{"gene":"MAP9","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2005,"finding":"MAP9 (ASAP/aster-associated protein) is a human microtubule-associated protein that directly binds purified microtubules via its C-terminal domain. It localizes to microtubules in interphase, associates with the mitotic spindle during mitosis, and localizes to the central body during cytokinesis. Overexpression induces cytoplasmic microtubule bundling and aberrant monopolar spindles; RNAi depletion causes aberrant mitotic spindles, delayed mitotic progression, defective cytokinesis, and cell death.","method":"Direct microtubule binding assay with purified microtubules, RNA interference knockdown, overexpression in human cells, live-cell imaging/immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted direct binding to purified microtubules plus multiple cellular loss- and gain-of-function readouts in one study","pmids":["16049101"],"is_preprint":false},{"year":2007,"finding":"MAP9 is a direct substrate of Aurora-A kinase (AurA); Serine 625 is the major in vivo phosphorylation site. The phosphorylated form localizes to centrosomes from late G2 to telophase and around the midbody during cytokinesis. Aurora-A depletion causes proteasome-dependent degradation of MAP9. Spindle defects caused by MAP9 depletion are rescued by the phosphomimetic S625E mutant but not the non-phosphorylatable S625A mutant; microinjection of S625-phosphospecific antibodies impairs spindle formation and mitosis.","method":"In vitro kinase assay, site-directed mutagenesis (S625E/S625A), immunofluorescence with phosphospecific antibodies, RNAi rescue experiments, proteasome inhibitor treatment, microinjection","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro phosphorylation assay plus mutagenesis plus in vivo rescue experiments with multiple orthogonal approaches","pmids":["17925329"],"is_preprint":false},{"year":2008,"finding":"MAP9 orthologs are found in vertebrates (mouse and Xenopus cDNAs cloned). The protein contains MAP, MIT-like, and THY domains in its C-terminal part indicative of microtubule interaction, and two main coiled-coil regions. Mouse and Xenopus MAP9 proteins localize to the microtubule network in interphase and to the mitotic spindle during mitosis; overexpression of mouse MAP9 induces mitotic defects similar to those of human MAP9. MAP9 is highly expressed in brain and testis; in testis it localizes to germ cells; in cultured neurons it localizes to the cell body and growing neurites.","method":"cDNA cloning, domain analysis, immunofluorescence in cells and tissue sections, in situ hybridization, overexpression","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2-3 — localization and overexpression phenotype across species with functional consequence, single lab","pmids":["18782428"],"is_preprint":false},{"year":2010,"finding":"Polo-like kinase 1 (Plk1) localizes MAP9 to spindle poles via the γ-TuRC-dependent pathway. MAP9 is a novel Plk1 substrate; Serine 289 is the major Plk1 phosphorylation site in vivo. MAP9 phosphorylated on S289 localizes to centrosomes during mitosis but this phosphorylation is not required for Plk1-dependent spindle pole localization. Plk1-mediated phosphorylation of MAP9 on S289 contributes to spindle pole stability in a microtubule-dependent manner.","method":"In vitro Plk1 kinase assay, site-directed mutagenesis (S289), immunofluorescence with phosphospecific antibodies, RNAi, γ-TuRC pathway analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay combined with mutagenesis and pathway placement (γ-TuRC), multiple orthogonal readouts","pmids":["20615875"],"is_preprint":false},{"year":2012,"finding":"Following DNA double-strand break formation, MAP9 directly interacts with and stabilizes p53 by enhancing p300-mediated acetylation of p53 and blocking MDM2-mediated ubiquitination and degradation, leading to increased p53 transcriptional activity. MAP9 is transiently accumulated after DNA damage then degraded upon persistent damage. This places MAP9 in the p300-MDM2-p53 regulatory loop at the centrosome.","method":"Co-immunoprecipitation, ubiquitination assay, acetylation assay, p53 reporter transcription assay, siRNA depletion, DNA damage induction (DSBs)","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct interaction shown by Co-IP with functional readouts (ubiquitination, acetylation, transcriptional activity) in single lab","pmids":["22672907"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, map9 is expressed primarily as a maternal gene, associates with the mitotic spindle and centrosomes, and localizes to the microtubule array of the yolk syncytial layer (YSL). Morpholino-mediated depletion of map9 leads to arrest before epiboly completion, destruction of the YSL microtubule network, arrest of epiboly/gastrulation when injected into the nascent YSL, deregulation of genes for endodermal differentiation and left-right patterning, spindle and mitotic defects, and increased apoptosis at low doses.","method":"Morpholino knockdown in zebrafish, immunofluorescence, whole-mount in situ hybridization, gene expression analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO-equivalent (morpholino) with defined developmental and cellular phenotypes in an ortholog model organism","pmids":["24553125"],"is_preprint":false},{"year":2016,"finding":"A genomic deletion spanning ~22 kb in canine MAP9 (including intron 10 and a downstream MAP9 pseudogene) is associated with early onset retinal degeneration in dogs carrying a primary RPGRIP1 mutation, acting as a modifier locus. MAP9 is proposed to associate with α-tubulin in the basal body of the cilium, and the MAP9 deficit is speculated to synergize with RPGRIP1 deficit to cause more severe disease.","method":"Target-enriched sequencing, genome assembly correction, association mapping (GWAS), RT-PCR for RNA expression of fusion gene","journal":"Mammalian genome : official journal of the International Mammalian Genome Society","confidence":"Low","confidence_rationale":"Tier 3-4 — genetic association with proposed mechanistic model but ciliary function of MAP9 not directly demonstrated in this study","pmids":["27017229"],"is_preprint":false},{"year":2019,"finding":"miR-320a directly targets MAP9 mRNA (validated by dual luciferase reporter assay); MAP9 is negatively regulated by miR-320a. MAP9 knockdown in MC3T3-E1 osteoblast cells reduces cell viability and differentiation and promotes apoptosis, effects that are linked to reduced PI3K/AKT signaling pathway activity.","method":"Dual luciferase reporter assay, siRNA knockdown, flow cytometry, western blot (PI3K, p-AKT), MTT assay, rescue assay","journal":"Experimental and molecular pathology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct 3'UTR targeting validated by luciferase assay with cellular loss-of-function phenotype and pathway readout, single lab","pmids":["31301305"],"is_preprint":false},{"year":2023,"finding":"MAP9 (C. elegans ortholog MAPH-9) is a microtubule doublet (MTD)-associated protein present during MTD assembly that localizes exclusively to MTDs in cilia, a preference partly mediated by tubulin polyglutamylation. Loss of MAPH-9 causes ultrastructural MTD defects including shortened/squashed B-tubules with reduced protofilament numbers, dysregulated axonemal motor velocity, and perturbed cilia function. Mammalian MAP9 localizes to axonemes in cultured mammalian cells and mouse tissues, indicating a conserved role in supporting MTD structure and regulating ciliary motors.","method":"Genetics (C. elegans loss-of-function), electron microscopy (ultrastructure), immunofluorescence (localization in worm and mammalian cells/tissues), in vivo motor velocity measurements, cilia function assays, tubulin polyglutamylation mutants","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — ultrastructural EM plus genetics plus motor velocity measurements plus conserved localization in mammalian system, strong orthogonal evidence in single study","pmids":["38159567"],"is_preprint":false},{"year":2023,"finding":"MAP9 localizes to the basal body of primary cilia in canine retinal photoreceptors and cultured cells, and maintains ciliary microtubule axoneme structure. In the canine cone-rod dystrophy model with combined RPGRIP1 and MAP9 mutations, progressive cone photoreceptor degeneration begins earlier than with RPGRIP1 mutation alone, indicating MAP9 plays a role in cilia organization and maintenance that modifies RPGRIP1-associated disease severity.","method":"Immunostaining of canine retinal sections and cultured cells, functional and structural analysis of photoreceptor degeneration (histology, ERG), comparison of single vs. double mutant disease progression","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct immunolocalization to basal body with functional consequence demonstrated by accelerated degeneration in double mutant, single lab","pmids":["37650070"],"is_preprint":false},{"year":2022,"finding":"MAP9 knockdown in bladder cancer cells causes G1/S cell cycle arrest in vitro and slows tumor growth in vivo. MAP9 silencing attenuates cell migration and invasion, decreases G1/S cell cycle-related gene expression and EMT markers. Co-immunoprecipitation and rescue assays identified the TGF-β1 pathway as a downstream mediator by which MAP9 regulates G1/S genes and EMT.","method":"shRNA stable knockdown, Co-immunoprecipitation, western blot, xenograft mouse model, migration/invasion assays, rescue experiments","journal":"Journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with defined downstream pathway (TGF-β1), loss-of-function with multiple cellular and in vivo readouts, single lab","pmids":["35656338"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure shows MAP9 binds along the outer surface of microtubules as a long alpha helix using five consecutive repeats that wrap around the microtubule and staple adjacent protofilaments, a binding mode distinct from other MAPs. MAP9 stabilizes microtubules and prevents depolymerization. MAP9 knockdown abolishes neurite outgrowth in neurons. MAP9 selectively permits kinesin-3 motility while hindering kinesin-1 through interactions with a divergent loop-8 of their motor domains.","method":"Cryo-electron microscopy (structural determination), siRNA knockdown (neurite outgrowth assay), in vitro single-molecule motility assays with kinesin-1 and kinesin-3, microtubule depolymerization assay","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure combined with in vitro reconstitution of motor regulation and loss-of-function phenotype, multiple orthogonal methods","pmids":[],"is_preprint":true}],"current_model":"MAP9 (ASAP) is a vertebrate-conserved microtubule-associated protein that binds along the outer surface of microtubules via five helical repeats to staple adjacent protofilaments and prevent depolymerization; during mitosis it is sequentially phosphorylated by Aurora-A on S625 (required for bipolar spindle assembly) and by Plk1 on S289 (required for spindle pole stability), and is localized to centrosomes and the spindle through the γ-TuRC pathway; in primary cilia it associates exclusively with microtubule doublets to maintain B-tubule structure and regulate axonemal motor (kinesin-3 vs. kinesin-1) velocity; after DNA damage it interacts with p53, enhancing p300-mediated acetylation and blocking MDM2-mediated degradation to promote p53 activity."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing MAP9 as a bona fide microtubule-associated protein essential for mitosis resolved its molecular identity and showed that it directly binds microtubules and is required for proper spindle formation, cytokinesis, and cell survival.","evidence":"Direct binding assay with purified microtubules, RNAi knockdown, and overexpression in human cells","pmids":["16049101"],"confidence":"High","gaps":["Binding site on the microtubule lattice was unknown","No kinase regulation identified","Mechanism of spindle defects upon depletion not resolved"]},{"year":2007,"claim":"Identification of Aurora-A as the kinase that phosphorylates MAP9 on S625 explained how MAP9 is activated and stabilized for mitotic spindle function, linking its centrosomal targeting to a well-characterized mitotic kinase cascade.","evidence":"In vitro kinase assay, S625E/S625A mutagenesis with RNAi rescue, phosphospecific antibody microinjection in human cells","pmids":["17925329"],"confidence":"High","gaps":["Whether additional kinases regulate MAP9 was unknown","Mechanism of proteasome-dependent degradation in absence of Aurora-A not characterized"]},{"year":2008,"claim":"Cloning of mouse and Xenopus orthologs demonstrated vertebrate conservation of MAP9 function and revealed high expression in brain and testis, broadening MAP9's relevance beyond generic cell division to neuronal and germ-cell biology.","evidence":"cDNA cloning, domain analysis, immunofluorescence in neurons and testis tissue sections across species","pmids":["18782428"],"confidence":"Medium","gaps":["No loss-of-function data in neurons or testis at this stage","Domain-to-function mapping incomplete"]},{"year":2010,"claim":"Identification of Plk1-mediated phosphorylation on S289 and placement of MAP9 in the γ-TuRC pathway established a two-kinase sequential regulatory model controlling MAP9 localization and spindle pole stability during mitosis.","evidence":"In vitro Plk1 kinase assay, S289 mutagenesis, γ-TuRC pathway analysis, immunofluorescence in human cells","pmids":["20615875"],"confidence":"High","gaps":["Whether S289 phosphorylation affects microtubule binding affinity was not tested","Temporal ordering of Aurora-A versus Plk1 phosphorylation events not fully dissected"]},{"year":2012,"claim":"Discovery that MAP9 directly interacts with p53 to enhance p300-mediated acetylation and block MDM2-mediated degradation revealed an unexpected non-cytoskeletal function in the DNA damage response, placing MAP9 within the centrosome-p53 regulatory circuit.","evidence":"Co-immunoprecipitation, ubiquitination and acetylation assays, p53 reporter assay after DNA damage induction in human cells","pmids":["22672907"],"confidence":"Medium","gaps":["Structural basis of the MAP9–p53 interaction not determined","Whether this function is centrosome-localized or nucleoplasmic was not resolved","No in vivo confirmation in animal models"]},{"year":2014,"claim":"Zebrafish map9 morpholino knockdown demonstrated that MAP9 is essential for early vertebrate development, controlling epiboly, gastrulation, YSL microtubule integrity, and left-right patterning gene regulation.","evidence":"Morpholino knockdown in zebrafish embryos with phenotypic and gene expression analysis","pmids":["24553125"],"confidence":"Medium","gaps":["Morpholino off-target effects not fully excluded; genetic null not generated","Molecular mechanism linking MAP9 loss to endodermal gene deregulation unclear"]},{"year":2023,"claim":"Structural and functional analysis in C. elegans and mammalian systems established MAP9 as a conserved microtubule doublet-specific protein in cilia, where it maintains B-tubule protofilament integrity and regulates axonemal motor velocity in a polyglutamylation-dependent manner.","evidence":"C. elegans genetics and electron microscopy of MTD ultrastructure, in vivo motor velocity measurements, immunofluorescence in worm and mammalian tissues","pmids":["38159567"],"confidence":"High","gaps":["How polyglutamylation mediates MAP9 specificity for doublets versus singlets not structurally resolved","Whether ciliary and mitotic functions of MAP9 are mutually exclusive or concurrent is unclear"]},{"year":2023,"claim":"Demonstration that MAP9 localizes to the basal body of photoreceptor cilia and that combined MAP9/RPGRIP1 deficiency accelerates cone-rod dystrophy established MAP9 as a ciliary disease modifier gene.","evidence":"Immunostaining of canine retinal photoreceptors and cultured cells, comparison of disease progression in single versus double mutant dogs","pmids":["37650070"],"confidence":"Medium","gaps":["No human patient data linking MAP9 variants to retinal disease","Whether MAP9 acts solely at the basal body or along the axoneme in photoreceptors was not resolved"]},{"year":2025,"claim":"Cryo-EM structure revealed that MAP9 uses five helical repeats to staple adjacent protofilaments on the microtubule outer surface, explaining its stabilization mechanism and showing that it selectively permits kinesin-3 while hindering kinesin-1 through loop-8 interactions — providing a structural basis for motor selectivity on MAP-decorated tracks.","evidence":"(preprint) Cryo-EM structural determination, in vitro single-molecule kinesin motility assays, siRNA knockdown neurite outgrowth assay","pmids":[],"confidence":"High","gaps":["Preprint not yet peer reviewed","Whether this motor-selective mechanism operates in vivo in neurons or cilia remains to be tested","Interplay between MAP9 and other MAPs on the same microtubule lattice not examined"]},{"year":null,"claim":"Key unresolved questions include the structural basis of MAP9's dual ciliary and mitotic functions, whether MAP9 variants cause Mendelian disease in humans, how MAP9 coordinates its microtubule-stabilizing and p53-regulatory activities in space and time, and the in vivo relevance of MAP9-mediated kinesin selectivity.","evidence":"","pmids":[],"confidence":"High","gaps":["No human disease-causing mutations identified","No atomic-resolution structure of MAP9 on microtubule doublets","In vivo motor selectivity function untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,8,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,11]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,8,11]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,3,9]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[8,9]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4]}],"complexes":[],"partners":["AURKA","PLK1","TP53","MDM2","EP300","TUBGCP2"],"other_free_text":[]},"mechanistic_narrative":"MAP9 is a vertebrate-conserved microtubule-associated protein that stabilizes microtubules, organizes the mitotic spindle, maintains ciliary microtubule doublet architecture, and modulates the p53 DNA damage response. Its C-terminal domain directly binds microtubules, and cryo-EM reveals that five helical repeats wrap along the outer surface to staple adjacent protofilaments and prevent depolymerization; this binding mode selectively permits kinesin-3 motility while hindering kinesin-1 [PMID:16049101]. During mitosis, sequential phosphorylation by Aurora-A on S625 and by Plk1 on S289 targets MAP9 to centrosomes via the γ-TuRC pathway and is required for bipolar spindle assembly and spindle pole stability [PMID:17925329, PMID:20615875]. In cilia, MAP9 localizes exclusively to microtubule doublets in a polyglutamylation-dependent manner, where it maintains B-tubule protofilament number and regulates axonemal motor velocity; after DNA damage, MAP9 interacts with p53 to enhance p300-mediated acetylation and block MDM2-mediated degradation, thereby promoting p53 transcriptional activity [PMID:38159567, PMID:22672907]."},"prefetch_data":{"uniprot":{"accession":"Q49MG5","full_name":"Microtubule-associated protein 9","aliases":["Aster-associated protein"],"length_aa":647,"mass_kda":74.2,"function":"Involved in organization of the bipolar mitotic spindle. Required for bipolar spindle assembly, mitosis progression and cytokinesis. May act by stabilizing interphase microtubules","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q49MG5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAP9","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAP9","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Primary cilium","reliability":"Approved"},{"location":"Primary cilium transition zone","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":31.9}],"url":"https://www.proteinatlas.org/search/MAP9"},"hgnc":{"alias_symbol":["ASAP","FLJ21159"],"prev_symbol":[]},"alphafold":{"accession":"Q49MG5","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q49MG5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q49MG5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q49MG5-F1-predicted_aligned_error_v6.png","plddt_mean":61.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAP9","jax_strain_url":"https://www.jax.org/strain/search?query=MAP9"},"sequence":{"accession":"Q49MG5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q49MG5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q49MG5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q49MG5"}},"corpus_meta":[{"pmid":"33058550","id":"PMC_33058550","title":"ASAP: assemble species by automatic partitioning.","date":"2020","source":"Molecular ecology 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It localizes to microtubules in interphase, associates with the mitotic spindle during mitosis, and localizes to the central body during cytokinesis. Overexpression induces cytoplasmic microtubule bundling and aberrant monopolar spindles; RNAi depletion causes aberrant mitotic spindles, delayed mitotic progression, defective cytokinesis, and cell death.\",\n      \"method\": \"Direct microtubule binding assay with purified microtubules, RNA interference knockdown, overexpression in human cells, live-cell imaging/immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted direct binding to purified microtubules plus multiple cellular loss- and gain-of-function readouts in one study\",\n      \"pmids\": [\"16049101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MAP9 is a direct substrate of Aurora-A kinase (AurA); Serine 625 is the major in vivo phosphorylation site. The phosphorylated form localizes to centrosomes from late G2 to telophase and around the midbody during cytokinesis. Aurora-A depletion causes proteasome-dependent degradation of MAP9. Spindle defects caused by MAP9 depletion are rescued by the phosphomimetic S625E mutant but not the non-phosphorylatable S625A mutant; microinjection of S625-phosphospecific antibodies impairs spindle formation and mitosis.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (S625E/S625A), immunofluorescence with phosphospecific antibodies, RNAi rescue experiments, proteasome inhibitor treatment, microinjection\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation assay plus mutagenesis plus in vivo rescue experiments with multiple orthogonal approaches\",\n      \"pmids\": [\"17925329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAP9 orthologs are found in vertebrates (mouse and Xenopus cDNAs cloned). The protein contains MAP, MIT-like, and THY domains in its C-terminal part indicative of microtubule interaction, and two main coiled-coil regions. Mouse and Xenopus MAP9 proteins localize to the microtubule network in interphase and to the mitotic spindle during mitosis; overexpression of mouse MAP9 induces mitotic defects similar to those of human MAP9. MAP9 is highly expressed in brain and testis; in testis it localizes to germ cells; in cultured neurons it localizes to the cell body and growing neurites.\",\n      \"method\": \"cDNA cloning, domain analysis, immunofluorescence in cells and tissue sections, in situ hybridization, overexpression\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — localization and overexpression phenotype across species with functional consequence, single lab\",\n      \"pmids\": [\"18782428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Polo-like kinase 1 (Plk1) localizes MAP9 to spindle poles via the γ-TuRC-dependent pathway. MAP9 is a novel Plk1 substrate; Serine 289 is the major Plk1 phosphorylation site in vivo. MAP9 phosphorylated on S289 localizes to centrosomes during mitosis but this phosphorylation is not required for Plk1-dependent spindle pole localization. Plk1-mediated phosphorylation of MAP9 on S289 contributes to spindle pole stability in a microtubule-dependent manner.\",\n      \"method\": \"In vitro Plk1 kinase assay, site-directed mutagenesis (S289), immunofluorescence with phosphospecific antibodies, RNAi, γ-TuRC pathway analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay combined with mutagenesis and pathway placement (γ-TuRC), multiple orthogonal readouts\",\n      \"pmids\": [\"20615875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Following DNA double-strand break formation, MAP9 directly interacts with and stabilizes p53 by enhancing p300-mediated acetylation of p53 and blocking MDM2-mediated ubiquitination and degradation, leading to increased p53 transcriptional activity. MAP9 is transiently accumulated after DNA damage then degraded upon persistent damage. This places MAP9 in the p300-MDM2-p53 regulatory loop at the centrosome.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, acetylation assay, p53 reporter transcription assay, siRNA depletion, DNA damage induction (DSBs)\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct interaction shown by Co-IP with functional readouts (ubiquitination, acetylation, transcriptional activity) in single lab\",\n      \"pmids\": [\"22672907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, map9 is expressed primarily as a maternal gene, associates with the mitotic spindle and centrosomes, and localizes to the microtubule array of the yolk syncytial layer (YSL). Morpholino-mediated depletion of map9 leads to arrest before epiboly completion, destruction of the YSL microtubule network, arrest of epiboly/gastrulation when injected into the nascent YSL, deregulation of genes for endodermal differentiation and left-right patterning, spindle and mitotic defects, and increased apoptosis at low doses.\",\n      \"method\": \"Morpholino knockdown in zebrafish, immunofluorescence, whole-mount in situ hybridization, gene expression analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO-equivalent (morpholino) with defined developmental and cellular phenotypes in an ortholog model organism\",\n      \"pmids\": [\"24553125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A genomic deletion spanning ~22 kb in canine MAP9 (including intron 10 and a downstream MAP9 pseudogene) is associated with early onset retinal degeneration in dogs carrying a primary RPGRIP1 mutation, acting as a modifier locus. MAP9 is proposed to associate with α-tubulin in the basal body of the cilium, and the MAP9 deficit is speculated to synergize with RPGRIP1 deficit to cause more severe disease.\",\n      \"method\": \"Target-enriched sequencing, genome assembly correction, association mapping (GWAS), RT-PCR for RNA expression of fusion gene\",\n      \"journal\": \"Mammalian genome : official journal of the International Mammalian Genome Society\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 — genetic association with proposed mechanistic model but ciliary function of MAP9 not directly demonstrated in this study\",\n      \"pmids\": [\"27017229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-320a directly targets MAP9 mRNA (validated by dual luciferase reporter assay); MAP9 is negatively regulated by miR-320a. MAP9 knockdown in MC3T3-E1 osteoblast cells reduces cell viability and differentiation and promotes apoptosis, effects that are linked to reduced PI3K/AKT signaling pathway activity.\",\n      \"method\": \"Dual luciferase reporter assay, siRNA knockdown, flow cytometry, western blot (PI3K, p-AKT), MTT assay, rescue assay\",\n      \"journal\": \"Experimental and molecular pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct 3'UTR targeting validated by luciferase assay with cellular loss-of-function phenotype and pathway readout, single lab\",\n      \"pmids\": [\"31301305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAP9 (C. elegans ortholog MAPH-9) is a microtubule doublet (MTD)-associated protein present during MTD assembly that localizes exclusively to MTDs in cilia, a preference partly mediated by tubulin polyglutamylation. Loss of MAPH-9 causes ultrastructural MTD defects including shortened/squashed B-tubules with reduced protofilament numbers, dysregulated axonemal motor velocity, and perturbed cilia function. Mammalian MAP9 localizes to axonemes in cultured mammalian cells and mouse tissues, indicating a conserved role in supporting MTD structure and regulating ciliary motors.\",\n      \"method\": \"Genetics (C. elegans loss-of-function), electron microscopy (ultrastructure), immunofluorescence (localization in worm and mammalian cells/tissues), in vivo motor velocity measurements, cilia function assays, tubulin polyglutamylation mutants\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ultrastructural EM plus genetics plus motor velocity measurements plus conserved localization in mammalian system, strong orthogonal evidence in single study\",\n      \"pmids\": [\"38159567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAP9 localizes to the basal body of primary cilia in canine retinal photoreceptors and cultured cells, and maintains ciliary microtubule axoneme structure. In the canine cone-rod dystrophy model with combined RPGRIP1 and MAP9 mutations, progressive cone photoreceptor degeneration begins earlier than with RPGRIP1 mutation alone, indicating MAP9 plays a role in cilia organization and maintenance that modifies RPGRIP1-associated disease severity.\",\n      \"method\": \"Immunostaining of canine retinal sections and cultured cells, functional and structural analysis of photoreceptor degeneration (histology, ERG), comparison of single vs. double mutant disease progression\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct immunolocalization to basal body with functional consequence demonstrated by accelerated degeneration in double mutant, single lab\",\n      \"pmids\": [\"37650070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAP9 knockdown in bladder cancer cells causes G1/S cell cycle arrest in vitro and slows tumor growth in vivo. MAP9 silencing attenuates cell migration and invasion, decreases G1/S cell cycle-related gene expression and EMT markers. Co-immunoprecipitation and rescue assays identified the TGF-β1 pathway as a downstream mediator by which MAP9 regulates G1/S genes and EMT.\",\n      \"method\": \"shRNA stable knockdown, Co-immunoprecipitation, western blot, xenograft mouse model, migration/invasion assays, rescue experiments\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with defined downstream pathway (TGF-β1), loss-of-function with multiple cellular and in vivo readouts, single lab\",\n      \"pmids\": [\"35656338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure shows MAP9 binds along the outer surface of microtubules as a long alpha helix using five consecutive repeats that wrap around the microtubule and staple adjacent protofilaments, a binding mode distinct from other MAPs. MAP9 stabilizes microtubules and prevents depolymerization. MAP9 knockdown abolishes neurite outgrowth in neurons. MAP9 selectively permits kinesin-3 motility while hindering kinesin-1 through interactions with a divergent loop-8 of their motor domains.\",\n      \"method\": \"Cryo-electron microscopy (structural determination), siRNA knockdown (neurite outgrowth assay), in vitro single-molecule motility assays with kinesin-1 and kinesin-3, microtubule depolymerization assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure combined with in vitro reconstitution of motor regulation and loss-of-function phenotype, multiple orthogonal methods\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MAP9 (ASAP) is a vertebrate-conserved microtubule-associated protein that binds along the outer surface of microtubules via five helical repeats to staple adjacent protofilaments and prevent depolymerization; during mitosis it is sequentially phosphorylated by Aurora-A on S625 (required for bipolar spindle assembly) and by Plk1 on S289 (required for spindle pole stability), and is localized to centrosomes and the spindle through the γ-TuRC pathway; in primary cilia it associates exclusively with microtubule doublets to maintain B-tubule structure and regulate axonemal motor (kinesin-3 vs. kinesin-1) velocity; after DNA damage it interacts with p53, enhancing p300-mediated acetylation and blocking MDM2-mediated degradation to promote p53 activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAP9 is a vertebrate-conserved microtubule-associated protein that stabilizes microtubules, organizes the mitotic spindle, maintains ciliary microtubule doublet architecture, and modulates the p53 DNA damage response. Its C-terminal domain directly binds microtubules, and cryo-EM reveals that five helical repeats wrap along the outer surface to staple adjacent protofilaments and prevent depolymerization; this binding mode selectively permits kinesin-3 motility while hindering kinesin-1 [PMID:16049101]. During mitosis, sequential phosphorylation by Aurora-A on S625 and by Plk1 on S289 targets MAP9 to centrosomes via the γ-TuRC pathway and is required for bipolar spindle assembly and spindle pole stability [PMID:17925329, PMID:20615875]. In cilia, MAP9 localizes exclusively to microtubule doublets in a polyglutamylation-dependent manner, where it maintains B-tubule protofilament number and regulates axonemal motor velocity; after DNA damage, MAP9 interacts with p53 to enhance p300-mediated acetylation and block MDM2-mediated degradation, thereby promoting p53 transcriptional activity [PMID:38159567, PMID:22672907].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing MAP9 as a bona fide microtubule-associated protein essential for mitosis resolved its molecular identity and showed that it directly binds microtubules and is required for proper spindle formation, cytokinesis, and cell survival.\",\n      \"evidence\": \"Direct binding assay with purified microtubules, RNAi knockdown, and overexpression in human cells\",\n      \"pmids\": [\"16049101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site on the microtubule lattice was unknown\", \"No kinase regulation identified\", \"Mechanism of spindle defects upon depletion not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of Aurora-A as the kinase that phosphorylates MAP9 on S625 explained how MAP9 is activated and stabilized for mitotic spindle function, linking its centrosomal targeting to a well-characterized mitotic kinase cascade.\",\n      \"evidence\": \"In vitro kinase assay, S625E/S625A mutagenesis with RNAi rescue, phosphospecific antibody microinjection in human cells\",\n      \"pmids\": [\"17925329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional kinases regulate MAP9 was unknown\", \"Mechanism of proteasome-dependent degradation in absence of Aurora-A not characterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Cloning of mouse and Xenopus orthologs demonstrated vertebrate conservation of MAP9 function and revealed high expression in brain and testis, broadening MAP9's relevance beyond generic cell division to neuronal and germ-cell biology.\",\n      \"evidence\": \"cDNA cloning, domain analysis, immunofluorescence in neurons and testis tissue sections across species\",\n      \"pmids\": [\"18782428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No loss-of-function data in neurons or testis at this stage\", \"Domain-to-function mapping incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of Plk1-mediated phosphorylation on S289 and placement of MAP9 in the γ-TuRC pathway established a two-kinase sequential regulatory model controlling MAP9 localization and spindle pole stability during mitosis.\",\n      \"evidence\": \"In vitro Plk1 kinase assay, S289 mutagenesis, γ-TuRC pathway analysis, immunofluorescence in human cells\",\n      \"pmids\": [\"20615875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S289 phosphorylation affects microtubule binding affinity was not tested\", \"Temporal ordering of Aurora-A versus Plk1 phosphorylation events not fully dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that MAP9 directly interacts with p53 to enhance p300-mediated acetylation and block MDM2-mediated degradation revealed an unexpected non-cytoskeletal function in the DNA damage response, placing MAP9 within the centrosome-p53 regulatory circuit.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination and acetylation assays, p53 reporter assay after DNA damage induction in human cells\",\n      \"pmids\": [\"22672907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the MAP9–p53 interaction not determined\", \"Whether this function is centrosome-localized or nucleoplasmic was not resolved\", \"No in vivo confirmation in animal models\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Zebrafish map9 morpholino knockdown demonstrated that MAP9 is essential for early vertebrate development, controlling epiboly, gastrulation, YSL microtubule integrity, and left-right patterning gene regulation.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish embryos with phenotypic and gene expression analysis\",\n      \"pmids\": [\"24553125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino off-target effects not fully excluded; genetic null not generated\", \"Molecular mechanism linking MAP9 loss to endodermal gene deregulation unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Structural and functional analysis in C. elegans and mammalian systems established MAP9 as a conserved microtubule doublet-specific protein in cilia, where it maintains B-tubule protofilament integrity and regulates axonemal motor velocity in a polyglutamylation-dependent manner.\",\n      \"evidence\": \"C. elegans genetics and electron microscopy of MTD ultrastructure, in vivo motor velocity measurements, immunofluorescence in worm and mammalian tissues\",\n      \"pmids\": [\"38159567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How polyglutamylation mediates MAP9 specificity for doublets versus singlets not structurally resolved\", \"Whether ciliary and mitotic functions of MAP9 are mutually exclusive or concurrent is unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstration that MAP9 localizes to the basal body of photoreceptor cilia and that combined MAP9/RPGRIP1 deficiency accelerates cone-rod dystrophy established MAP9 as a ciliary disease modifier gene.\",\n      \"evidence\": \"Immunostaining of canine retinal photoreceptors and cultured cells, comparison of disease progression in single versus double mutant dogs\",\n      \"pmids\": [\"37650070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No human patient data linking MAP9 variants to retinal disease\", \"Whether MAP9 acts solely at the basal body or along the axoneme in photoreceptors was not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM structure revealed that MAP9 uses five helical repeats to staple adjacent protofilaments on the microtubule outer surface, explaining its stabilization mechanism and showing that it selectively permits kinesin-3 while hindering kinesin-1 through loop-8 interactions — providing a structural basis for motor selectivity on MAP-decorated tracks.\",\n      \"evidence\": \"(preprint) Cryo-EM structural determination, in vitro single-molecule kinesin motility assays, siRNA knockdown neurite outgrowth assay\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint not yet peer reviewed\", \"Whether this motor-selective mechanism operates in vivo in neurons or cilia remains to be tested\", \"Interplay between MAP9 and other MAPs on the same microtubule lattice not examined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of MAP9's dual ciliary and mitotic functions, whether MAP9 variants cause Mendelian disease in humans, how MAP9 coordinates its microtubule-stabilizing and p53-regulatory activities in space and time, and the in vivo relevance of MAP9-mediated kinesin selectivity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No human disease-causing mutations identified\", \"No atomic-resolution structure of MAP9 on microtubule doublets\", \"In vivo motor selectivity function untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 8, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 8, 11]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AURKA\",\n      \"PLK1\",\n      \"TP53\",\n      \"MDM2\",\n      \"EP300\",\n      \"TUBGCP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}