{"gene":"REEP3","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2013,"finding":"REEP3 and REEP4 function redundantly to clear the endoplasmic reticulum from metaphase chromosomes during mitosis. Depletion of REEP3/4 from HeLa cells causes ER accumulation on metaphase chromosomes, defects in cell division, and proliferation of intranuclear membranes derived from the nuclear envelope. Microtubule binding and mitotic ER clearance depend on a short, positively charged amino acid sequence connecting the two hydrophobic domains of REEP4 (and by inference REEP3).","method":"Biochemical screen for microtubule-membrane linkers; siRNA depletion of REEP3/4 in HeLa cells; live-cell imaging; electron microscopy of nuclear envelope architecture","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical screen, siRNA depletion with defined cellular phenotypes, domain mutagenesis, replicated findings across multiple orthogonal methods in one rigorous study","pmids":["23911198"],"is_preprint":false},{"year":2019,"finding":"REEP3 and REEP4 are major determinants of ER morphology in metaphase cells, promoting high-curvature ER tubulation through their reticulon homology domains (RHDs). This ER-shaping activity is distinct from their function in clearing ER from metaphase chromatin. Related REEP proteins do not contribute to mitotic ER shaping, and the REEP3/4 C-terminus mediates regulation of the proteins.","method":"siRNA depletion of REEP3/4 in cultured cells; electron tomography (3View) of ER morphology; domain deletion/mutation analysis; live-cell fluorescence imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain mutagenesis combined with ultrastructural imaging and functional rescue, multiple orthogonal methods, same lab extending prior work with new mechanistic distinction","pmids":["30995177"],"is_preprint":false},{"year":2007,"finding":"REEP3 expression is abolished by a chromosomal position effect caused by a de novo balanced paracentric inversion inv(10)(q11.1;q21.3) in a patient with autism, placing REEP3 as a candidate gene whose loss-of-expression may contribute to neurodevelopmental phenotypes. REEP3 is described as a homolog of yeast Yop1p, a regulator of vesicle trafficking between ER and Golgi.","method":"Cytogenetic mapping; RT-PCR quantification of REEP3 mRNA expression in patient lymphoblasts; positional cloning","journal":"European journal of human genetics : EJHG","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient, expression measurement only, no functional rescue or mechanistic experiment beyond demonstrating position-effect loss of expression","pmids":["17290275"],"is_preprint":false},{"year":2019,"finding":"Silencing of REEP3 in the human liver cell line HuH7 using siRNA upregulated Factor VII (F7) mRNA and FVII protein expression, indicating that REEP3 negatively regulates F7 expression in hepatic cells.","method":"siRNA-mediated silencing of REEP3 in HuH7 cells followed by measurement of F7 mRNA and FVII protein expression","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined molecular phenotype (F7 upregulation), single lab, single cell line, single method","pmids":["30642921"],"is_preprint":false},{"year":2021,"finding":"REEP3 was identified as a positive regulator of adipogenesis in an m6A-independent pathway. Rhein treatment altered REEP3 expression, and modulation of REEP3 levels affected adipocyte differentiation.","method":"Transcriptome profiling; m6A methylome analysis; REEP3 overexpression/knockdown in adipocyte differentiation assays","journal":"Frontiers in nutrition","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional assay with overexpression/knockdown but limited mechanistic detail in abstract, no reconstitution or domain analysis","pmids":["34790688"],"is_preprint":false},{"year":2025,"finding":"Loss-of-function analysis using CRISPR/Cas9 disruption of Reep3 in mouse cortical cells affected cortical cell fate and the composition of cortical neurons, suggesting a role for REEP3 in generating appropriate cortical neuronal composition.","method":"CRISPR/Cas9 loss-of-function in mouse neocortex; cortical cell fate analysis","journal":"Progress in neuro-psychopharmacology & biological psychiatry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, CRISPR KO with cellular phenotype but limited mechanistic detail available in abstract, no pathway placement","pmids":["39862915"],"is_preprint":false},{"year":2025,"finding":"REEP3, along with FAM118A, RCN3, and PCSK7, was found to promote airway stenosis by activating the KRAS→PI3K-AKT pathway, leading to upregulation of fibroblast activation markers. REEP3 expression is transcriptionally regulated by TBX20, and the ILF3-AS1/miR-212-5p axis regulates REEP3 expression.","method":"Integration of single-cell and bulk RNA-seq; molecular biology validation assays; pathway activation measurement","journal":"Functional & integrative genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, multi-gene analysis making REEP3-specific conclusions uncertain, limited mechanistic detail for REEP3 specifically in the abstract","pmids":["41432785"],"is_preprint":false}],"current_model":"REEP3 is an ER-resident membrane protein that, together with the closely related REEP4, redundantly promotes ER clearance from metaphase chromosomes and drives high-curvature ER tubulation through its reticulon homology domain (RHD) during mitosis, thereby ensuring proper cell division and nuclear envelope architecture; additional experiments indicate it negatively regulates hepatic F7 (Factor VII) expression and may play roles in adipogenesis and cortical neuronal development."},"narrative":{"mechanistic_narrative":"REEP3 is an endoplasmic reticulum membrane protein that, acting redundantly with the closely related REEP4, governs ER organization during mitosis to ensure proper cell division and nuclear envelope architecture [PMID:23911198]. It links the ER to microtubules through a short, positively charged sequence between its two hydrophobic domains, an interaction required to clear ER membranes from metaphase chromosomes; loss of REEP3/4 causes ER accumulation on chromatin, division defects, and proliferation of intranuclear membranes derived from the nuclear envelope [PMID:23911198]. Separately from this clearance function, REEP3 shapes metaphase ER by promoting high-curvature tubulation via its reticulon homology domain, with its C-terminus mediating regulation of the protein [PMID:30995177]. Beyond mitotic ER biology, REEP3 negatively regulates hepatic Factor VII (F7) expression, as its silencing in liver cells upregulates F7 mRNA and FVII protein [PMID:30642921]. Reported roles in adipogenesis, cortical neuronal fate, and airway stenosis have not been mechanistically resolved in the available corpus.","teleology":[{"year":2007,"claim":"Before any function was defined, a position-effect loss of REEP3 expression in an autism patient first nominated REEP3 as a candidate neurodevelopmental gene and noted its homology to a yeast ER/Golgi trafficking regulator.","evidence":"Cytogenetic mapping and RT-PCR of patient lymphoblasts identifying a de novo balanced inversion abolishing REEP3 expression","pmids":["17290275"],"confidence":"Low","gaps":["Single patient, expression measurement only","No functional rescue or mechanistic link between REEP3 loss and phenotype","Molecular function of REEP3 unaddressed"]},{"year":2013,"claim":"The core mechanistic role was established by showing REEP3/4 act as microtubule-membrane linkers that clear ER from metaphase chromosomes, settling how the ER is excluded from chromatin during division.","evidence":"Biochemical screen for microtubule-membrane linkers plus siRNA depletion, live-cell imaging, electron microscopy, and domain mutagenesis in HeLa cells","pmids":["23911198"],"confidence":"High","gaps":["Direct microtubule-binding partners and regulators not fully defined","Redundancy with REEP4 complicates assignment of REEP3-specific contribution","Mechanism of intranuclear membrane proliferation upon depletion not resolved"]},{"year":2019,"claim":"Mitotic ER shaping was separated from ER clearance, defining the reticulon homology domain as the driver of high-curvature tubulation distinct from the chromosome-clearance activity.","evidence":"siRNA depletion, electron tomography of ER morphology, and domain deletion/mutation with rescue in cultured cells","pmids":["30995177"],"confidence":"High","gaps":["How C-terminal regulation couples the two activities not detailed","Structural basis of RHD-induced curvature not determined"]},{"year":2019,"claim":"A function outside mitosis emerged: REEP3 negatively regulates hepatic coagulation Factor VII, linking it to control of F7 expression.","evidence":"siRNA silencing of REEP3 in HuH7 liver cells with measurement of F7 mRNA and FVII protein","pmids":["30642921"],"confidence":"Medium","gaps":["Single cell line and single method","Mechanism connecting an ER-shaping protein to F7 transcription unknown","No in vivo confirmation"]},{"year":2025,"claim":"Candidate organismal roles in adipogenesis and cortical neuronal composition were probed, extending REEP3 beyond cell-division biology.","evidence":"Overexpression/knockdown in adipocyte differentiation assays; CRISPR/Cas9 disruption in mouse neocortex with cell-fate analysis","pmids":["34790688","39862915"],"confidence":"Low","gaps":["No molecular mechanism or pathway placement for either role","Limited mechanistic detail in source reports","Relationship to the ER-shaping function untested"]},{"year":null,"claim":"It remains unresolved how REEP3's defined ER-membrane/microtubule activities mechanistically connect to its proposed roles in transcriptional control of F7, adipogenesis, and neuronal fate.","evidence":"No timeline study bridges the structural ER function to the tissue-specific phenotypes","pmids":[],"confidence":"Low","gaps":["No unifying molecular mechanism across contexts","REEP3-specific (vs REEP4-redundant) contributions largely undefined","No structural model of the protein"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1]}],"complexes":[],"partners":["REEP4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NUK4","full_name":"Receptor expression-enhancing protein 3","aliases":[],"length_aa":255,"mass_kda":29.3,"function":"Microtubule-binding protein required to ensure proper cell division and nuclear envelope reassembly by sequestering the endoplasmic reticulum away from chromosomes during mitosis. Probably acts by clearing the endoplasmic reticulum membrane from metaphase chromosomes","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6NUK4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/REEP3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000165476","cell_line_id":"CID001882","localizations":[{"compartment":"er","grade":3}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001882","total_profiled":1310},"omim":[{"mim_id":"612369","title":"ALKALINE PHOSPHATASE, PLASMA LEVEL OF, QUANTITATIVE TRAIT LOCUS 4","url":"https://www.omim.org/entry/612369"},{"mim_id":"609348","title":"RECEPTOR EXPRESSION-ENHANCING PROTEIN 3; REEP3","url":"https://www.omim.org/entry/609348"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/REEP3"},"hgnc":{"alias_symbol":["Yip2b"],"prev_symbol":["C10orf74"]},"alphafold":{"accession":"Q6NUK4","domains":[{"cath_id":"-","chopping":"1-81","consensus_level":"medium","plddt":75.8725,"start":1,"end":81}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NUK4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NUK4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NUK4-F1-predicted_aligned_error_v6.png","plddt_mean":64.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=REEP3","jax_strain_url":"https://www.jax.org/strain/search?query=REEP3"},"sequence":{"accession":"Q6NUK4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NUK4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NUK4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NUK4"}},"corpus_meta":[{"pmid":"18940312","id":"PMC_18940312","title":"Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18940312","citation_count":358,"is_preprint":false},{"pmid":"37337107","id":"PMC_37337107","title":"Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy.","date":"2023","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37337107","citation_count":146,"is_preprint":false},{"pmid":"23911198","id":"PMC_23911198","title":"REEP3/4 ensure endoplasmic reticulum clearance from metaphase chromatin and proper nuclear envelope architecture.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/23911198","citation_count":113,"is_preprint":false},{"pmid":"17290275","id":"PMC_17290275","title":"Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21.3 as novel candidate genes for 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Depletion of REEP3/4 from HeLa cells causes ER accumulation on metaphase chromosomes, defects in cell division, and proliferation of intranuclear membranes derived from the nuclear envelope. Microtubule binding and mitotic ER clearance depend on a short, positively charged amino acid sequence connecting the two hydrophobic domains of REEP4 (and by inference REEP3).\",\n      \"method\": \"Biochemical screen for microtubule-membrane linkers; siRNA depletion of REEP3/4 in HeLa cells; live-cell imaging; electron microscopy of nuclear envelope architecture\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical screen, siRNA depletion with defined cellular phenotypes, domain mutagenesis, replicated findings across multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"23911198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"REEP3 and REEP4 are major determinants of ER morphology in metaphase cells, promoting high-curvature ER tubulation through their reticulon homology domains (RHDs). This ER-shaping activity is distinct from their function in clearing ER from metaphase chromatin. Related REEP proteins do not contribute to mitotic ER shaping, and the REEP3/4 C-terminus mediates regulation of the proteins.\",\n      \"method\": \"siRNA depletion of REEP3/4 in cultured cells; electron tomography (3View) of ER morphology; domain deletion/mutation analysis; live-cell fluorescence imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain mutagenesis combined with ultrastructural imaging and functional rescue, multiple orthogonal methods, same lab extending prior work with new mechanistic distinction\",\n      \"pmids\": [\"30995177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"REEP3 expression is abolished by a chromosomal position effect caused by a de novo balanced paracentric inversion inv(10)(q11.1;q21.3) in a patient with autism, placing REEP3 as a candidate gene whose loss-of-expression may contribute to neurodevelopmental phenotypes. REEP3 is described as a homolog of yeast Yop1p, a regulator of vesicle trafficking between ER and Golgi.\",\n      \"method\": \"Cytogenetic mapping; RT-PCR quantification of REEP3 mRNA expression in patient lymphoblasts; positional cloning\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient, expression measurement only, no functional rescue or mechanistic experiment beyond demonstrating position-effect loss of expression\",\n      \"pmids\": [\"17290275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Silencing of REEP3 in the human liver cell line HuH7 using siRNA upregulated Factor VII (F7) mRNA and FVII protein expression, indicating that REEP3 negatively regulates F7 expression in hepatic cells.\",\n      \"method\": \"siRNA-mediated silencing of REEP3 in HuH7 cells followed by measurement of F7 mRNA and FVII protein expression\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined molecular phenotype (F7 upregulation), single lab, single cell line, single method\",\n      \"pmids\": [\"30642921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"REEP3 was identified as a positive regulator of adipogenesis in an m6A-independent pathway. Rhein treatment altered REEP3 expression, and modulation of REEP3 levels affected adipocyte differentiation.\",\n      \"method\": \"Transcriptome profiling; m6A methylome analysis; REEP3 overexpression/knockdown in adipocyte differentiation assays\",\n      \"journal\": \"Frontiers in nutrition\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional assay with overexpression/knockdown but limited mechanistic detail in abstract, no reconstitution or domain analysis\",\n      \"pmids\": [\"34790688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss-of-function analysis using CRISPR/Cas9 disruption of Reep3 in mouse cortical cells affected cortical cell fate and the composition of cortical neurons, suggesting a role for REEP3 in generating appropriate cortical neuronal composition.\",\n      \"method\": \"CRISPR/Cas9 loss-of-function in mouse neocortex; cortical cell fate analysis\",\n      \"journal\": \"Progress in neuro-psychopharmacology & biological psychiatry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, CRISPR KO with cellular phenotype but limited mechanistic detail available in abstract, no pathway placement\",\n      \"pmids\": [\"39862915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"REEP3, along with FAM118A, RCN3, and PCSK7, was found to promote airway stenosis by activating the KRAS→PI3K-AKT pathway, leading to upregulation of fibroblast activation markers. REEP3 expression is transcriptionally regulated by TBX20, and the ILF3-AS1/miR-212-5p axis regulates REEP3 expression.\",\n      \"method\": \"Integration of single-cell and bulk RNA-seq; molecular biology validation assays; pathway activation measurement\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, multi-gene analysis making REEP3-specific conclusions uncertain, limited mechanistic detail for REEP3 specifically in the abstract\",\n      \"pmids\": [\"41432785\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"REEP3 is an ER-resident membrane protein that, together with the closely related REEP4, redundantly promotes ER clearance from metaphase chromosomes and drives high-curvature ER tubulation through its reticulon homology domain (RHD) during mitosis, thereby ensuring proper cell division and nuclear envelope architecture; additional experiments indicate it negatively regulates hepatic F7 (Factor VII) expression and may play roles in adipogenesis and cortical neuronal development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"REEP3 is an endoplasmic reticulum membrane protein that, acting redundantly with the closely related REEP4, governs ER organization during mitosis to ensure proper cell division and nuclear envelope architecture [#0]. It links the ER to microtubules through a short, positively charged sequence between its two hydrophobic domains, an interaction required to clear ER membranes from metaphase chromosomes; loss of REEP3/4 causes ER accumulation on chromatin, division defects, and proliferation of intranuclear membranes derived from the nuclear envelope [#0]. Separately from this clearance function, REEP3 shapes metaphase ER by promoting high-curvature tubulation via its reticulon homology domain, with its C-terminus mediating regulation of the protein [#1]. Beyond mitotic ER biology, REEP3 negatively regulates hepatic Factor VII (F7) expression, as its silencing in liver cells upregulates F7 mRNA and FVII protein [#3]. Reported roles in adipogenesis, cortical neuronal fate, and airway stenosis have not been mechanistically resolved in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Before any function was defined, a position-effect loss of REEP3 expression in an autism patient first nominated REEP3 as a candidate neurodevelopmental gene and noted its homology to a yeast ER/Golgi trafficking regulator.\",\n      \"evidence\": \"Cytogenetic mapping and RT-PCR of patient lymphoblasts identifying a de novo balanced inversion abolishing REEP3 expression\",\n      \"pmids\": [\"17290275\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single patient, expression measurement only\", \"No functional rescue or mechanistic link between REEP3 loss and phenotype\", \"Molecular function of REEP3 unaddressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The core mechanistic role was established by showing REEP3/4 act as microtubule-membrane linkers that clear ER from metaphase chromosomes, settling how the ER is excluded from chromatin during division.\",\n      \"evidence\": \"Biochemical screen for microtubule-membrane linkers plus siRNA depletion, live-cell imaging, electron microscopy, and domain mutagenesis in HeLa cells\",\n      \"pmids\": [\"23911198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct microtubule-binding partners and regulators not fully defined\", \"Redundancy with REEP4 complicates assignment of REEP3-specific contribution\", \"Mechanism of intranuclear membrane proliferation upon depletion not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mitotic ER shaping was separated from ER clearance, defining the reticulon homology domain as the driver of high-curvature tubulation distinct from the chromosome-clearance activity.\",\n      \"evidence\": \"siRNA depletion, electron tomography of ER morphology, and domain deletion/mutation with rescue in cultured cells\",\n      \"pmids\": [\"30995177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How C-terminal regulation couples the two activities not detailed\", \"Structural basis of RHD-induced curvature not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A function outside mitosis emerged: REEP3 negatively regulates hepatic coagulation Factor VII, linking it to control of F7 expression.\",\n      \"evidence\": \"siRNA silencing of REEP3 in HuH7 liver cells with measurement of F7 mRNA and FVII protein\",\n      \"pmids\": [\"30642921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line and single method\", \"Mechanism connecting an ER-shaping protein to F7 transcription unknown\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Candidate organismal roles in adipogenesis and cortical neuronal composition were probed, extending REEP3 beyond cell-division biology.\",\n      \"evidence\": \"Overexpression/knockdown in adipocyte differentiation assays; CRISPR/Cas9 disruption in mouse neocortex with cell-fate analysis\",\n      \"pmids\": [\"34790688\", \"39862915\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular mechanism or pathway placement for either role\", \"Limited mechanistic detail in source reports\", \"Relationship to the ER-shaping function untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how REEP3's defined ER-membrane/microtubule activities mechanistically connect to its proposed roles in transcriptional control of F7, adipogenesis, and neuronal fate.\",\n      \"evidence\": \"No timeline study bridges the structural ER function to the tissue-specific phenotypes\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying molecular mechanism across contexts\", \"REEP3-specific (vs REEP4-redundant) contributions largely undefined\", \"No structural model of the protein\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"REEP4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}