{"gene":"REEP2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2014,"finding":"REEP2 is an ER-shaping protein that binds membranes; a dominant-negative missense variant (p.Val36Glu) inhibits normal membrane binding of wild-type REEP2, while a recessive missense variant (p.Phe72Tyr) decreases the mutant protein's affinity for membranes, collectively demonstrating that membrane association is required for REEP2 function and that loss of this association underlies hereditary spastic paraplegia (SPG72).","method":"In vitro membrane-binding assays, fibroblast ER morphology analysis, exome sequencing with functional validation of mutant alleles","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro membrane-binding assay with defined mutant alleles and cellular ER morphology phenotype, single lab but two orthogonal functional methods","pmids":["24388663"],"is_preprint":false},{"year":2010,"finding":"REEP2 is an integral membrane protein expressed in taste cells that physically associates with both subunits of the T1R2/T1R3 sweet receptor; it enhances sweet and bitter receptor responses not by increasing cell surface expression but by recruiting the receptors into lipid raft microdomains near the apical region of taste cells, thereby improving GPCR signaling.","method":"Co-immunoprecipitation (physical association), lipid raft fractionation, siRNA knockdown of endogenous REEP2 in GLUTag cells, heterologous receptor functional assays","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, biochemical fractionation, and loss-of-function with defined functional readout, single lab with multiple orthogonal methods","pmids":["20943918"],"is_preprint":false},{"year":2013,"finding":"REEP1 and REEP2 are localized primarily to the ER (not plasma membranes); they interact with and alter glycosidic processing of α2C adrenergic receptors (but not α2A ARs), enhancing ER cargo capacity and surface expression of select GPCRs; a C-terminal truncation mutant of REEP1 (SPG31 allele) abolishes this interaction, indicating the C-terminus is required for cargo interaction.","method":"Immunolocalization, co-immunoprecipitation, glycosylation/biochemical processing assays, dominant-negative mutant expression","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and biochemical glycosylation assay in single lab; REEP2 included alongside REEP1 and REEP6, so REEP2-specific conclusions are partially inferred","pmids":["24098485"],"is_preprint":false},{"year":2018,"finding":"DNA damage induces p53-mediated transcriptional upregulation of REEP1 and REEP2, which drives extension of the peripheral tubular ER; this promotes formation of ER-mitochondria contacts (via EI24–VDAC2 interaction), facilitates Ca2+ transfer from ER to mitochondria, and promotes apoptosis.","method":"p53 transcriptional reporter assays, live-cell imaging of ER morphology, ER-mitochondria contact site quantification, Ca2+ transfer assays, apoptosis readouts following knockdown/overexpression","journal":"Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple cellular imaging and functional assays in single lab; REEP2 role established alongside REEP1 and EI24, so REEP2-specific contribution is partially shared","pmids":["30030520"],"is_preprint":false},{"year":2013,"finding":"REEP1 and REEP2 protein expression is restricted to neuronal tissues (brain, spinal cord) and tissues with neuronal-like exocytosis (testes, pituitary, adrenal gland), consistent with a specialized role in neuronal/exocytotic cell function.","method":"Immunoblotting with validated monoclonal antibodies, immunofluorescence microscopy, RT-PCR, gene expression microarray","journal":"Brain Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated antibody immunoblotting and immunofluorescence across multiple tissues, single lab, two orthogonal methods","pmids":["24355597"],"is_preprint":false},{"year":2023,"finding":"REEP2 acts as a negative regulator of adipogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs); REEP2 expression is decreased during adipogenesis, and restoring REEP2 expression (via chidamide treatment) suppresses adipocyte development.","method":"Gene expression analysis, siRNA/overexpression in BM-MSCs during induced adipogenesis, pharmacological HDAC inhibition with chidamide","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss- and gain-of-function with defined cellular phenotype, single lab, functional readout of adipogenesis inhibition","pmids":["36879811"],"is_preprint":false},{"year":2025,"finding":"ZEB1 upregulates REEP2 expression through repression of miR-183 and miR-193a (which normally suppress REEP2); elevated REEP2 promotes transport of secretory cargoes from ER exit sites (ERES) to the Golgi, augmenting secretion of pro-tumorigenic factors that drive cancer cell proliferation, migration, and myeloid-derived suppressor cell infiltration.","method":"CRISPRi in vivo screen, miRNA functional assays, ER-to-Golgi trafficking assays, orthotopic syngeneic mouse model, secretion/functional readouts","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo CRISPRi screen plus mechanistic trafficking assays and miRNA validation, single lab preprint not yet peer-reviewed","pmids":["41292834"],"is_preprint":true}],"current_model":"REEP2 is an integral ER-shaping membrane protein that tubulates the peripheral ER by binding membranes; it physically associates with select GPCRs (including sweet taste receptor subunits T1R2/T1R3 and α2C adrenergic receptors) to enhance their signaling by recruiting them to lipid rafts or augmenting ER cargo capacity, and it promotes ER-to-Golgi trafficking of secretory cargoes; under DNA damage, p53-driven upregulation of REEP2 extends tubular ER and facilitates ER-mitochondria Ca2+ transfer to promote apoptosis; loss of REEP2 membrane association—caused by specific missense mutations—underlies hereditary spastic paraplegia SPG72."},"narrative":{"mechanistic_narrative":"REEP2 is an integral endoplasmic reticulum membrane protein that shapes the peripheral tubular ER through membrane binding and modulates the trafficking and signaling of secretory cargoes [PMID:24388663, PMID:24098485]. Its membrane association is the core determinant of function: a dominant-negative variant (p.Val36Glu) blocks normal membrane binding of wild-type protein and a recessive variant (p.Phe72Tyr) lowers mutant affinity for membranes, and loss of this association causes hereditary spastic paraplegia SPG72 [PMID:24388663]. Beyond ER morphogenesis, REEP2 physically associates with select GPCRs — the T1R2/T1R3 sweet receptor subunits and α2C adrenergic receptors — where it enhances signaling by recruiting receptors into lipid raft microdomains and by augmenting ER cargo capacity and surface delivery rather than by globally increasing surface expression [PMID:20943918, PMID:24098485]. REEP2 functions in an integrated program of ER remodeling that supports regulated secretion: it is restricted to neuronal and neuroendocrine exocytotic tissues [PMID:24355597], promotes ER-to-Golgi transport of secretory cargoes from ER exit sites [PMID:41292834], and is transcriptionally upregulated by p53 upon DNA damage to extend tubular ER, build ER-mitochondria contacts, and drive Ca2+ transfer-dependent apoptosis [PMID:30030520]. REEP2 also acts as a negative regulator of adipogenic differentiation in mesenchymal stem cells [PMID:36879811].","teleology":[{"year":2010,"claim":"Established that REEP2 is not merely structural but actively modulates GPCR signaling, by showing it physically associates with sweet receptor subunits and recruits receptors into lipid rafts.","evidence":"Reciprocal co-IP, lipid raft fractionation, and siRNA knockdown with heterologous receptor functional assays in taste/GLUTag cells","pmids":["20943918"],"confidence":"High","gaps":["Does not define the structural basis of REEP2-receptor binding","Mechanism of raft recruitment versus direct receptor stabilization not resolved"]},{"year":2013,"claim":"Localized REEP2 to the ER and showed it interacts with and alters glycosidic processing of specific GPCR cargoes (α2C but not α2A AR), framing it as a selective ER cargo-capacity factor.","evidence":"Immunolocalization, co-IP, glycosylation processing assays, and dominant-negative C-terminal truncation in cell models","pmids":["24098485"],"confidence":"Medium","gaps":["REEP2-specific conclusions partially inferred from shared REEP1 experiments","Basis of cargo selectivity (α2C vs α2A) unknown"]},{"year":2013,"claim":"Defined the tissue scope of REEP2, restricting expression to neuronal and neuroendocrine exocytotic tissues and pointing to a specialized secretory role.","evidence":"Validated antibody immunoblotting, immunofluorescence, RT-PCR, and microarray across tissues","pmids":["24355597"],"confidence":"Medium","gaps":["Tissue expression does not establish cell-type-specific function","Subcellular distribution within secretory cells not detailed"]},{"year":2014,"claim":"Demonstrated that membrane association is mechanistically required for REEP2 function and that disrupting it causes disease, defining the basis of SPG72.","evidence":"In vitro membrane-binding assays with defined mutant alleles, fibroblast ER morphology analysis, and exome sequencing with functional validation","pmids":["24388663"],"confidence":"High","gaps":["No structural model of the membrane-binding interface","Connection between ER-shaping defect and axonal/neuronal pathology not mechanistically traced"]},{"year":2018,"claim":"Placed REEP2 in a stress-responsive pathway, showing p53-driven upregulation extends tubular ER and promotes ER-mitochondria Ca2+ transfer and apoptosis.","evidence":"p53 reporter assays, live-cell ER imaging, ER-mitochondria contact quantification, Ca2+ transfer and apoptosis readouts with knockdown/overexpression","pmids":["30030520"],"confidence":"Medium","gaps":["REEP2 contribution shared with REEP1 and EI24","Whether REEP2 directly forms or only enables contact sites unresolved"]},{"year":2023,"claim":"Identified a developmental role for REEP2 as a negative regulator of adipogenic differentiation, expanding its function beyond neuronal secretion.","evidence":"Gene expression analysis, siRNA/overexpression during induced adipogenesis, and HDAC inhibition with chidamide in BM-MSCs","pmids":["36879811"],"confidence":"Medium","gaps":["Molecular mechanism linking REEP2 to adipogenic suppression not defined","Whether ER-shaping activity underlies the effect unknown"]},{"year":2025,"claim":"Connected REEP2-mediated ER-to-Golgi cargo transport to a tumor-promoting secretory program controlled by a ZEB1/miR-183/miR-193a regulatory axis.","evidence":"In vivo CRISPRi screen, miRNA functional assays, ER-to-Golgi trafficking assays, and orthotopic syngeneic mouse model (preprint)","pmids":["41292834"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Specific secreted cargoes dependent on REEP2 not fully enumerated","Direct biochemical role at ER exit sites not resolved"]},{"year":null,"claim":"How REEP2 mechanistically couples its ER-shaping membrane activity to cargo selection, raft recruitment, and contact-site formation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the membrane-binding or cargo-binding interfaces","Unclear whether tubulation, trafficking, and GPCR modulation are one mechanism or separable activities","Causal chain from ER defect to neuronal axonopathy in SPG72 undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,3]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]}],"complexes":[],"partners":["T1R2","T1R3","REEP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BRK0","full_name":"Receptor expression-enhancing protein 2","aliases":[],"length_aa":252,"mass_kda":28.3,"function":"Required for endoplasmic reticulum (ER) network formation, shaping and remodeling. May enhance the cell surface expression of odorant receptors (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9BRK0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/REEP2","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000132563","cell_line_id":"CID001521","localizations":[{"compartment":"er","grade":3},{"compartment":"nuclear_punctae","grade":2}],"interactors":[{"gene":"REEP4","stoichiometry":10.0},{"gene":"MED18","stoichiometry":10.0},{"gene":"TPR","stoichiometry":4.0},{"gene":"COPE","stoichiometry":0.2},{"gene":"RCBTB2","stoichiometry":0.2},{"gene":"LMNB1","stoichiometry":0.2},{"gene":"NUP50","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001521","total_profiled":1310},"omim":[{"mim_id":"620606","title":"SPASTIC PARAPLEGIA 72B, AUTOSOMAL RECESSIVE; SPG72B","url":"https://www.omim.org/entry/620606"},{"mim_id":"615625","title":"SPASTIC PARAPLEGIA 72A, AUTOSOMAL DOMINANT; SPG72A","url":"https://www.omim.org/entry/615625"},{"mim_id":"609347","title":"RECEPTOR EXPRESSION-ENHANCING PROTEIN 2; REEP2","url":"https://www.omim.org/entry/609347"},{"mim_id":"609139","title":"RECEPTOR EXPRESSION-ENHANCING PROTEIN 1; REEP1","url":"https://www.omim.org/entry/609139"},{"mim_id":"270800","title":"SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE; SPG5A","url":"https://www.omim.org/entry/270800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":141.9},{"tissue":"choroid plexus","ntpm":97.9}],"url":"https://www.proteinatlas.org/search/REEP2"},"hgnc":{"alias_symbol":["SGC32445","SPG72","Yip2d"],"prev_symbol":["C5orf19"]},"alphafold":{"accession":"Q9BRK0","domains":[{"cath_id":"-","chopping":"1-80","consensus_level":"medium","plddt":74.8718,"start":1,"end":80}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRK0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRK0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRK0-F1-predicted_aligned_error_v6.png","plddt_mean":64.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=REEP2","jax_strain_url":"https://www.jax.org/strain/search?query=REEP2"},"sequence":{"accession":"Q9BRK0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BRK0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BRK0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRK0"}},"corpus_meta":[{"pmid":"30030520","id":"PMC_30030520","title":"DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling.","date":"2018","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30030520","citation_count":112,"is_preprint":false},{"pmid":"24388663","id":"PMC_24388663","title":"Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24388663","citation_count":79,"is_preprint":false},{"pmid":"24098485","id":"PMC_24098485","title":"REEPs are membrane shaping adapter proteins that modulate specific g protein-coupled receptor trafficking by affecting ER cargo capacity.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24098485","citation_count":70,"is_preprint":false},{"pmid":"20943918","id":"PMC_20943918","title":"REEP2 enhances sweet receptor function by recruitment to lipid rafts.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20943918","citation_count":41,"is_preprint":false},{"pmid":"7961732","id":"PMC_7961732","title":"Rab3A effector domain peptides induce insulin exocytosis via a specific interaction with a cytosolic protein doublet.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7961732","citation_count":38,"is_preprint":false},{"pmid":"24355597","id":"PMC_24355597","title":"REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues.","date":"2013","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/24355597","citation_count":33,"is_preprint":false},{"pmid":"20217129","id":"PMC_20217129","title":"Identification of genes related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells.","date":"2010","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20217129","citation_count":27,"is_preprint":false},{"pmid":"30838228","id":"PMC_30838228","title":"An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models.","date":"2015","source":"Movement disorders clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/30838228","citation_count":26,"is_preprint":false},{"pmid":"36191880","id":"PMC_36191880","title":"The REEP family of proteins: Molecular targets and role in pathophysiology.","date":"2022","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/36191880","citation_count":25,"is_preprint":false},{"pmid":"28491902","id":"PMC_28491902","title":"De novo REEP2 missense mutation in pure hereditary spastic paraplegia.","date":"2017","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28491902","citation_count":11,"is_preprint":false},{"pmid":"38532632","id":"PMC_38532632","title":"M6A-mediated molecular patterns and tumor microenvironment infiltration characterization in nasopharyngeal carcinoma.","date":"2024","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38532632","citation_count":8,"is_preprint":false},{"pmid":"36879811","id":"PMC_36879811","title":"Chidamide suppresses adipogenic differentiation of bone marrow derived mesenchymal stem cells via increasing REEP2 expression.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36879811","citation_count":7,"is_preprint":false},{"pmid":"32502168","id":"PMC_32502168","title":"Genetic locus responsible for diabetic phenotype in the insulin hyposecretion (ihs) mouse.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32502168","citation_count":7,"is_preprint":false},{"pmid":"31236401","id":"PMC_31236401","title":"Novel ATL1 mutation in a Chinese family with hereditary spastic paraplegia: A case report and review of literature.","date":"2019","source":"World journal of clinical cases","url":"https://pubmed.ncbi.nlm.nih.gov/31236401","citation_count":3,"is_preprint":false},{"pmid":"33526816","id":"PMC_33526816","title":"A Nepalese family with an REEP2 mutation: clinical and genetic study.","date":"2021","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33526816","citation_count":1,"is_preprint":false},{"pmid":"41292834","id":"PMC_41292834","title":"EMT activates ER-to-Golgi trafficking through upregulation of REEP2 to promote lung cancer progression.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41292834","citation_count":0,"is_preprint":false},{"pmid":"41815155","id":"PMC_41815155","title":"Mature tertiary lymphoid structures tumor microenvironment-based risk model to assess patients with pancreatic ductal adenocarcinoma.","date":"2026","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41815155","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10450,"output_tokens":1941,"usd":0.030232,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8855,"output_tokens":2706,"usd":0.055962,"stage2_stop_reason":"end_turn"},"total_usd":0.086194,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"REEP2 is an ER-shaping protein that binds membranes; a dominant-negative missense variant (p.Val36Glu) inhibits normal membrane binding of wild-type REEP2, while a recessive missense variant (p.Phe72Tyr) decreases the mutant protein's affinity for membranes, collectively demonstrating that membrane association is required for REEP2 function and that loss of this association underlies hereditary spastic paraplegia (SPG72).\",\n      \"method\": \"In vitro membrane-binding assays, fibroblast ER morphology analysis, exome sequencing with functional validation of mutant alleles\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro membrane-binding assay with defined mutant alleles and cellular ER morphology phenotype, single lab but two orthogonal functional methods\",\n      \"pmids\": [\"24388663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"REEP2 is an integral membrane protein expressed in taste cells that physically associates with both subunits of the T1R2/T1R3 sweet receptor; it enhances sweet and bitter receptor responses not by increasing cell surface expression but by recruiting the receptors into lipid raft microdomains near the apical region of taste cells, thereby improving GPCR signaling.\",\n      \"method\": \"Co-immunoprecipitation (physical association), lipid raft fractionation, siRNA knockdown of endogenous REEP2 in GLUTag cells, heterologous receptor functional assays\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, biochemical fractionation, and loss-of-function with defined functional readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20943918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"REEP1 and REEP2 are localized primarily to the ER (not plasma membranes); they interact with and alter glycosidic processing of α2C adrenergic receptors (but not α2A ARs), enhancing ER cargo capacity and surface expression of select GPCRs; a C-terminal truncation mutant of REEP1 (SPG31 allele) abolishes this interaction, indicating the C-terminus is required for cargo interaction.\",\n      \"method\": \"Immunolocalization, co-immunoprecipitation, glycosylation/biochemical processing assays, dominant-negative mutant expression\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and biochemical glycosylation assay in single lab; REEP2 included alongside REEP1 and REEP6, so REEP2-specific conclusions are partially inferred\",\n      \"pmids\": [\"24098485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DNA damage induces p53-mediated transcriptional upregulation of REEP1 and REEP2, which drives extension of the peripheral tubular ER; this promotes formation of ER-mitochondria contacts (via EI24–VDAC2 interaction), facilitates Ca2+ transfer from ER to mitochondria, and promotes apoptosis.\",\n      \"method\": \"p53 transcriptional reporter assays, live-cell imaging of ER morphology, ER-mitochondria contact site quantification, Ca2+ transfer assays, apoptosis readouts following knockdown/overexpression\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple cellular imaging and functional assays in single lab; REEP2 role established alongside REEP1 and EI24, so REEP2-specific contribution is partially shared\",\n      \"pmids\": [\"30030520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"REEP1 and REEP2 protein expression is restricted to neuronal tissues (brain, spinal cord) and tissues with neuronal-like exocytosis (testes, pituitary, adrenal gland), consistent with a specialized role in neuronal/exocytotic cell function.\",\n      \"method\": \"Immunoblotting with validated monoclonal antibodies, immunofluorescence microscopy, RT-PCR, gene expression microarray\",\n      \"journal\": \"Brain Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated antibody immunoblotting and immunofluorescence across multiple tissues, single lab, two orthogonal methods\",\n      \"pmids\": [\"24355597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"REEP2 acts as a negative regulator of adipogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs); REEP2 expression is decreased during adipogenesis, and restoring REEP2 expression (via chidamide treatment) suppresses adipocyte development.\",\n      \"method\": \"Gene expression analysis, siRNA/overexpression in BM-MSCs during induced adipogenesis, pharmacological HDAC inhibition with chidamide\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss- and gain-of-function with defined cellular phenotype, single lab, functional readout of adipogenesis inhibition\",\n      \"pmids\": [\"36879811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZEB1 upregulates REEP2 expression through repression of miR-183 and miR-193a (which normally suppress REEP2); elevated REEP2 promotes transport of secretory cargoes from ER exit sites (ERES) to the Golgi, augmenting secretion of pro-tumorigenic factors that drive cancer cell proliferation, migration, and myeloid-derived suppressor cell infiltration.\",\n      \"method\": \"CRISPRi in vivo screen, miRNA functional assays, ER-to-Golgi trafficking assays, orthotopic syngeneic mouse model, secretion/functional readouts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo CRISPRi screen plus mechanistic trafficking assays and miRNA validation, single lab preprint not yet peer-reviewed\",\n      \"pmids\": [\"41292834\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"REEP2 is an integral ER-shaping membrane protein that tubulates the peripheral ER by binding membranes; it physically associates with select GPCRs (including sweet taste receptor subunits T1R2/T1R3 and α2C adrenergic receptors) to enhance their signaling by recruiting them to lipid rafts or augmenting ER cargo capacity, and it promotes ER-to-Golgi trafficking of secretory cargoes; under DNA damage, p53-driven upregulation of REEP2 extends tubular ER and facilitates ER-mitochondria Ca2+ transfer to promote apoptosis; loss of REEP2 membrane association—caused by specific missense mutations—underlies hereditary spastic paraplegia SPG72.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"REEP2 is an integral endoplasmic reticulum membrane protein that shapes the peripheral tubular ER through membrane binding and modulates the trafficking and signaling of secretory cargoes [#0, #2]. Its membrane association is the core determinant of function: a dominant-negative variant (p.Val36Glu) blocks normal membrane binding of wild-type protein and a recessive variant (p.Phe72Tyr) lowers mutant affinity for membranes, and loss of this association causes hereditary spastic paraplegia SPG72 [#0]. Beyond ER morphogenesis, REEP2 physically associates with select GPCRs — the T1R2/T1R3 sweet receptor subunits and \\u03b12C adrenergic receptors — where it enhances signaling by recruiting receptors into lipid raft microdomains and by augmenting ER cargo capacity and surface delivery rather than by globally increasing surface expression [#1, #2]. REEP2 functions in an integrated program of ER remodeling that supports regulated secretion: it is restricted to neuronal and neuroendocrine exocytotic tissues [#4], promotes ER-to-Golgi transport of secretory cargoes from ER exit sites [#6], and is transcriptionally upregulated by p53 upon DNA damage to extend tubular ER, build ER-mitochondria contacts, and drive Ca2+ transfer-dependent apoptosis [#3]. REEP2 also acts as a negative regulator of adipogenic differentiation in mesenchymal stem cells [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that REEP2 is not merely structural but actively modulates GPCR signaling, by showing it physically associates with sweet receptor subunits and recruits receptors into lipid rafts.\",\n      \"evidence\": \"Reciprocal co-IP, lipid raft fractionation, and siRNA knockdown with heterologous receptor functional assays in taste/GLUTag cells\",\n      \"pmids\": [\"20943918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the structural basis of REEP2-receptor binding\", \"Mechanism of raft recruitment versus direct receptor stabilization not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Localized REEP2 to the ER and showed it interacts with and alters glycosidic processing of specific GPCR cargoes (\\u03b12C but not \\u03b12A AR), framing it as a selective ER cargo-capacity factor.\",\n      \"evidence\": \"Immunolocalization, co-IP, glycosylation processing assays, and dominant-negative C-terminal truncation in cell models\",\n      \"pmids\": [\"24098485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"REEP2-specific conclusions partially inferred from shared REEP1 experiments\", \"Basis of cargo selectivity (\\u03b12C vs \\u03b12A) unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the tissue scope of REEP2, restricting expression to neuronal and neuroendocrine exocytotic tissues and pointing to a specialized secretory role.\",\n      \"evidence\": \"Validated antibody immunoblotting, immunofluorescence, RT-PCR, and microarray across tissues\",\n      \"pmids\": [\"24355597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue expression does not establish cell-type-specific function\", \"Subcellular distribution within secretory cells not detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that membrane association is mechanistically required for REEP2 function and that disrupting it causes disease, defining the basis of SPG72.\",\n      \"evidence\": \"In vitro membrane-binding assays with defined mutant alleles, fibroblast ER morphology analysis, and exome sequencing with functional validation\",\n      \"pmids\": [\"24388663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the membrane-binding interface\", \"Connection between ER-shaping defect and axonal/neuronal pathology not mechanistically traced\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed REEP2 in a stress-responsive pathway, showing p53-driven upregulation extends tubular ER and promotes ER-mitochondria Ca2+ transfer and apoptosis.\",\n      \"evidence\": \"p53 reporter assays, live-cell ER imaging, ER-mitochondria contact quantification, Ca2+ transfer and apoptosis readouts with knockdown/overexpression\",\n      \"pmids\": [\"30030520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"REEP2 contribution shared with REEP1 and EI24\", \"Whether REEP2 directly forms or only enables contact sites unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a developmental role for REEP2 as a negative regulator of adipogenic differentiation, expanding its function beyond neuronal secretion.\",\n      \"evidence\": \"Gene expression analysis, siRNA/overexpression during induced adipogenesis, and HDAC inhibition with chidamide in BM-MSCs\",\n      \"pmids\": [\"36879811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking REEP2 to adipogenic suppression not defined\", \"Whether ER-shaping activity underlies the effect unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected REEP2-mediated ER-to-Golgi cargo transport to a tumor-promoting secretory program controlled by a ZEB1/miR-183/miR-193a regulatory axis.\",\n      \"evidence\": \"In vivo CRISPRi screen, miRNA functional assays, ER-to-Golgi trafficking assays, and orthotopic syngeneic mouse model (preprint)\",\n      \"pmids\": [\"41292834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Specific secreted cargoes dependent on REEP2 not fully enumerated\", \"Direct biochemical role at ER exit sites not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How REEP2 mechanistically couples its ER-shaping membrane activity to cargo selection, raft recruitment, and contact-site formation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the membrane-binding or cargo-binding interfaces\", \"Unclear whether tubulation, trafficking, and GPCR modulation are one mechanism or separable activities\", \"Causal chain from ER defect to neuronal axonopathy in SPG72 undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"T1R2\", \"T1R3\", \"REEP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}