yet defined\", \"Mechanism of segregation delay unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined KNSTRN as part of an Astrin-SKAP-LC8 complex restricted to bioriented kinetochores by Aurora B, linking it to tension-sensing and CLASP recruitment.\",\n      \"evidence\": \"Co-IP, RNAi, live imaging, in vitro microtubule binding\",\n      \"pmids\": [\"20937697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full subunit composition incomplete (MYCBP not yet identified)\", \"Direct vs indirect microtubule contacts unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed KNSTRN/kinastrin is the principal astrin-targeting factor and a CENP-E-cooperating microtubule binder, establishing both its complex hierarchy and contribution to inter-kinetochore tension.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro binding, immunoelectron microscopy, RNAi\",\n      \"pmids\": [\"21402792\", \"22110139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetochore receptor for SKAP not identified\", \"Quantitative contribution to attachment strength unmeasured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified MIS13/KMN as the kinetochore receptor specifying SKAP localization and demonstrated EB1-dependent plus-end tracking in vitro, connecting recruitment to plus-end dynamics.\",\n      \"evidence\": \"Co-IP, siRNA, in vitro TIRF reconstitution, live imaging\",\n      \"pmids\": [\"23035123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Separation of kinetochore vs plus-tip functions not yet achieved\", \"Mechanism of dynamics regulation unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked KNSTRN to chromatid cohesion and tumorigenesis, showing the recurrent p.Ser24Phe mutation disrupts cohesion and drives aneuploidy, and tied SKAP to UV-induced apoptosis via Prp19.\",\n      \"evidence\": \"Cancer mutant expression with cohesion assay, tumorigenesis model, tumor sequencing; Co-IP and rescue for Prp19\",\n      \"pmids\": [\"25194279\", \"24718257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of cohesion defect not mechanistically resolved\", \"Prp19 regulatory mechanism partly defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended KNSTRN function beyond mitosis by mapping an IQGAP1 interaction (C-terminus) distinct from its N-terminal EB1 binding, required for directed cell migration.\",\n      \"evidence\": \"Co-IP, domain mapping, peptide perturbation, migration assay\",\n      \"pmids\": [\"26242911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between mitotic and migratory roles unclear\", \"Structural basis of dual-terminus binding not solved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved isoform-specific function and architecture: a short mitotic isoform mediates plus-end tracking via a dedicated microtubule-binding domain separable from the SXIP/EB module, with mutations giving separation-of-function phenotypes.\",\n      \"evidence\": \"Isoform rescue, in vitro microtubule binding, cross-linking MS, mutagenesis, live imaging\",\n      \"pmids\": [\"27138257\", \"27095104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the microtubule-binding domain undetermined\", \"Testis isoform mitotic relevance excluded but its own role unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed KNSTRN under kinase control, showing GSK3\\u03b2 phosphorylation couples SKAP to the Kif2b depolymerase to regulate plus-end dynamics.\",\n      \"evidence\": \"In vitro kinase assay, phosphosite mapping, Co-IP, phosphomimetic rescue, live imaging\",\n      \"pmids\": [\"27982129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo phosphorylation stoichiometry unknown\", \"Single lab; reciprocal Kif2b regulation not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Completed the complex by reconstituting a four-subunit Astrin-SKAP complex with MYCBP and demonstrated synergistic microtubule binding with the Ndc80 complex, defining an integrated attachment interface; also tied SKAP loss to Roifman-Chitayat syndrome immune-cell defects via MAP4.\",\n      \"evidence\": \"Complex reconstitution, cross-linking MS, in vitro microtubule binding; patient genetics with MAP4 Co-IP and T-cell assays\",\n      \"pmids\": [\"28841134\", \"29180244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the Ndc80-Astrin/SKAP interface not solved\", \"MAP4 functional axis single study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added further regulatory and signaling layers: Src phosphorylation at Tyr-87 displaces SKAP from microtubules, Plk1 acts via astrin within the complex to stabilize attachments, and KNSTRN activates AKT by outcompeting PTEN at the membrane in cancer.\",\n      \"evidence\": \"MS phosphosite mapping with phosphomimetics; Co-IP and phosphomutant analysis; Co-IP, PIP3 pulldown and AKT inhibitor rescue in tumor models\",\n      \"pmids\": [\"33510346\", \"33288550\", \"33452459\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological trigger for Src/Plk1 modification unclear\", \"AKT axis mechanistic detail from single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reframed the mechanical role of Astrin-SKAP as a friction-reducing 'lubricant' that coordinates sister kinetochores and dissipates force, and linked a SKAP-Aurora B phase-separation behavior to lateral-to-end-on attachment conversion.\",\n      \"evidence\": \"Live imaging, laser ablation force measurements, RNAi; in vitro phase separation and Co-IP\",\n      \"pmids\": [\"35580605\", \"34554241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of in vitro coacervates uncertain\", \"Molecular origin of reduced friction not structurally defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed that SKAP's direct microtubule binding is the basis of force dissipation, attachment force-responsiveness, and prevention of detachment under applied force.\",\n      \"evidence\": \"Microtubule-binding mutants, live imaging, laser ablation, microneedle force application\",\n      \"pmids\": [\"40154475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative model of grip/slip behavior incomplete\", \"Interplay with Ndc80 under force not directly tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated KNSTRN in cancer cell survival through autophagy, where its loss causes ROS accumulation and lysosomal dysfunction that block autophagic flux.\",\n      \"evidence\": \"siRNA, ROS and lysosomal assays, autophagic flux measurement, pharmacological rescue, in vivo\",\n      \"pmids\": [\"41704764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between KNSTRN and lysosome/ROS biology unidentified\", \"Relationship to its mitotic function unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KNSTRN's mechanical role at the kinetochore is coordinated with its diverse non-mitotic functions (migration, AKT signaling, autophagy) through a single shared biochemistry remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the microtubule- or Ndc80-binding interfaces\", \"Unclear whether mitotic and non-mitotic roles use overlapping domains\", \"Mechanism linking KNSTRN to lysosomal/ROS homeostasis undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 7, 8, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 6, 7]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 3, 4, 8, 12, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\n      \"Astrin-SKAP complex (Astrin/SPAG5-KNSTRN-DYNLL1-MYCBP)\",\n      \"kinetochore corona\"\n    ],\n    \"partners\": [\n      \"SPAG5\",\n      \"DYNLL1\",\n      \"MYCBP\",\n      \"CENP-E\",\n      \"MIS13\",\n      \"EB1\",\n      \"IQGAP1\",\n      \"MAP4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}