{"gene":"CIMAP3","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2010,"finding":"Pitchfork (Pifo/CIMAP3) associates with ciliary targeting complexes and accumulates at the basal body during cilia disassembly. Haploinsufficiency causes node cilia duplication, left-right asymmetry defects, and heart failure in mice. PIFO (but not the R80K mutant) is sufficient to activate Aurora A kinase, which induces cilia retraction. Pifo/PIFO mutation causes cilia retraction, basal body liberation, and overreplication defects.","method":"Mouse genetics (haploinsufficiency model), co-immunoprecipitation with ciliary targeting complexes, functional assays for Aurora A activation, human patient mutation (R80K) functional comparison, in vivo phenotypic analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction studies with ciliary targeting complexes, Aurora A activation assay, in vivo genetic model with defined phenotype, human mutation functional validation, multiple orthogonal methods in one study","pmids":["20643351"],"is_preprint":false},{"year":2016,"finding":"Pitchfork (Pifo/CIMAP3) and GPRASP2 form an essential ciliary targeting complex that regulates Smoothened (Smo) translocation to the primary cilium. Depletion of Pifo or Gprasp2 leads to failure of Smo translocation to the primary cilium and lack of Hedgehog (Hh) target gene activation.","method":"siRNA depletion of Pifo and Gprasp2, immunofluorescence for Smo localization to primary cilia, Hh target gene expression assays, protein complex identification","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockdown with defined molecular phenotype (Smo mislocalization) and pathway readout (Hh target gene activation), complex identification, two orthogonal methods (localization + transcriptional output)","pmids":["26901434"],"is_preprint":false},{"year":2014,"finding":"Pitchfork is highly expressed in the developing mouse secondary palate (E12.5–E13.5). Pitchfork over-expression in cultured palates induces primary cilia disassembly, alters Sonic hedgehog and Patched1 expression levels, and changes palatine rugae morphology, indicating a role in normal secondary palate morphogenesis.","method":"In situ expression analysis, in vitro palate culture with Pitchfork over-expression, immunostaining for primary cilia, Shh/Ptc1 expression analysis","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — over-expression with defined cellular phenotype (cilia disassembly) and pathway changes, but single lab and no loss-of-function genetic model","pmids":["25080064"],"is_preprint":false},{"year":2021,"finding":"GPRASP2 plays a key role in Hedgehog pathway signaling in the primary cilium through a Smoothened-GPRASP2-Pifo complex, and small compound inhibitors of this complex have been identified as potential treatments for drug-resistant Smoothened-derived cancers.","method":"Complex characterization (Smoothened-GPRASP2-Pifo), in vitro and in vivo functional experiments referenced in review context","journal":"Current topics in medicinal chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper summarizing complex data; original experimental detail not available in this abstract; corroborates PMID 26901434 but adds small molecule inhibitor finding","pmids":["33267763"],"is_preprint":false},{"year":2022,"finding":"Variants in PIFO (CIMAP3) were identified in patients with laterality defects in a whole-exome sequencing study, suggesting that dysfunction of PIFO results in laterality defects in humans.","method":"Whole-exome sequencing with CNV analysis in consanguineous families with laterality defects; patient variant identification","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic variant identification in patients without functional mechanistic validation in this study; supports previously established role but no new mechanism demonstrated","pmids":["35547246"],"is_preprint":false}],"current_model":"CIMAP3/Pitchfork (PIFO) is a basal body-associated protein that accumulates at the basal body during primary cilia disassembly, where it activates Aurora A kinase to drive cilia retraction; it also forms a complex with GPRASP2 to facilitate Smoothened translocation into the primary cilium for Hedgehog pathway activation, and haploinsufficiency causes node cilia duplication, left-right asymmetry defects, and heart failure in mice."},"narrative":{"mechanistic_narrative":"CIMAP3 (PIFO/Pitchfork) is a basal body-associated protein that governs primary cilium dynamics and ciliary signaling during development [PMID:20643351, PMID:26901434]. It accumulates at the basal body during cilia disassembly and, in its wild-type form (but not the patient-derived R80K mutant), activates Aurora A kinase to drive cilia retraction; loss of one copy in mice causes node cilia duplication, left-right asymmetry defects, basal body liberation, overreplication, and heart failure [PMID:20643351]. Independently of its disassembly role, CIMAP3 forms an essential ciliary targeting complex with GPRASP2 that mediates Smoothened translocation into the primary cilium and is required for Hedgehog target gene activation [PMID:26901434]. CIMAP3 is expressed in the developing secondary palate, where its over-expression triggers cilia disassembly and alters Sonic hedgehog and Patched1 expression, linking it to palate morphogenesis [PMID:25080064]. Human PIFO variants are associated with laterality defects, consistent with its role in left-right patterning [PMID:35547246].","teleology":[{"year":2010,"claim":"Established CIMAP3/PIFO as a basal body regulator of cilia disassembly by showing it activates Aurora A kinase and that its dysfunction disrupts left-right asymmetry, answering how a single protein couples ciliary targeting machinery to cilia retraction.","evidence":"Mouse haploinsufficiency model, co-immunoprecipitation with ciliary targeting complexes, Aurora A activation assays, and R80K human mutation functional comparison","pmids":["20643351"],"confidence":"High","gaps":["Molecular mechanism by which PIFO activates Aurora A (direct vs. scaffolded) not resolved","Identity of the ciliary targeting complex components beyond the interaction not defined","Structural basis for the R80K loss of function unknown"]},{"year":2014,"claim":"Extended CIMAP3 function to tissue morphogenesis by showing its expression and over-expression in the secondary palate drive cilia disassembly and modulate Hedgehog component expression.","evidence":"In situ expression analysis and in vitro palate culture with Pitchfork over-expression, with Shh/Ptc1 readouts","pmids":["25080064"],"confidence":"Medium","gaps":["No loss-of-function genetic model in palate","Single-lab over-expression phenotype","Mechanistic link between cilia disassembly and Shh/Ptc1 changes not dissected"]},{"year":2016,"claim":"Defined a distinct CIMAP3 function in ciliary signaling input by showing a PIFO-GPRASP2 complex is required for Smoothened entry into the cilium and Hedgehog activation, separating its disassembly role from a Hedgehog-targeting role.","evidence":"siRNA depletion of Pifo and Gprasp2 with Smo immunofluorescence and Hh target gene assays plus complex identification","pmids":["26901434"],"confidence":"High","gaps":["Direct binding interface between PIFO and GPRASP2 not mapped","How the same protein governs both cilia assembly/disassembly and Smo trafficking unresolved","Stoichiometry and dynamics of the Smo-GPRASP2-PIFO complex unknown"]},{"year":2021,"claim":"Reframed the Smoothened-GPRASP2-PIFO complex as a candidate therapeutic target by identifying small-molecule inhibitors against drug-resistant Smoothened cancers.","evidence":"Complex characterization summarized with referenced functional experiments in a review","pmids":["33267763"],"confidence":"Low","gaps":["Review-level summary without primary experimental detail in this entry","Specificity and on-target action of inhibitors for PIFO not demonstrated here","No structural validation of the inhibitor-complex interaction"]},{"year":2022,"claim":"Provided human genetic support for the left-right patterning role by identifying PIFO variants in patients with laterality defects.","evidence":"Whole-exome sequencing with CNV analysis in consanguineous families","pmids":["35547246"],"confidence":"Low","gaps":["No functional validation of the patient variants in this study","Causality versus association not established","No mechanism linking specific variants to phenotype demonstrated"]},{"year":null,"claim":"How CIMAP3 mechanistically partitions between promoting cilia disassembly (via Aurora A) and enabling ciliary Hedgehog signaling (via GPRASP2/Smoothened) within a single basal body context remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PIFO or its complexes","Mechanism of Aurora A activation undefined","Spatiotemporal regulation distinguishing its two functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[],"complexes":["Smoothened-GPRASP2-PIFO complex"],"partners":["GPRASP2","AURKA","SMO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TCI5","full_name":"Ciliary microtubule-associated protein 3","aliases":["Protein pitchfork"],"length_aa":191,"mass_kda":22.0,"function":"During primary cilia disassembly, involved in cilia disassembly. Required specifically to control cilia retraction as well as the liberation and duplication of the basal body/centrosome. May act by stimulating AURKA activity at the basal body in a cell cycle-dependent manner","subcellular_location":"Cytoplasmic vesicle; Golgi apparatus, trans-Golgi network; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8TCI5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIMAP3","classification":"Not Classified","n_dependent_lines":86,"n_total_lines":1208,"dependency_fraction":0.07119205298013245},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CIMAP3","total_profiled":1310},"omim":[{"mim_id":"614234","title":"CILIARY MICROTUBULE-ASSOCIATED PROTEIN 3; CIMAP3","url":"https://www.omim.org/entry/614234"}],"hpa":{"profiled":true,"resolved_as":"PIFO","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":134.0},{"tissue":"fallopian tube","ntpm":163.8}],"url":"https://www.proteinatlas.org/search/PIFO"},"hgnc":{"alias_symbol":["FLJ23853","pitchfork"],"prev_symbol":["C1orf88","PIFO"]},"alphafold":{"accession":"Q8TCI5","domains":[{"cath_id":"-","chopping":"22-65","consensus_level":"medium","plddt":73.9068,"start":22,"end":65}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCI5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCI5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TCI5-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CIMAP3","jax_strain_url":"https://www.jax.org/strain/search?query=CIMAP3"},"sequence":{"accession":"Q8TCI5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TCI5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TCI5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TCI5"}},"corpus_meta":[{"pmid":"22677291","id":"PMC_22677291","title":"Bistability, 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Haploinsufficiency causes node cilia duplication, left-right asymmetry defects, and heart failure in mice. PIFO (but not the R80K mutant) is sufficient to activate Aurora A kinase, which induces cilia retraction. Pifo/PIFO mutation causes cilia retraction, basal body liberation, and overreplication defects.\",\n      \"method\": \"Mouse genetics (haploinsufficiency model), co-immunoprecipitation with ciliary targeting complexes, functional assays for Aurora A activation, human patient mutation (R80K) functional comparison, in vivo phenotypic analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction studies with ciliary targeting complexes, Aurora A activation assay, in vivo genetic model with defined phenotype, human mutation functional validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20643351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pitchfork (Pifo/CIMAP3) and GPRASP2 form an essential ciliary targeting complex that regulates Smoothened (Smo) translocation to the primary cilium. Depletion of Pifo or Gprasp2 leads to failure of Smo translocation to the primary cilium and lack of Hedgehog (Hh) target gene activation.\",\n      \"method\": \"siRNA depletion of Pifo and Gprasp2, immunofluorescence for Smo localization to primary cilia, Hh target gene expression assays, protein complex identification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined molecular phenotype (Smo mislocalization) and pathway readout (Hh target gene activation), complex identification, two orthogonal methods (localization + transcriptional output)\",\n      \"pmids\": [\"26901434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Pitchfork is highly expressed in the developing mouse secondary palate (E12.5–E13.5). Pitchfork over-expression in cultured palates induces primary cilia disassembly, alters Sonic hedgehog and Patched1 expression levels, and changes palatine rugae morphology, indicating a role in normal secondary palate morphogenesis.\",\n      \"method\": \"In situ expression analysis, in vitro palate culture with Pitchfork over-expression, immunostaining for primary cilia, Shh/Ptc1 expression analysis\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — over-expression with defined cellular phenotype (cilia disassembly) and pathway changes, but single lab and no loss-of-function genetic model\",\n      \"pmids\": [\"25080064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPRASP2 plays a key role in Hedgehog pathway signaling in the primary cilium through a Smoothened-GPRASP2-Pifo complex, and small compound inhibitors of this complex have been identified as potential treatments for drug-resistant Smoothened-derived cancers.\",\n      \"method\": \"Complex characterization (Smoothened-GPRASP2-Pifo), in vitro and in vivo functional experiments referenced in review context\",\n      \"journal\": \"Current topics in medicinal chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper summarizing complex data; original experimental detail not available in this abstract; corroborates PMID 26901434 but adds small molecule inhibitor finding\",\n      \"pmids\": [\"33267763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Variants in PIFO (CIMAP3) were identified in patients with laterality defects in a whole-exome sequencing study, suggesting that dysfunction of PIFO results in laterality defects in humans.\",\n      \"method\": \"Whole-exome sequencing with CNV analysis in consanguineous families with laterality defects; patient variant identification\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic variant identification in patients without functional mechanistic validation in this study; supports previously established role but no new mechanism demonstrated\",\n      \"pmids\": [\"35547246\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CIMAP3/Pitchfork (PIFO) is a basal body-associated protein that accumulates at the basal body during primary cilia disassembly, where it activates Aurora A kinase to drive cilia retraction; it also forms a complex with GPRASP2 to facilitate Smoothened translocation into the primary cilium for Hedgehog pathway activation, and haploinsufficiency causes node cilia duplication, left-right asymmetry defects, and heart failure in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIMAP3 (PIFO/Pitchfork) is a basal body-associated protein that governs primary cilium dynamics and ciliary signaling during development [#0, #1]. It accumulates at the basal body during cilia disassembly and, in its wild-type form (but not the patient-derived R80K mutant), activates Aurora A kinase to drive cilia retraction; loss of one copy in mice causes node cilia duplication, left-right asymmetry defects, basal body liberation, overreplication, and heart failure [#0]. Independently of its disassembly role, CIMAP3 forms an essential ciliary targeting complex with GPRASP2 that mediates Smoothened translocation into the primary cilium and is required for Hedgehog target gene activation [#1]. CIMAP3 is expressed in the developing secondary palate, where its over-expression triggers cilia disassembly and alters Sonic hedgehog and Patched1 expression, linking it to palate morphogenesis [#2]. Human PIFO variants are associated with laterality defects, consistent with its role in left-right patterning [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established CIMAP3/PIFO as a basal body regulator of cilia disassembly by showing it activates Aurora A kinase and that its dysfunction disrupts left-right asymmetry, answering how a single protein couples ciliary targeting machinery to cilia retraction.\",\n      \"evidence\": \"Mouse haploinsufficiency model, co-immunoprecipitation with ciliary targeting complexes, Aurora A activation assays, and R80K human mutation functional comparison\",\n      \"pmids\": [\"20643351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which PIFO activates Aurora A (direct vs. scaffolded) not resolved\",\n        \"Identity of the ciliary targeting complex components beyond the interaction not defined\",\n        \"Structural basis for the R80K loss of function unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended CIMAP3 function to tissue morphogenesis by showing its expression and over-expression in the secondary palate drive cilia disassembly and modulate Hedgehog component expression.\",\n      \"evidence\": \"In situ expression analysis and in vitro palate culture with Pitchfork over-expression, with Shh/Ptc1 readouts\",\n      \"pmids\": [\"25080064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No loss-of-function genetic model in palate\",\n        \"Single-lab over-expression phenotype\",\n        \"Mechanistic link between cilia disassembly and Shh/Ptc1 changes not dissected\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a distinct CIMAP3 function in ciliary signaling input by showing a PIFO-GPRASP2 complex is required for Smoothened entry into the cilium and Hedgehog activation, separating its disassembly role from a Hedgehog-targeting role.\",\n      \"evidence\": \"siRNA depletion of Pifo and Gprasp2 with Smo immunofluorescence and Hh target gene assays plus complex identification\",\n      \"pmids\": [\"26901434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding interface between PIFO and GPRASP2 not mapped\",\n        \"How the same protein governs both cilia assembly/disassembly and Smo trafficking unresolved\",\n        \"Stoichiometry and dynamics of the Smo-GPRASP2-PIFO complex unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reframed the Smoothened-GPRASP2-PIFO complex as a candidate therapeutic target by identifying small-molecule inhibitors against drug-resistant Smoothened cancers.\",\n      \"evidence\": \"Complex characterization summarized with referenced functional experiments in a review\",\n      \"pmids\": [\"33267763\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Review-level summary without primary experimental detail in this entry\",\n        \"Specificity and on-target action of inhibitors for PIFO not demonstrated here\",\n        \"No structural validation of the inhibitor-complex interaction\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided human genetic support for the left-right patterning role by identifying PIFO variants in patients with laterality defects.\",\n      \"evidence\": \"Whole-exome sequencing with CNV analysis in consanguineous families\",\n      \"pmids\": [\"35547246\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional validation of the patient variants in this study\",\n        \"Causality versus association not established\",\n        \"No mechanism linking specific variants to phenotype demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CIMAP3 mechanistically partitions between promoting cilia disassembly (via Aurora A) and enabling ciliary Hedgehog signaling (via GPRASP2/Smoothened) within a single basal body context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of PIFO or its complexes\",\n        \"Mechanism of Aurora A activation undefined\",\n        \"Spatiotemporal regulation distinguishing its two functions unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007224\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"Smoothened-GPRASP2-PIFO complex\"\n    ],\n    \"partners\": [\n      \"GPRASP2\",\n      \"AURKA\",\n      \"SMO\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}