{"gene":"INTU","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2009,"finding":"Fuz (a PCP effector like Intu) is essential for membrane trafficking to basal bodies and apical tips of cilia, and interacts with a Rab-related small GTPase required for ciliogenesis and secretion; Intu is identified as a related PCP effector protein in the same pathway.","method":"In vivo mucociliary epithelium imaging, genetic mutant analysis, interaction screen","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — foundational study on PCP effectors including Intu/Fuz pathway, replicated in vivo with multiple readouts, but Intu-specific mechanistic detail limited here","pmids":["19767740"],"is_preprint":false},{"year":2010,"finding":"Mouse Intu null mutants exhibit loss of primary cilia, defective Hedgehog signaling (reduced Gli1, Ptch1 expression and compromised Gli3 proteolytic processing), and a cytoplasmic GFP-Intu fusion protein rescues ciliogenic defects in Intu mutant cells, demonstrating that Intu acts cytoplasmically to regulate ciliogenesis and Hh signal transduction.","method":"Gene targeting/knockout, immunofluorescence, RT-PCR for Hh targets, rescue experiment with GFP-Intu in mutant fibroblasts","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — clean null KO with defined molecular phenotypes (Gli3 processing, Gli1/Ptch1 expression), rescue experiment confirms cytoplasmic localization requirement","pmids":["20067783"],"is_preprint":false},{"year":2011,"finding":"The functions of both Intu and Fuz in neural tube patterning are dependent on the presence of cilia, and neither Intu nor Fuz genetically interacts with the core PCP regulator Vangl2 in convergent extension; Intu and Fuz are not functionally redundant with each other.","method":"Genetic epistasis (double mutants, Vangl2 compound mutants), neural tube phenotype analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis analysis in mouse with defined phenotypic readouts, single lab","pmids":["21761479"],"is_preprint":false},{"year":2012,"finding":"Tissue-specific disruption of Intu in embryonic epidermis causes almost complete loss of primary cilia in epidermal and follicular keratinocytes and suppression of Hedgehog signaling, arresting hair follicle morphogenesis through failure of follicular keratinocyte differentiation, while epidermal stratification and barrier function are unaffected.","method":"Conditional (tissue-specific) knockout, immunofluorescence for cilia, Hh pathway analysis, histology","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with specific molecular pathway readout (Hh signaling) and cellular phenotype (ciliogenesis, differentiation), clear mechanistic placement","pmids":["22935613"],"is_preprint":false},{"year":2015,"finding":"A hypomorphic missense mutation in Intu (I813N, near C-terminus) causes moderate loss of cilia, reduced Hh signaling, and skeletal defects including polydactyly; the Intu(I813N) protein shows compromised ability to rescue ciliogenesis in Intu null cells, establishing the C-terminal region as functionally critical for ciliogenesis.","method":"Hypomorphic allele knock-in mouse, cilia quantification, rescue assay in null cells, Hh pathway analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — structure-function mutagenesis in vivo and in vitro rescue, single lab","pmids":["25774014"],"is_preprint":false},{"year":2017,"finding":"RSG1 (a small GTPase) localizes to the mother centriole in a process that depends on the CPLANE protein INTU, and RSG1 is required for final maturation of the mother centriole to allow axonemal extension during cilia initiation.","method":"Mouse knockout, localization by immunofluorescence, epistasis with INTU and TTBK2","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — epistasis and localization experiments with clear pathway placement, published in top cell biology journal","pmids":["29038301"],"is_preprint":false},{"year":2017,"finding":"INTU is essential for IFT-A (intraflagellar transport A) complex assembly during ciliogenesis; loss of INTU blocks primary cilia formation and Hh pathway activation downstream of Smoothened but upstream of Gli2; INTU acts permissively during BCC tumorigenesis.","method":"Conditional mouse knockout of Intu in SmoM2-driven BCC model, IFT-A complex analysis, Hh pathway epistasis (Gli2ΔN rescue), MEF ciliogenesis assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including epistasis (Gli2ΔN rescue), complex assembly, in vivo tumor model and in vitro MEF assays","pmids":["28459465"],"is_preprint":false},{"year":2017,"finding":"INTU mutations cause oral-facial-digital syndrome (OFDS) in humans; functional studies place INTU in the CPLANE complex necessary for IFT-A assembly and intraflagellar transport.","method":"Whole-exome sequencing, functional characterization of ciliary protein modules","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 — genetic identification with functional module assignment, corroborated by other studies","pmids":["28289185"],"is_preprint":false},{"year":2018,"finding":"INTU (CPLANE protein) interacts with STAT1 at the centriole/basal body area and promotes proteasomal degradation of STAT1; Intu expression preserves cilia length and cell viability during stress, effects antagonized by STAT1 expression; kidney proximal tubule-specific ablation of Intu aggravates ischemia-reperfusion injury and causes defective post-injury ciliogenesis.","method":"Conditional kidney-specific KO, Co-immunoprecipitation (Intu-STAT1), colocalization by immunofluorescence, proteasomal inhibitor assay, cell viability assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, colocalization, functional rescue, in vivo conditional KO with defined molecular mechanism","pmids":["29581513"],"is_preprint":false},{"year":2020,"finding":"Evolutionary analysis identifies INTU and FUZ as forming a heterodimer with homology to HerMon (Hermansky-Pudlak syndrome and MON1-CCZ1) complexes; each protein contains a triplicated Longin domain, suggesting INTU/FUZ acts as a GEF (guanine nucleotide exchange factor) for Rab GTPases during ciliogenesis.","method":"Coevolution-based contact prediction, sequence conservation analysis (computational/bioinformatic)","journal":"Bioinformatics","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction only, no direct biochemical validation in this study","pmids":["31562761"],"is_preprint":false},{"year":2022,"finding":"CPLANE complex is composed of INTU, FUZ, and WDPCP, which bind to JBTS17 and RSG1 for cilia formation; defects in CPLANE components cause defective IFT-A assembly, defective PCP, and defective Hedgehog signaling.","method":"Review/synthesis of functional studies (genetic, biochemical, ciliogenesis assays from multiple studies)","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 — synthesis of replicated findings from multiple independent labs; INTU's role in CPLANE and IFT-A assembly is well-established","pmids":["35740972"],"is_preprint":false},{"year":2022,"finding":"Conditional knockout of Intu in renal tubules delays kidney repair and ameliorates renal fibrosis after ischemic injury; Intu KO kidneys show less senescence but higher cell proliferation and apoptosis; in vitro, Intu knockdown suppresses scratch wound healing with abnormal centrosome orientation, placing Intu in planar cell polarity-mediated tubular repair.","method":"Conditional KO mouse, histology/immunohistochemistry, in vitro scratch wound assay with Intu knockdown, centrosome orientation analysis","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with in vitro mechanistic follow-up (centrosome orientation), single lab","pmids":["36586478"],"is_preprint":false},{"year":2024,"finding":"Loss of Intu severely disrupts lung growth and branching morphogenesis through cilia-dependent Hh signaling; genetic removal of both Gli2 and Intu completely abolishes lung branching, providing epistatic evidence that Intu regulates lung development via the Gli2 arm of the Hh pathway.","method":"Mouse knockout, Smo agonist treatment of lung explants, Gli2/Intu double mutant epistasis, transcriptomics (RNA-seq)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — double mutant epistasis plus pharmacological and transcriptomic evidence, multiple orthogonal approaches","pmids":["39029571"],"is_preprint":false},{"year":2026,"finding":"Inturned contains a unique PDZ-like domain that does not interact with membranes or with the core PCP protein Vangl2; crystal structure of the Intu-PDZ domain reveals a unique fold lacking a canonical interaction site for PDZ-binding motifs; Intu and Fuz are members of the tri-longin domain (TLD) RabGEF family and activate Rab23 downstream of Vangl2 and Prickle.","method":"Crystal structure determination, biochemical binding assays (pulldown/interaction assays), structural analysis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with biochemical validation, directly defines domain function and interaction interface","pmids":["41797376"],"is_preprint":false}],"current_model":"INTU (Inturned) is a core subunit of the CPLANE complex (with FUZ and WDPCP) that functions as a tri-longin domain RabGEF to activate Rab23 and facilitate IFT-A complex assembly at the mother centriole/basal body, thereby enabling primary cilia formation and cilia-dependent Hedgehog signaling through Gli2; it also targets STAT1 for proteasomal degradation at the centriole to protect cells from stress, and acts downstream of core PCP proteins Vangl2/Prickle but via a PDZ-like domain distinct from canonical PDZ interaction."},"narrative":{"teleology":[{"year":2009,"claim":"Establishing that INTU belongs to a PCP effector pathway involving membrane trafficking to basal bodies revealed its functional context distinct from core PCP regulators.","evidence":"In vivo imaging of mucociliary epithelium plus genetic mutant analysis and interaction screening in Xenopus","pmids":["19767740"],"confidence":"Medium","gaps":["Direct molecular function of INTU itself not tested in this study","Mechanism by which INTU contributes to membrane trafficking unresolved"]},{"year":2010,"claim":"Demonstrating that Intu null mice lose primary cilia and show defective Hedgehog signaling (Gli3 processing, Gli1/Ptch1 expression) established INTU as a bona fide ciliogenesis factor acting cytoplasmically.","evidence":"Mouse gene targeting/knockout, immunofluorescence, RT-PCR for Hh targets, GFP-Intu rescue in null fibroblasts","pmids":["20067783"],"confidence":"High","gaps":["Molecular target or binding partner of INTU in ciliogenesis unknown","Whether INTU acts on IFT or basal body maturation not distinguished"]},{"year":2011,"claim":"Genetic epistasis showed INTU does not interact with the core PCP regulator Vangl2 for convergent extension, separating its cilia-dependent function from canonical PCP.","evidence":"Double mutant analysis (Intu;Vangl2 compound mutants) with neural tube phenotyping in mouse","pmids":["21761479"],"confidence":"Medium","gaps":["Single-lab study; independent replication in other tissues not performed","How INTU connects to PCP effector cascade molecularly still undefined"]},{"year":2012,"claim":"Tissue-specific deletion in epidermis showed INTU is required for cilia and Hedgehog signaling in keratinocytes but dispensable for stratification, defining its tissue-selective requirement.","evidence":"Conditional knockout in mouse epidermis with immunofluorescence for cilia and Hh pathway analysis","pmids":["22935613"],"confidence":"High","gaps":["Whether INTU loss affects other signaling pathways in keratinocytes not explored"]},{"year":2015,"claim":"A hypomorphic missense allele (I813N) identified the C-terminal region of INTU as functionally critical for ciliogenesis and Hedgehog signaling, providing the first structure-function insight.","evidence":"Knock-in mouse with hypomorphic allele, cilia quantification, rescue assay in null cells","pmids":["25774014"],"confidence":"Medium","gaps":["Structural basis for C-terminal requirement not determined","Whether I813N disrupts protein folding versus specific interactions unknown"]},{"year":2017,"claim":"Three studies collectively established that INTU functions within the CPLANE complex to assemble the IFT-A complex, recruits RSG1 to the mother centriole for axonemal extension, and that INTU mutations cause oral-facial-digital syndrome in humans.","evidence":"Conditional mouse KO in BCC model with IFT-A analysis and Gli2ΔN epistasis (PMID:28459465); RSG1 localization and epistasis with INTU/TTBK2 (PMID:29038301); whole-exome sequencing of OFDS patients (PMID:28289185)","pmids":["28459465","29038301","28289185"],"confidence":"High","gaps":["Biochemical mechanism by which INTU promotes IFT-A assembly not defined","Whether INTU directly binds IFT-A subunits or acts indirectly through Rab GTPases unknown"]},{"year":2018,"claim":"Discovery that INTU interacts with STAT1 at the centriole and promotes its proteasomal degradation revealed a non-canonical, cilia-protective function during cellular stress.","evidence":"Reciprocal co-immunoprecipitation, colocalization by immunofluorescence, proteasome inhibitor assay, conditional kidney-specific KO with ischemia-reperfusion model","pmids":["29581513"],"confidence":"High","gaps":["Whether INTU directly ubiquitinates STAT1 or recruits an E3 ligase not determined","Relationship between STAT1 degradation and IFT-A assembly functions unclear"]},{"year":2020,"claim":"Computational analysis predicted that INTU and FUZ form a heterodimeric tri-longin domain RabGEF homologous to HerMon complexes, generating the hypothesis that CPLANE activates Rab GTPases.","evidence":"Coevolution-based contact prediction and sequence conservation analysis (bioinformatic)","pmids":["31562761"],"confidence":"Low","gaps":["Purely computational — no biochemical validation of GEF activity in this study","Identity of the target Rab GTPase not experimentally determined"]},{"year":2022,"claim":"Conditional Intu knockout in renal tubules revealed its role in planar cell polarity-mediated tubular repair, linking INTU to centrosome orientation during wound healing.","evidence":"Conditional KO mouse with histology, in vitro scratch wound assay with Intu knockdown, centrosome orientation analysis","pmids":["36586478"],"confidence":"Medium","gaps":["Whether centrosome orientation defect is secondary to cilia loss not resolved","Single-lab finding without independent replication"]},{"year":2024,"claim":"Double-mutant epistasis (Gli2;Intu) showed that INTU controls lung branching morphogenesis specifically through the Gli2 arm of the Hedgehog pathway, pinpointing the downstream effector.","evidence":"Mouse knockout, Smo agonist treatment of lung explants, Gli2/Intu double mutant, RNA-seq transcriptomics","pmids":["39029571"],"confidence":"High","gaps":["Whether INTU has Hh-independent roles in lung development not excluded","Mechanism by which cilia loss specifically impairs Gli2 activation versus Gli3 processing in lung not detailed"]},{"year":2026,"claim":"Crystal structure of the INTU PDZ-like domain revealed a unique fold lacking canonical PDZ-binding capability, and biochemical assays confirmed that INTU/FUZ acts as a TLD RabGEF activating Rab23 downstream of Vangl2/Prickle, unifying the PCP-cilia connection.","evidence":"Crystal structure determination, pulldown/binding assays, structural analysis","pmids":["41797376"],"confidence":"High","gaps":["Kinetic parameters of Rab23 GEF activity not reported","Whether INTU/FUZ activates Rabs other than Rab23 not tested","Structure of the full INTU-FUZ-WDPCP ternary complex not determined"]},{"year":null,"claim":"The structural basis for how INTU promotes IFT-A assembly, whether its Rab23 GEF activity is the sole mechanism driving IFT-A recruitment, and how INTU coordinates its STAT1-degradation and ciliogenesis functions remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted IFT-A assembly assay with purified CPLANE components","Relationship between Rab23 activation and IFT-A assembly mechanistically undefined","No structure of full-length INTU or the CPLANE ternary complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[5,8]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,5,6,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,6,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,12]}],"complexes":["CPLANE (INTU-FUZ-WDPCP)"],"partners":["FUZ","WDPCP","RSG1","STAT1","RAB23","JBTS17"],"other_free_text":[]},"mechanistic_narrative":"INTU (Inturned) is a core subunit of the CPLANE complex (with FUZ and WDPCP) that functions as a ciliary assembly factor essential for primary cilia formation, intraflagellar transport A (IFT-A) complex assembly, and cilia-dependent Hedgehog signaling. INTU and FUZ form a heterodimeric tri-longin domain (TLD) RabGEF that activates Rab23 downstream of core planar cell polarity proteins Vangl2 and Prickle, and INTU recruits the small GTPase RSG1 to the mother centriole to enable axonemal extension [PMID:41797376, PMID:29038301, PMID:28459465]. Beyond ciliogenesis, INTU interacts with STAT1 at the centriole and promotes its proteasomal degradation, thereby preserving cilia integrity and cell viability during stress such as renal ischemia-reperfusion injury [PMID:29581513]. Loss-of-function mutations in INTU cause oral-facial-digital syndrome in humans, and mouse knockouts demonstrate that INTU is required for Hedgehog-dependent processes including neural tube patterning, hair follicle morphogenesis, lung branching, and suppression of basal cell carcinoma [PMID:28289185, PMID:20067783, PMID:22935613, PMID:39029571]."},"prefetch_data":{"uniprot":{"accession":"Q9ULD6","full_name":"Protein inturned","aliases":["Inturned planar cell polarity effector homolog","PDZ domain-containing protein 6"],"length_aa":942,"mass_kda":105.6,"function":"Plays a key role in ciliogenesis and embryonic development. Regulator of cilia formation by controlling the organization of the apical actin cytoskeleton and the positioning of the basal bodies at the apical cell surface, which in turn is essential for the normal orientation of elongating ciliary microtubules. Plays a key role in definition of cell polarity via its role in ciliogenesis but not via conversion extension. Has an indirect effect on hedgehog signaling (By similarity). Proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies (PubMed:27158779). Required for recruitment of CPLANE2 to the mother centriole (By similarity). Binds phosphatidylinositol 3-phosphate with highest affinity, followed by phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate (By similarity)","subcellular_location":"Cytoplasm; Cell surface; Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q9ULD6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INTU","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":[],"url":"https://opencell.sf.czbiohub.org/search/INTU","total_profiled":1310},"omim":[{"mim_id":"621180","title":"CRANIOECTODERMAL DYSPLASIA 5; CED5","url":"https://www.omim.org/entry/621180"},{"mim_id":"620566","title":"CLAUDIN 22; CLDN22","url":"https://www.omim.org/entry/620566"},{"mim_id":"620487","title":"CILIOGENESIS AND PLANAR POLARITY EFFECTOR COMPLEX, SUBUNIT 2; CPLANE2","url":"https://www.omim.org/entry/620487"},{"mim_id":"617926","title":"OROFACIODIGITAL SYNDROME XVII; OFD17","url":"https://www.omim.org/entry/617926"},{"mim_id":"617925","title":"SHORT-RIB THORACIC DYSPLASIA 20 WITH POLYDACTYLY; SRTD20","url":"https://www.omim.org/entry/617925"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Basal body","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":12.2}],"url":"https://www.proteinatlas.org/search/INTU"},"hgnc":{"alias_symbol":["KIAA1284","CPLANE4"],"prev_symbol":["PDZK6","PDZD6"]},"alphafold":{"accession":"Q9ULD6","domains":[{"cath_id":"-","chopping":"56-78_284-303_472-572_585-649","consensus_level":"medium","plddt":84.0971,"start":56,"end":649},{"cath_id":"2.30.42.10","chopping":"159-172_179-192_207-263","consensus_level":"high","plddt":83.0041,"start":159,"end":263},{"cath_id":"3.30.450.70","chopping":"307-456","consensus_level":"high","plddt":87.263,"start":307,"end":456},{"cath_id":"-","chopping":"650-661_770-857_875-942","consensus_level":"medium","plddt":75.2898,"start":650,"end":942}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULD6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULD6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULD6-F1-predicted_aligned_error_v6.png","plddt_mean":66.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INTU","jax_strain_url":"https://www.jax.org/strain/search?query=INTU"},"sequence":{"accession":"Q9ULD6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULD6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULD6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULD6"}},"corpus_meta":[{"pmid":"19767740","id":"PMC_19767740","title":"The 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Intu is identified as a related PCP effector protein in the same pathway.\",\n      \"method\": \"In vivo mucociliary epithelium imaging, genetic mutant analysis, interaction screen\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — foundational study on PCP effectors including Intu/Fuz pathway, replicated in vivo with multiple readouts, but Intu-specific mechanistic detail limited here\",\n      \"pmids\": [\"19767740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mouse Intu null mutants exhibit loss of primary cilia, defective Hedgehog signaling (reduced Gli1, Ptch1 expression and compromised Gli3 proteolytic processing), and a cytoplasmic GFP-Intu fusion protein rescues ciliogenic defects in Intu mutant cells, demonstrating that Intu acts cytoplasmically to regulate ciliogenesis and Hh signal transduction.\",\n      \"method\": \"Gene targeting/knockout, immunofluorescence, RT-PCR for Hh targets, rescue experiment with GFP-Intu in mutant fibroblasts\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean null KO with defined molecular phenotypes (Gli3 processing, Gli1/Ptch1 expression), rescue experiment confirms cytoplasmic localization requirement\",\n      \"pmids\": [\"20067783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The functions of both Intu and Fuz in neural tube patterning are dependent on the presence of cilia, and neither Intu nor Fuz genetically interacts with the core PCP regulator Vangl2 in convergent extension; Intu and Fuz are not functionally redundant with each other.\",\n      \"method\": \"Genetic epistasis (double mutants, Vangl2 compound mutants), neural tube phenotype analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis analysis in mouse with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"21761479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tissue-specific disruption of Intu in embryonic epidermis causes almost complete loss of primary cilia in epidermal and follicular keratinocytes and suppression of Hedgehog signaling, arresting hair follicle morphogenesis through failure of follicular keratinocyte differentiation, while epidermal stratification and barrier function are unaffected.\",\n      \"method\": \"Conditional (tissue-specific) knockout, immunofluorescence for cilia, Hh pathway analysis, histology\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with specific molecular pathway readout (Hh signaling) and cellular phenotype (ciliogenesis, differentiation), clear mechanistic placement\",\n      \"pmids\": [\"22935613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A hypomorphic missense mutation in Intu (I813N, near C-terminus) causes moderate loss of cilia, reduced Hh signaling, and skeletal defects including polydactyly; the Intu(I813N) protein shows compromised ability to rescue ciliogenesis in Intu null cells, establishing the C-terminal region as functionally critical for ciliogenesis.\",\n      \"method\": \"Hypomorphic allele knock-in mouse, cilia quantification, rescue assay in null cells, Hh pathway analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structure-function mutagenesis in vivo and in vitro rescue, single lab\",\n      \"pmids\": [\"25774014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RSG1 (a small GTPase) localizes to the mother centriole in a process that depends on the CPLANE protein INTU, and RSG1 is required for final maturation of the mother centriole to allow axonemal extension during cilia initiation.\",\n      \"method\": \"Mouse knockout, localization by immunofluorescence, epistasis with INTU and TTBK2\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis and localization experiments with clear pathway placement, published in top cell biology journal\",\n      \"pmids\": [\"29038301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"INTU is essential for IFT-A (intraflagellar transport A) complex assembly during ciliogenesis; loss of INTU blocks primary cilia formation and Hh pathway activation downstream of Smoothened but upstream of Gli2; INTU acts permissively during BCC tumorigenesis.\",\n      \"method\": \"Conditional mouse knockout of Intu in SmoM2-driven BCC model, IFT-A complex analysis, Hh pathway epistasis (Gli2ΔN rescue), MEF ciliogenesis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including epistasis (Gli2ΔN rescue), complex assembly, in vivo tumor model and in vitro MEF assays\",\n      \"pmids\": [\"28459465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"INTU mutations cause oral-facial-digital syndrome (OFDS) in humans; functional studies place INTU in the CPLANE complex necessary for IFT-A assembly and intraflagellar transport.\",\n      \"method\": \"Whole-exome sequencing, functional characterization of ciliary protein modules\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic identification with functional module assignment, corroborated by other studies\",\n      \"pmids\": [\"28289185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"INTU (CPLANE protein) interacts with STAT1 at the centriole/basal body area and promotes proteasomal degradation of STAT1; Intu expression preserves cilia length and cell viability during stress, effects antagonized by STAT1 expression; kidney proximal tubule-specific ablation of Intu aggravates ischemia-reperfusion injury and causes defective post-injury ciliogenesis.\",\n      \"method\": \"Conditional kidney-specific KO, Co-immunoprecipitation (Intu-STAT1), colocalization by immunofluorescence, proteasomal inhibitor assay, cell viability assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, colocalization, functional rescue, in vivo conditional KO with defined molecular mechanism\",\n      \"pmids\": [\"29581513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Evolutionary analysis identifies INTU and FUZ as forming a heterodimer with homology to HerMon (Hermansky-Pudlak syndrome and MON1-CCZ1) complexes; each protein contains a triplicated Longin domain, suggesting INTU/FUZ acts as a GEF (guanine nucleotide exchange factor) for Rab GTPases during ciliogenesis.\",\n      \"method\": \"Coevolution-based contact prediction, sequence conservation analysis (computational/bioinformatic)\",\n      \"journal\": \"Bioinformatics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no direct biochemical validation in this study\",\n      \"pmids\": [\"31562761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPLANE complex is composed of INTU, FUZ, and WDPCP, which bind to JBTS17 and RSG1 for cilia formation; defects in CPLANE components cause defective IFT-A assembly, defective PCP, and defective Hedgehog signaling.\",\n      \"method\": \"Review/synthesis of functional studies (genetic, biochemical, ciliogenesis assays from multiple studies)\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — synthesis of replicated findings from multiple independent labs; INTU's role in CPLANE and IFT-A assembly is well-established\",\n      \"pmids\": [\"35740972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional knockout of Intu in renal tubules delays kidney repair and ameliorates renal fibrosis after ischemic injury; Intu KO kidneys show less senescence but higher cell proliferation and apoptosis; in vitro, Intu knockdown suppresses scratch wound healing with abnormal centrosome orientation, placing Intu in planar cell polarity-mediated tubular repair.\",\n      \"method\": \"Conditional KO mouse, histology/immunohistochemistry, in vitro scratch wound assay with Intu knockdown, centrosome orientation analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with in vitro mechanistic follow-up (centrosome orientation), single lab\",\n      \"pmids\": [\"36586478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of Intu severely disrupts lung growth and branching morphogenesis through cilia-dependent Hh signaling; genetic removal of both Gli2 and Intu completely abolishes lung branching, providing epistatic evidence that Intu regulates lung development via the Gli2 arm of the Hh pathway.\",\n      \"method\": \"Mouse knockout, Smo agonist treatment of lung explants, Gli2/Intu double mutant epistasis, transcriptomics (RNA-seq)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double mutant epistasis plus pharmacological and transcriptomic evidence, multiple orthogonal approaches\",\n      \"pmids\": [\"39029571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Inturned contains a unique PDZ-like domain that does not interact with membranes or with the core PCP protein Vangl2; crystal structure of the Intu-PDZ domain reveals a unique fold lacking a canonical interaction site for PDZ-binding motifs; Intu and Fuz are members of the tri-longin domain (TLD) RabGEF family and activate Rab23 downstream of Vangl2 and Prickle.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays (pulldown/interaction assays), structural analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with biochemical validation, directly defines domain function and interaction interface\",\n      \"pmids\": [\"41797376\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INTU (Inturned) is a core subunit of the CPLANE complex (with FUZ and WDPCP) that functions as a tri-longin domain RabGEF to activate Rab23 and facilitate IFT-A complex assembly at the mother centriole/basal body, thereby enabling primary cilia formation and cilia-dependent Hedgehog signaling through Gli2; it also targets STAT1 for proteasomal degradation at the centriole to protect cells from stress, and acts downstream of core PCP proteins Vangl2/Prickle but via a PDZ-like domain distinct from canonical PDZ interaction.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"INTU (Inturned) is a core subunit of the CPLANE complex (with FUZ and WDPCP) that functions as a ciliary assembly factor essential for primary cilia formation, intraflagellar transport A (IFT-A) complex assembly, and cilia-dependent Hedgehog signaling. INTU and FUZ form a heterodimeric tri-longin domain (TLD) RabGEF that activates Rab23 downstream of core planar cell polarity proteins Vangl2 and Prickle, and INTU recruits the small GTPase RSG1 to the mother centriole to enable axonemal extension [PMID:41797376, PMID:29038301, PMID:28459465]. Beyond ciliogenesis, INTU interacts with STAT1 at the centriole and promotes its proteasomal degradation, thereby preserving cilia integrity and cell viability during stress such as renal ischemia-reperfusion injury [PMID:29581513]. Loss-of-function mutations in INTU cause oral-facial-digital syndrome in humans, and mouse knockouts demonstrate that INTU is required for Hedgehog-dependent processes including neural tube patterning, hair follicle morphogenesis, lung branching, and suppression of basal cell carcinoma [PMID:28289185, PMID:20067783, PMID:22935613, PMID:39029571].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that INTU belongs to a PCP effector pathway involving membrane trafficking to basal bodies revealed its functional context distinct from core PCP regulators.\",\n      \"evidence\": \"In vivo imaging of mucociliary epithelium plus genetic mutant analysis and interaction screening in Xenopus\",\n      \"pmids\": [\"19767740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular function of INTU itself not tested in this study\",\n        \"Mechanism by which INTU contributes to membrane trafficking unresolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that Intu null mice lose primary cilia and show defective Hedgehog signaling (Gli3 processing, Gli1/Ptch1 expression) established INTU as a bona fide ciliogenesis factor acting cytoplasmically.\",\n      \"evidence\": \"Mouse gene targeting/knockout, immunofluorescence, RT-PCR for Hh targets, GFP-Intu rescue in null fibroblasts\",\n      \"pmids\": [\"20067783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular target or binding partner of INTU in ciliogenesis unknown\",\n        \"Whether INTU acts on IFT or basal body maturation not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic epistasis showed INTU does not interact with the core PCP regulator Vangl2 for convergent extension, separating its cilia-dependent function from canonical PCP.\",\n      \"evidence\": \"Double mutant analysis (Intu;Vangl2 compound mutants) with neural tube phenotyping in mouse\",\n      \"pmids\": [\"21761479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; independent replication in other tissues not performed\",\n        \"How INTU connects to PCP effector cascade molecularly still undefined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Tissue-specific deletion in epidermis showed INTU is required for cilia and Hedgehog signaling in keratinocytes but dispensable for stratification, defining its tissue-selective requirement.\",\n      \"evidence\": \"Conditional knockout in mouse epidermis with immunofluorescence for cilia and Hh pathway analysis\",\n      \"pmids\": [\"22935613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether INTU loss affects other signaling pathways in keratinocytes not explored\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A hypomorphic missense allele (I813N) identified the C-terminal region of INTU as functionally critical for ciliogenesis and Hedgehog signaling, providing the first structure-function insight.\",\n      \"evidence\": \"Knock-in mouse with hypomorphic allele, cilia quantification, rescue assay in null cells\",\n      \"pmids\": [\"25774014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for C-terminal requirement not determined\",\n        \"Whether I813N disrupts protein folding versus specific interactions unknown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Three studies collectively established that INTU functions within the CPLANE complex to assemble the IFT-A complex, recruits RSG1 to the mother centriole for axonemal extension, and that INTU mutations cause oral-facial-digital syndrome in humans.\",\n      \"evidence\": \"Conditional mouse KO in BCC model with IFT-A analysis and Gli2ΔN epistasis (PMID:28459465); RSG1 localization and epistasis with INTU/TTBK2 (PMID:29038301); whole-exome sequencing of OFDS patients (PMID:28289185)\",\n      \"pmids\": [\"28459465\", \"29038301\", \"28289185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biochemical mechanism by which INTU promotes IFT-A assembly not defined\",\n        \"Whether INTU directly binds IFT-A subunits or acts indirectly through Rab GTPases unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that INTU interacts with STAT1 at the centriole and promotes its proteasomal degradation revealed a non-canonical, cilia-protective function during cellular stress.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, colocalization by immunofluorescence, proteasome inhibitor assay, conditional kidney-specific KO with ischemia-reperfusion model\",\n      \"pmids\": [\"29581513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether INTU directly ubiquitinates STAT1 or recruits an E3 ligase not determined\",\n        \"Relationship between STAT1 degradation and IFT-A assembly functions unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Computational analysis predicted that INTU and FUZ form a heterodimeric tri-longin domain RabGEF homologous to HerMon complexes, generating the hypothesis that CPLANE activates Rab GTPases.\",\n      \"evidence\": \"Coevolution-based contact prediction and sequence conservation analysis (bioinformatic)\",\n      \"pmids\": [\"31562761\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Purely computational — no biochemical validation of GEF activity in this study\",\n        \"Identity of the target Rab GTPase not experimentally determined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Conditional Intu knockout in renal tubules revealed its role in planar cell polarity-mediated tubular repair, linking INTU to centrosome orientation during wound healing.\",\n      \"evidence\": \"Conditional KO mouse with histology, in vitro scratch wound assay with Intu knockdown, centrosome orientation analysis\",\n      \"pmids\": [\"36586478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether centrosome orientation defect is secondary to cilia loss not resolved\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Double-mutant epistasis (Gli2;Intu) showed that INTU controls lung branching morphogenesis specifically through the Gli2 arm of the Hedgehog pathway, pinpointing the downstream effector.\",\n      \"evidence\": \"Mouse knockout, Smo agonist treatment of lung explants, Gli2/Intu double mutant, RNA-seq transcriptomics\",\n      \"pmids\": [\"39029571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether INTU has Hh-independent roles in lung development not excluded\",\n        \"Mechanism by which cilia loss specifically impairs Gli2 activation versus Gli3 processing in lung not detailed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Crystal structure of the INTU PDZ-like domain revealed a unique fold lacking canonical PDZ-binding capability, and biochemical assays confirmed that INTU/FUZ acts as a TLD RabGEF activating Rab23 downstream of Vangl2/Prickle, unifying the PCP-cilia connection.\",\n      \"evidence\": \"Crystal structure determination, pulldown/binding assays, structural analysis\",\n      \"pmids\": [\"41797376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Kinetic parameters of Rab23 GEF activity not reported\",\n        \"Whether INTU/FUZ activates Rabs other than Rab23 not tested\",\n        \"Structure of the full INTU-FUZ-WDPCP ternary complex not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how INTU promotes IFT-A assembly, whether its Rab23 GEF activity is the sole mechanism driving IFT-A recruitment, and how INTU coordinates its STAT1-degradation and ciliogenesis functions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstituted IFT-A assembly assay with purified CPLANE components\",\n        \"Relationship between Rab23 activation and IFT-A assembly mechanistically undefined\",\n        \"No structure of full-length INTU or the CPLANE ternary complex\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [8, 13]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005829\",\n        \"supporting_discovery_ids\": [1]\n      },\n      {\n        \"term_id\": \"GO:0005815\",\n        \"supporting_discovery_ids\": [5, 8]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1852241\",\n        \"supporting_discovery_ids\": [1, 5, 6, 10]\n      },\n      {\n        \"term_id\": \"R-HSA-162582\",\n        \"supporting_discovery_ids\": [1, 3, 6, 12]\n      },\n      {\n        \"term_id\": \"R-HSA-1266738\",\n        \"supporting_discovery_ids\": [3, 12]\n      }\n    ],\n    \"complexes\": [\n      \"CPLANE (INTU-FUZ-WDPCP)\"\n    ],\n    \"partners\": [\n      \"FUZ\",\n      \"WDPCP\",\n      \"RSG1\",\n      \"STAT1\",\n      \"RAB23\",\n      \"JBTS17\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}