{"gene":"EMP1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1999,"finding":"The Tmp gene (encoding EMP1) is a direct transcriptional target of the c-Myc oncoprotein. The c-Myc–Max protein complex binds to a CACGTG E-box element located in the first intron of Tmp, and an inducible MycER fusion protein activates the endogenous Tmp gene. Overexpression of Tmp in fibroblasts induces rapidly growing tumors in nude mice, indicating tumorigenic activity.","method":"Reporter gene assays with Tmp promoter/intron constructs, EMSA (c-Myc-Max binding to CACGTG element), inducible MycER system for endogenous gene activation, nude mouse xenograft tumorigenic assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (reporter assay, EMSA, inducible system, in vivo xenograft) in a single focused study on this gene","pmids":["10207076"],"is_preprint":false},{"year":1997,"finding":"CL-20/EMP1 encodes an integral membrane protein of 157 amino acids with four hydrophobic transmembrane domains, placing it in the PMP22 gene family. The second hydrophobic domain (fourth exon) is highly conserved among CL-20, EMP-1, and PMP22, suggesting a functional role. EMP1 mRNA is abundant in squamous-differentiated bronchial epithelial cells and is repressed by retinoic acid. The human gene maps to chromosome 12p12.","method":"cDNA cloning and sequencing, Northern analysis, FISH chromosomal mapping, retinoic acid treatment of normal human bronchial epithelial cells","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning, expression analysis, and chromosomal mapping; multiple orthogonal methods but foundational characterization rather than deep mechanistic dissection","pmids":["9126480"],"is_preprint":false},{"year":1998,"finding":"Chromosomal mapping identified Tmp (Emp1) as a member of a novel mammalian membrane glycoprotein family with four transmembrane domains related to Pmp22. Mouse Tmp was mapped to chromosome 6, and it was expressed in highly proliferative cell types. The gene family is proposed to have evolved through chromosomal duplications.","method":"cDNA isolation, chromosomal mapping by linkage analysis and fluorescence in situ hybridization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal mapping and cloning; complements the human characterization paper","pmids":["9615230"],"is_preprint":false},{"year":2005,"finding":"EMP1 (EMP-1) localizes to intercellular borders in a liver stem cell line (Lig-8) and to epithelial junctions (bile duct epithelia, oval cell ductules, bile canaliculi) in the liver harboring proliferating oval cells. Co-localization with dipeptidyl peptidase IV confirmed junctional localization at bile canaliculi, establishing EMP1 as a junctional protein.","method":"Immunofluorescence and immunohistochemistry with anti-EMP1 antiserum on cell monolayers and liver tissue sections; co-localization with dipeptidyl peptidase IV marker","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional context (junctional marker), single lab, two co-localization markers","pmids":["16036215"],"is_preprint":false},{"year":2014,"finding":"SOS1 acts through the Ras/MEK/ERK pathway to transcriptionally upregulate EMP1 in human bronchial epithelial cells (16HBE). EMP1 is indispensable for tight junction formation and function in 16HBE cells and in a human airway basal progenitor-like cell line (BCi-NS1.1); RNAi knockdown of EMP1 disrupts tight junction assembly during airway morphogenesis.","method":"RNAi screen for GEFs in 16HBE cells, global microarray analysis identifying EMP1 as SOS1/Ras/MEK/ERK transcriptional target, EMP1 knockdown with tight junction functional readouts in two human airway cell lines","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (RNAi screen + pathway validation), functional readout (tight junction formation), two orthogonal cell models, single lab","pmids":["25394671"],"is_preprint":false},{"year":2017,"finding":"EMP1 loss in bladder cancer cells promotes migration and confers resistance to ferroptosis/oxidative stress by increasing PPARG expression and its activation, leading to upregulation of pFAK(Y397) (promoting migration) and SLC7A11 (promoting anti-ferroptotic cell death). EMP1-deficient cells were sensitized to PPARG ligand; FABP4 knockdown mitigated this effect.","method":"EMP1 knockdown/overexpression in BCa cells, Western blot for PPARG/pFAK/SLC7A11, migration assays, ferroptosis/oxidative stress assays, PPARG ligand treatment, FABP4 siRNA rescue experiments","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway (EMP1→PPARG→pFAK/SLC7A11), rescue experiments, single lab","pmids":["35850179"],"is_preprint":false},{"year":2020,"finding":"EMP1 overexpression in ovarian cancer cells promotes proliferation, invasion, and EMT by activating the RAS/RAF/MAPK/c-JUN signaling pathway, as shown by increased protein levels of these components after EMP1 overexpression and inhibition of these phenotypes by EMP1 siRNA.","method":"siRNA interference, colony formation, migration and invasion assays, Western blot for RAS/RAF/MAPK/c-JUN pathway components","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss- and gain-of-function with pathway readout (Western blot), single lab, multiple orthogonal phenotypic assays","pmids":["32210572"],"is_preprint":false},{"year":2019,"finding":"EMP1 promotes glioma cell proliferation, migration, invasion, and stemness through activation of the PI3K-AKT signaling pathway and regulation of CD44 expression in glioma stem cells. Silencing EMP1 inhibited these processes by suppressing PI3K-AKT signaling.","method":"EMP1 siRNA knockdown in glioma cells, invasion/proliferation assays, Western blot for PI3K-AKT pathway, CD44 expression analysis in glioma stem cells","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with pathway and stemness readouts, single lab","pmids":["31111534"],"is_preprint":false},{"year":2012,"finding":"EMP1 overexpression in NSCLC cell line PC9 promotes proliferation and activates the PI3K/AKT signaling pathway; EMP1 promoted growth of PC9 xenografts in nude mice.","method":"Recombinant adenovirus overexpression of EMP1, Ki67 staining for proliferation, Western blot for PI3K/AKT pathway, subcutaneous xenograft tumor model","journal":"Journal of Huazhong University of Science and Technology. Medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, gain-of-function only, PI3K/AKT pathway assignment based on Western blot without deeper mechanistic validation","pmids":["23271282"],"is_preprint":false},{"year":2013,"finding":"EMP1 overexpression in prostate cancer PC-3 cells increases apoptosis and decreases migration and invasion, associated with higher caspase-9 and lower VEGFC protein expression. EMP1 overexpression in nasopharyngeal cancer CNE2 cells similarly increases apoptosis, decreases migration/invasion, elevates caspase-9, and reduces VEGFC. EMP1 overexpression in breast cancer MCF-7 cells shows the same pattern.","method":"Lentiviral EMP1 overexpression, MTT/migration/invasion assays, Western blot for caspase-9 and VEGFC, flow cytometry for apoptosis","journal":"Tumour biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain-of-function only in each cancer type, mechanistic link to caspase-9/VEGFC by Western blot, single lab per paper, no rescue or epistasis","pmids":["24338711","24292952","24402572"],"is_preprint":false},{"year":2002,"finding":"Overexpression of EMP1 in the esophageal cancer cell line EC9706 accelerated cell growth and was linked to induction of S-phase cell cycle arrest.","method":"Eukaryotic vector transfection, Western blot/RT-PCR confirmation, cell growth curve, FACS cell cycle analysis","journal":"Ai zheng = Chinese journal of cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single gain-of-function experiment, single lab, no pathway mechanism identified","pmids":["12451984"],"is_preprint":false},{"year":2022,"finding":"EMP1-high (HRC) residual tumor cells are responsible for metastatic recurrence in colorectal cancer. Using Emp1 as a marker, genetic ablation of EMP1-high cells prevented metastatic recurrence in a mouse model of microsatellite-stable CRC after primary tumor surgery. These cells gave rise to LGR5+ stem-like tumor cells over time during metastatic outgrowth, and their micrometastases transitioned from T-cell infiltrated to progressively immune-excluded.","method":"Single-cell transcriptomics, mouse model of CRC with surgical resection, genetic cell ablation of EMP1-high cells, tumor cell tracking over time in vivo","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic ablation with specific metastatic relapse phenotype, single-cell transcriptomics, in vivo tracking, corroborated by multiple orthogonal approaches in one rigorous study","pmids":["36352230"],"is_preprint":false},{"year":2023,"finding":"The histone methyltransferase SMYD3 epigenetically represses EMP1 expression in gastric cancer cells in an H4K20me3-dependent manner. ChIP assays showed SMYD3-mediated H4K20me3 deposition at the EMP1 locus. EMP1, in turn, inhibits GC cell proliferation and reduces p-Akt (S473) levels.","method":"ChIP assay for H4K20me3 at EMP1 locus, SMYD3 shRNA knockdown, EMP1 gain-of-function and rescue experiments, Western blot for p-Akt (S473)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay with gain/loss-of-function rescue experiments, single lab, direct epigenetic mechanism identified","pmids":["37386026"],"is_preprint":false},{"year":2021,"finding":"ETV4 binds to the EMP1 promoter and positively regulates EMP1 transcription. Knockdown of ETV4 reduced EMP1 expression, inhibited PI3K/AKT/mTOR pathway activity, and promoted autophagy-dependent apoptosis in GBM cells; overexpressing EMP1 partially reversed these effects.","method":"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP) for ETV4 at EMP1 promoter, ETV4 knockdown with EMP1 rescue overexpression, Western blot for PI3K/AKT/mTOR and autophagy/apoptosis markers, TUNEL assay","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + luciferase reporter + rescue experiments define transcriptional regulation and downstream pathway, single lab","pmids":["34976153"],"is_preprint":false},{"year":2021,"finding":"miR-95-3p promotes cisplatin resistance in gastric cancer by directly targeting EMP1 (confirmed by dual luciferase assay), suppressing EMP1 expression, and thereby activating PI3K/AKT signaling and promoting EMT and drug-resistance. EMP1 knockdown phenocopied miR-95-3p overexpression.","method":"Dual luciferase reporter assay to confirm miR-95-3p targeting of EMP1, qRT-PCR, Western blot, BrdU/MTT proliferation assays, transwell invasion/migration, in vivo tumorigenic experiments","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA-target validation by luciferase assay + loss-of-function phenotypic rescue, single lab","pmids":["33714198"],"is_preprint":false},{"year":2019,"finding":"TFF3 signaling in Y79 retinoblastoma cells activates p53 and downstream miR-34a, which in turn inhibits EMP1 expression (as a predicted miR-34a target). EMP1 knockdown decreases viability and proliferation while increasing apoptosis (partially caspase-3/7 dependent) in Y79 cells; EMP1 overexpression produces the opposite effects. EMP1 overexpressing cells also show increased colony formation and larger CAM tumors.","method":"pG13-luciferase reporter for p53 activity, Western blot, WST-1 and BrdU assays, DAPI counts, caspase-3/7 assay, colony formation, soft agarose, in ovo CAM assay, EMP1 knockdown/overexpression","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays placing EMP1 downstream of TFF3/p53/miR-34a; epistasis established by reporter and rescue experiments, single lab","pmids":["31450568"],"is_preprint":false},{"year":2025,"finding":"EMP1 expression in TNBC cells is required for cancer-associated fibroblast (CAF) infiltration in the tumor microenvironment. Mechanistically, EMP1 knockdown substantially decreased IL-6 secretion from TNBC cells through the NF-κB signaling pathway, reducing CAF proliferation and inhibiting TNBC progression and metastasis in vitro and in vivo.","method":"Cell co-culture assays, xenograft tumor experiments, EMP1 loss-of-function and gain-of-function, RNA sequencing, rescue assays, IL-6 ELISA, Western blot for NF-κB pathway","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with in vivo validation and rescue; mechanistic pathway (EMP1→NF-κB→IL-6→CAF) identified by multiple orthogonal methods, single lab","pmids":["40016223"],"is_preprint":false},{"year":2020,"finding":"EMP1 promotes osteosarcoma malignant progression by upregulating IRX2 and subsequently MMP9. Knockdown of EMP1 inhibited migration and invasion; overexpression of EMP1 increased IRX2 and MMP9 protein levels; rescue experiments confirmed IRX2 is involved in EMP1-regulated osteosarcoma progression.","method":"Transwell and wound healing migration/invasion assays, EMP1 knockdown/overexpression, Western blot for IRX2 and MMP9, rescue experiments with IRX2","journal":"Panminerva medica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, axis assignment by Western blot and partial rescue, no direct binding or promoter experiments","pmids":["32716150"],"is_preprint":false},{"year":2026,"finding":"In metastatic colorectal cancer, KRAS-G12D inhibition converts EMP1+ tumor cells to a WNT-driven LGR5+ stem cell-like state through a shift in transcription factor usage with limited chromatin remodeling, occurring within hours of treatment. Genetic ablation of the LGR5+ population after forced conversion reduced metastatic burden and prolonged survival.","method":"Preclinical colorectal cancer mouse models, RMC-9945 RAS(ON) inhibitor treatment, transcriptomic cell-state profiling, genetic ablation of LGR5+ cells, chromatin remodeling analysis","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic experiments with cell-state tracking, mechanistic cell plasticity pathway established, single lab","pmids":["41128661"],"is_preprint":false}],"current_model":"EMP1 (also known as TMP/CL-20) is an integral tetraspan membrane glycoprotein (PMP22 family, four transmembrane domains) whose expression is transcriptionally driven by c-Myc (via a first-intron CACGTG E-box) and by the SOS1/Ras/MEK/ERK pathway (which induces EMP1 to enable tight junction assembly in airway epithelium), and is epigenetically silenced by SMYD3-mediated H4K20me3; it localizes to epithelial junctions in the liver, where it marks a high-relapse colorectal cancer cell state (HRC/EMP1+) that transitions to LGR5+ stem-like cells under KRAS inhibition, and it exerts context-dependent tumor-suppressive or oncogenic effects in various cancers by modulating the PI3K/AKT, MAPK, and NF-κB pathways, as well as PPARG-driven ferroptosis resistance and IL-6-mediated cancer-associated fibroblast infiltration."},"narrative":{"mechanistic_narrative":"EMP1 (TMP/CL-20) is a tetraspan integral membrane glycoprotein of the PMP22 family that functions at epithelial cell junctions and as a regulator of epithelial proliferation, cell-state plasticity, and cancer progression [PMID:9126480, PMID:16036215]. It localizes to intercellular borders and epithelial junctions, including bile duct epithelia and bile canaliculi, marking it as a junctional protein [PMID:16036215], and it is indispensable for tight junction assembly during airway morphogenesis downstream of SOS1/Ras/MEK/ERK signaling [PMID:25394671]. EMP1 transcription is controlled at multiple levels: it is a direct c-Myc-Max target through a CACGTG E-box in its first intron, conferring tumorigenic activity when overexpressed [PMID:10207076]; it is induced by ETV4 [PMID:34976153]; and it is silenced epigenetically by SMYD3-mediated H4K20me3 deposition and post-transcriptionally by miR-95-3p and miR-34a [PMID:37386026, PMID:33714198, PMID:31450568]. EMP1 exerts context-dependent effects on tumor behavior by modulating the PI3K/AKT/mTOR, RAS/RAF/MAPK, and NF-κB pathways: it activates PI3K-AKT and CD44-linked stemness in glioma [PMID:31111534], drives RAS/RAF/MAPK/c-JUN-dependent proliferation and EMT in ovarian cancer [PMID:32210572], and promotes IL-6 secretion via NF-κB to recruit cancer-associated fibroblasts in triple-negative breast cancer [PMID:40016223], while opposing AKT signaling and proliferation in gastric cancer [PMID:37386026]. EMP1 loss confers ferroptosis resistance through PPARG-driven upregulation of pFAK and SLC7A11 in bladder cancer [PMID:35850179]. In microsatellite-stable colorectal cancer, EMP1 marks a high-relapse residual tumor cell state whose genetic ablation prevents metastatic recurrence, and these EMP1+ cells convert to WNT-driven LGR5+ stem-like cells, including rapidly upon KRAS-G12D inhibition [PMID:36352230, PMID:41128661].","teleology":[{"year":1997,"claim":"Established the molecular identity of EMP1 as a four-transmembrane PMP22-family membrane protein, providing the structural framework for all later functional work.","evidence":"cDNA cloning/sequencing, Northern analysis, and FISH mapping in human bronchial epithelial cells","pmids":["9126480"],"confidence":"Medium","gaps":["No membrane topology confirmed experimentally","Function of the protein not addressed","Binding partners unknown"]},{"year":1998,"claim":"Confirmed EMP1 as part of a duplicated mammalian membrane glycoprotein family expressed in proliferative cells, hinting at a proliferation-linked role.","evidence":"cDNA isolation and chromosomal mapping by linkage and FISH in mouse","pmids":["9615230"],"confidence":"Medium","gaps":["Correlation with proliferation not mechanistically tested","No functional assay"]},{"year":1999,"claim":"Answered how EMP1 connects to oncogenic transcription by showing it is a direct c-Myc target with intrinsic tumorigenic activity.","evidence":"Reporter assays, EMSA for c-Myc-Max binding to an intronic E-box, inducible MycER activation, and nude mouse xenografts","pmids":["10207076"],"confidence":"High","gaps":["Downstream mechanism of tumorigenicity not defined","Did not address normal physiological role"]},{"year":2005,"claim":"Defined EMP1 as a bona fide junctional protein by localizing it to epithelial cell-cell borders and bile canaliculi.","evidence":"Immunofluorescence/IHC with anti-EMP1 antiserum and co-localization with dipeptidyl peptidase IV in liver tissue and a liver stem cell line","pmids":["16036215"],"confidence":"Medium","gaps":["Functional role at junctions not tested","No interacting junctional proteins identified"]},{"year":2014,"claim":"Provided a physiological function by placing EMP1 downstream of SOS1/Ras/MEK/ERK as an essential factor for tight junction assembly.","evidence":"GEF RNAi screen, microarray identification of EMP1 as pathway target, and EMP1 knockdown with tight junction readouts in two human airway cell lines","pmids":["25394671"],"confidence":"High","gaps":["Molecular mechanism by which EMP1 promotes junction assembly unknown","Direct junctional partners not identified"]},{"year":2019,"claim":"Showed EMP1 can act oncogenically through PI3K-AKT signaling and stemness, broadening its role beyond junction biology.","evidence":"EMP1 siRNA knockdown in glioma cells with proliferation/invasion assays and PI3K-AKT and CD44 readouts","pmids":["31111534"],"confidence":"Medium","gaps":["No direct link between EMP1 and PI3K-AKT components","Gain-of-function not included"]},{"year":2020,"claim":"Extended EMP1 oncogenic signaling to the RAS/RAF/MAPK/c-JUN axis driving proliferation, invasion, and EMT.","evidence":"siRNA and overexpression in ovarian cancer cells with phenotypic assays and Western blot of pathway components","pmids":["32210572"],"confidence":"Medium","gaps":["Pathway activation inferred from protein levels, not direct binding","Tissue specificity of the axis unclear"]},{"year":2022,"claim":"Identified EMP1 as a functional marker of high-relapse residual tumor cells whose elimination prevents metastatic recurrence.","evidence":"Single-cell transcriptomics, genetic ablation of EMP1-high cells, and in vivo tracking in a microsatellite-stable CRC mouse model","pmids":["36352230"],"confidence":"High","gaps":["Whether EMP1 protein is causal or merely a marker not resolved","Mechanism of EMP1+ to LGR5+ transition not defined here"]},{"year":2023,"claim":"Revealed epigenetic control of EMP1 by SMYD3 and a tumor-suppressive output via AKT, illustrating its context-dependent role.","evidence":"ChIP for H4K20me3 at the EMP1 locus, SMYD3 knockdown, and EMP1 gain-of-function/rescue with p-Akt readout in gastric cancer cells","pmids":["37386026"],"confidence":"Medium","gaps":["How EMP1 suppresses AKT mechanistically unknown","Reconciliation with oncogenic PI3K-AKT activation in other tissues unaddressed"]},{"year":2021,"claim":"Defined transcriptional and post-transcriptional regulators of EMP1 (ETV4, miR-95-3p, miR-34a) linking its expression to PI3K/AKT-driven phenotypes and drug resistance.","evidence":"Luciferase reporter and ChIP for ETV4, dual-luciferase miRNA-target validation, and rescue experiments with downstream pathway readouts in GBM and gastric cancer","pmids":["34976153","33714198","31450568"],"confidence":"Medium","gaps":["Opposing directions of EMP1 effect across these studies not unified","Direct effectors downstream of EMP1 not isolated"]},{"year":2022,"claim":"Linked EMP1 loss to ferroptosis resistance and migration through a PPARG-pFAK-SLC7A11 program.","evidence":"EMP1 knockdown/overexpression in bladder cancer cells with ferroptosis and migration assays, PPARG ligand treatment, and FABP4 siRNA rescue","pmids":["35850179"],"confidence":"Medium","gaps":["Mechanism by which EMP1 restrains PPARG unknown","Single cell-line context"]},{"year":2025,"claim":"Showed EMP1 shapes the tumor microenvironment by driving NF-κB-dependent IL-6 secretion and CAF infiltration.","evidence":"Co-culture, xenografts, loss/gain-of-function, RNA-seq, IL-6 ELISA, and NF-κB Western blot in TNBC","pmids":["40016223"],"confidence":"Medium","gaps":["How a tetraspan membrane protein activates NF-κB not defined","Direct EMP1 signaling partners unidentified"]},{"year":2026,"claim":"Demonstrated that EMP1+ tumor cells undergo rapid KRAS-inhibition-driven conversion to LGR5+ stem-like cells via transcription factor rewiring, identifying a plasticity mechanism underlying relapse.","evidence":"Preclinical CRC mouse models, RAS(ON) inhibitor treatment, transcriptomic cell-state profiling, chromatin analysis, and genetic ablation of LGR5+ cells","pmids":["41128661"],"confidence":"Medium","gaps":["Role of EMP1 protein itself in the conversion not isolated","Transcription factors driving the switch not fully enumerated"]},{"year":null,"claim":"It remains unknown what direct molecular partners EMP1 engages at the membrane to transduce its signaling and junctional functions, and how the same protein produces opposing tumor-suppressive and oncogenic outputs across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct physical interactor or receptor identified","No structural model of the tetraspan protein in complex","Context-determinant of suppressor-vs-oncogene switch unresolved"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,7,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,11,18]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P54849","full_name":"Epithelial membrane protein 1","aliases":["CL-20","Protein B4B","Tumor-associated membrane protein"],"length_aa":157,"mass_kda":17.6,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P54849/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EMP1","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/EMP1","total_profiled":1310},"omim":[{"mim_id":"610143","title":"DEAFNESS, AUTOSOMAL RECESSIVE 62; DFNB62","url":"https://www.omim.org/entry/610143"},{"mim_id":"602335","title":"EPITHELIAL MEMBRANE PROTEIN 3; EMP3","url":"https://www.omim.org/entry/602335"},{"mim_id":"602334","title":"EPITHELIAL MEMBRANE PROTEIN 2; EMP2","url":"https://www.omim.org/entry/602334"},{"mim_id":"602333","title":"EPITHELIAL MEMBRANE PROTEIN 1; EMP1","url":"https://www.omim.org/entry/602333"},{"mim_id":"601097","title":"PERIPHERAL MYELIN PROTEIN 22; PMP22","url":"https://www.omim.org/entry/601097"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":1936.4},{"tissue":"vagina","ntpm":705.5}],"url":"https://www.proteinatlas.org/search/EMP1"},"hgnc":{"alias_symbol":["TMP","CL-20"],"prev_symbol":[]},"alphafold":{"accession":"P54849","domains":[{"cath_id":"1.20.140.150","chopping":"1-157","consensus_level":"medium","plddt":90.0127,"start":1,"end":157}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P54849","model_url":"https://alphafold.ebi.ac.uk/files/AF-P54849-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P54849-F1-predicted_aligned_error_v6.png","plddt_mean":90.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EMP1","jax_strain_url":"https://www.jax.org/strain/search?query=EMP1"},"sequence":{"accession":"P54849","fasta_url":"https://rest.uniprot.org/uniprotkb/P54849.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P54849/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P54849"}},"corpus_meta":[{"pmid":"36352230","id":"PMC_36352230","title":"Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/36352230","citation_count":188,"is_preprint":false},{"pmid":"29649743","id":"PMC_29649743","title":"Recent advances in trimethoxyphenyl (TMP) based tubulin inhibitors targeting the colchicine binding site.","date":"2018","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29649743","citation_count":170,"is_preprint":false},{"pmid":"22873118","id":"PMC_22873118","title":"Second-generation covalent TMP-tag for live cell imaging.","date":"2012","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/22873118","citation_count":101,"is_preprint":false},{"pmid":"19492849","id":"PMC_19492849","title":"An in vivo covalent TMP-tag based on proximity-induced reactivity.","date":"2009","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/19492849","citation_count":94,"is_preprint":false},{"pmid":"2445051","id":"PMC_2445051","title":"2,2,4-Trimethylpentane-induced nephrotoxicity. II. The reversible binding of a TMP metabolite to a renal protein fraction containing alpha 2u-globulin.","date":"1987","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2445051","citation_count":94,"is_preprint":false},{"pmid":"9521688","id":"PMC_9521688","title":"Identification of a 13 amino acid peptide mimetic of erythropoietin and description of amino acids critical for the mimetic activity of EMP1.","date":"1998","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9521688","citation_count":91,"is_preprint":false},{"pmid":"11469859","id":"PMC_11469859","title":"X-ray structure of TMP kinase from Mycobacterium tuberculosis complexed with TMP at 1.95 A resolution.","date":"2001","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11469859","citation_count":88,"is_preprint":false},{"pmid":"24961358","id":"PMC_24961358","title":"Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death.","date":"2014","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/24961358","citation_count":80,"is_preprint":false},{"pmid":"28408326","id":"PMC_28408326","title":"EMP1, EMP 2, and EMP3 as novel therapeutic targets in human cancer.","date":"2017","source":"Biochimica et biophysica acta. 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32770971","citation_count":7,"is_preprint":false},{"pmid":"32857809","id":"PMC_32857809","title":"Expression of EMP1, EMP2, and EMP3 in breast phyllodes tumors.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32857809","citation_count":6,"is_preprint":false},{"pmid":"32716150","id":"PMC_32716150","title":"EMP1 promotes the malignant progression of osteosarcoma through the IRX2/MMP9 axis.","date":"2020","source":"Panminerva medica","url":"https://pubmed.ncbi.nlm.nih.gov/32716150","citation_count":6,"is_preprint":false},{"pmid":"25401400","id":"PMC_25401400","title":"The crystal structure and morphology of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) p-xylene solvate: a joint experimental and simulation study.","date":"2014","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/25401400","citation_count":6,"is_preprint":false},{"pmid":"33013318","id":"PMC_33013318","title":"Regional Differences in Penetration of the Protein Stabilizer Trimethoprim (TMP) in the Rat Central Nervous System.","date":"2020","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33013318","citation_count":6,"is_preprint":false},{"pmid":"34737741","id":"PMC_34737741","title":"Antibody- Based Immunotherapy Combined With Antimycotic Drug TMP- SMX to Treat Infection With Paracoccidioides brasiliensis.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34737741","citation_count":6,"is_preprint":false},{"pmid":"1092364","id":"PMC_1092364","title":"Mitochondrial and cellular inhibition by the folate analogue pyrimethamine in Saccharomyces cerevisiae: reversal of cellular effects by TMP.","date":"1975","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/1092364","citation_count":6,"is_preprint":false},{"pmid":"41128661","id":"PMC_41128661","title":"A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer.","date":"2026","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41128661","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51609,"output_tokens":5164,"usd":0.116143,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13495,"output_tokens":3926,"usd":0.082812,"stage2_stop_reason":"end_turn"},"total_usd":0.198955,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"The Tmp gene (encoding EMP1) is a direct transcriptional target of the c-Myc oncoprotein. The c-Myc–Max protein complex binds to a CACGTG E-box element located in the first intron of Tmp, and an inducible MycER fusion protein activates the endogenous Tmp gene. Overexpression of Tmp in fibroblasts induces rapidly growing tumors in nude mice, indicating tumorigenic activity.\",\n      \"method\": \"Reporter gene assays with Tmp promoter/intron constructs, EMSA (c-Myc-Max binding to CACGTG element), inducible MycER system for endogenous gene activation, nude mouse xenograft tumorigenic assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (reporter assay, EMSA, inducible system, in vivo xenograft) in a single focused study on this gene\",\n      \"pmids\": [\"10207076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CL-20/EMP1 encodes an integral membrane protein of 157 amino acids with four hydrophobic transmembrane domains, placing it in the PMP22 gene family. The second hydrophobic domain (fourth exon) is highly conserved among CL-20, EMP-1, and PMP22, suggesting a functional role. EMP1 mRNA is abundant in squamous-differentiated bronchial epithelial cells and is repressed by retinoic acid. The human gene maps to chromosome 12p12.\",\n      \"method\": \"cDNA cloning and sequencing, Northern analysis, FISH chromosomal mapping, retinoic acid treatment of normal human bronchial epithelial cells\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning, expression analysis, and chromosomal mapping; multiple orthogonal methods but foundational characterization rather than deep mechanistic dissection\",\n      \"pmids\": [\"9126480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Chromosomal mapping identified Tmp (Emp1) as a member of a novel mammalian membrane glycoprotein family with four transmembrane domains related to Pmp22. Mouse Tmp was mapped to chromosome 6, and it was expressed in highly proliferative cell types. The gene family is proposed to have evolved through chromosomal duplications.\",\n      \"method\": \"cDNA isolation, chromosomal mapping by linkage analysis and fluorescence in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal mapping and cloning; complements the human characterization paper\",\n      \"pmids\": [\"9615230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EMP1 (EMP-1) localizes to intercellular borders in a liver stem cell line (Lig-8) and to epithelial junctions (bile duct epithelia, oval cell ductules, bile canaliculi) in the liver harboring proliferating oval cells. Co-localization with dipeptidyl peptidase IV confirmed junctional localization at bile canaliculi, establishing EMP1 as a junctional protein.\",\n      \"method\": \"Immunofluorescence and immunohistochemistry with anti-EMP1 antiserum on cell monolayers and liver tissue sections; co-localization with dipeptidyl peptidase IV marker\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional context (junctional marker), single lab, two co-localization markers\",\n      \"pmids\": [\"16036215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SOS1 acts through the Ras/MEK/ERK pathway to transcriptionally upregulate EMP1 in human bronchial epithelial cells (16HBE). EMP1 is indispensable for tight junction formation and function in 16HBE cells and in a human airway basal progenitor-like cell line (BCi-NS1.1); RNAi knockdown of EMP1 disrupts tight junction assembly during airway morphogenesis.\",\n      \"method\": \"RNAi screen for GEFs in 16HBE cells, global microarray analysis identifying EMP1 as SOS1/Ras/MEK/ERK transcriptional target, EMP1 knockdown with tight junction functional readouts in two human airway cell lines\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (RNAi screen + pathway validation), functional readout (tight junction formation), two orthogonal cell models, single lab\",\n      \"pmids\": [\"25394671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EMP1 loss in bladder cancer cells promotes migration and confers resistance to ferroptosis/oxidative stress by increasing PPARG expression and its activation, leading to upregulation of pFAK(Y397) (promoting migration) and SLC7A11 (promoting anti-ferroptotic cell death). EMP1-deficient cells were sensitized to PPARG ligand; FABP4 knockdown mitigated this effect.\",\n      \"method\": \"EMP1 knockdown/overexpression in BCa cells, Western blot for PPARG/pFAK/SLC7A11, migration assays, ferroptosis/oxidative stress assays, PPARG ligand treatment, FABP4 siRNA rescue experiments\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway (EMP1→PPARG→pFAK/SLC7A11), rescue experiments, single lab\",\n      \"pmids\": [\"35850179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EMP1 overexpression in ovarian cancer cells promotes proliferation, invasion, and EMT by activating the RAS/RAF/MAPK/c-JUN signaling pathway, as shown by increased protein levels of these components after EMP1 overexpression and inhibition of these phenotypes by EMP1 siRNA.\",\n      \"method\": \"siRNA interference, colony formation, migration and invasion assays, Western blot for RAS/RAF/MAPK/c-JUN pathway components\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss- and gain-of-function with pathway readout (Western blot), single lab, multiple orthogonal phenotypic assays\",\n      \"pmids\": [\"32210572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EMP1 promotes glioma cell proliferation, migration, invasion, and stemness through activation of the PI3K-AKT signaling pathway and regulation of CD44 expression in glioma stem cells. Silencing EMP1 inhibited these processes by suppressing PI3K-AKT signaling.\",\n      \"method\": \"EMP1 siRNA knockdown in glioma cells, invasion/proliferation assays, Western blot for PI3K-AKT pathway, CD44 expression analysis in glioma stem cells\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with pathway and stemness readouts, single lab\",\n      \"pmids\": [\"31111534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EMP1 overexpression in NSCLC cell line PC9 promotes proliferation and activates the PI3K/AKT signaling pathway; EMP1 promoted growth of PC9 xenografts in nude mice.\",\n      \"method\": \"Recombinant adenovirus overexpression of EMP1, Ki67 staining for proliferation, Western blot for PI3K/AKT pathway, subcutaneous xenograft tumor model\",\n      \"journal\": \"Journal of Huazhong University of Science and Technology. Medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gain-of-function only, PI3K/AKT pathway assignment based on Western blot without deeper mechanistic validation\",\n      \"pmids\": [\"23271282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EMP1 overexpression in prostate cancer PC-3 cells increases apoptosis and decreases migration and invasion, associated with higher caspase-9 and lower VEGFC protein expression. EMP1 overexpression in nasopharyngeal cancer CNE2 cells similarly increases apoptosis, decreases migration/invasion, elevates caspase-9, and reduces VEGFC. EMP1 overexpression in breast cancer MCF-7 cells shows the same pattern.\",\n      \"method\": \"Lentiviral EMP1 overexpression, MTT/migration/invasion assays, Western blot for caspase-9 and VEGFC, flow cytometry for apoptosis\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain-of-function only in each cancer type, mechanistic link to caspase-9/VEGFC by Western blot, single lab per paper, no rescue or epistasis\",\n      \"pmids\": [\"24338711\", \"24292952\", \"24402572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Overexpression of EMP1 in the esophageal cancer cell line EC9706 accelerated cell growth and was linked to induction of S-phase cell cycle arrest.\",\n      \"method\": \"Eukaryotic vector transfection, Western blot/RT-PCR confirmation, cell growth curve, FACS cell cycle analysis\",\n      \"journal\": \"Ai zheng = Chinese journal of cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single gain-of-function experiment, single lab, no pathway mechanism identified\",\n      \"pmids\": [\"12451984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EMP1-high (HRC) residual tumor cells are responsible for metastatic recurrence in colorectal cancer. Using Emp1 as a marker, genetic ablation of EMP1-high cells prevented metastatic recurrence in a mouse model of microsatellite-stable CRC after primary tumor surgery. These cells gave rise to LGR5+ stem-like tumor cells over time during metastatic outgrowth, and their micrometastases transitioned from T-cell infiltrated to progressively immune-excluded.\",\n      \"method\": \"Single-cell transcriptomics, mouse model of CRC with surgical resection, genetic cell ablation of EMP1-high cells, tumor cell tracking over time in vivo\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic ablation with specific metastatic relapse phenotype, single-cell transcriptomics, in vivo tracking, corroborated by multiple orthogonal approaches in one rigorous study\",\n      \"pmids\": [\"36352230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The histone methyltransferase SMYD3 epigenetically represses EMP1 expression in gastric cancer cells in an H4K20me3-dependent manner. ChIP assays showed SMYD3-mediated H4K20me3 deposition at the EMP1 locus. EMP1, in turn, inhibits GC cell proliferation and reduces p-Akt (S473) levels.\",\n      \"method\": \"ChIP assay for H4K20me3 at EMP1 locus, SMYD3 shRNA knockdown, EMP1 gain-of-function and rescue experiments, Western blot for p-Akt (S473)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay with gain/loss-of-function rescue experiments, single lab, direct epigenetic mechanism identified\",\n      \"pmids\": [\"37386026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ETV4 binds to the EMP1 promoter and positively regulates EMP1 transcription. Knockdown of ETV4 reduced EMP1 expression, inhibited PI3K/AKT/mTOR pathway activity, and promoted autophagy-dependent apoptosis in GBM cells; overexpressing EMP1 partially reversed these effects.\",\n      \"method\": \"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP) for ETV4 at EMP1 promoter, ETV4 knockdown with EMP1 rescue overexpression, Western blot for PI3K/AKT/mTOR and autophagy/apoptosis markers, TUNEL assay\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + luciferase reporter + rescue experiments define transcriptional regulation and downstream pathway, single lab\",\n      \"pmids\": [\"34976153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-95-3p promotes cisplatin resistance in gastric cancer by directly targeting EMP1 (confirmed by dual luciferase assay), suppressing EMP1 expression, and thereby activating PI3K/AKT signaling and promoting EMT and drug-resistance. EMP1 knockdown phenocopied miR-95-3p overexpression.\",\n      \"method\": \"Dual luciferase reporter assay to confirm miR-95-3p targeting of EMP1, qRT-PCR, Western blot, BrdU/MTT proliferation assays, transwell invasion/migration, in vivo tumorigenic experiments\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA-target validation by luciferase assay + loss-of-function phenotypic rescue, single lab\",\n      \"pmids\": [\"33714198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TFF3 signaling in Y79 retinoblastoma cells activates p53 and downstream miR-34a, which in turn inhibits EMP1 expression (as a predicted miR-34a target). EMP1 knockdown decreases viability and proliferation while increasing apoptosis (partially caspase-3/7 dependent) in Y79 cells; EMP1 overexpression produces the opposite effects. EMP1 overexpressing cells also show increased colony formation and larger CAM tumors.\",\n      \"method\": \"pG13-luciferase reporter for p53 activity, Western blot, WST-1 and BrdU assays, DAPI counts, caspase-3/7 assay, colony formation, soft agarose, in ovo CAM assay, EMP1 knockdown/overexpression\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays placing EMP1 downstream of TFF3/p53/miR-34a; epistasis established by reporter and rescue experiments, single lab\",\n      \"pmids\": [\"31450568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EMP1 expression in TNBC cells is required for cancer-associated fibroblast (CAF) infiltration in the tumor microenvironment. Mechanistically, EMP1 knockdown substantially decreased IL-6 secretion from TNBC cells through the NF-κB signaling pathway, reducing CAF proliferation and inhibiting TNBC progression and metastasis in vitro and in vivo.\",\n      \"method\": \"Cell co-culture assays, xenograft tumor experiments, EMP1 loss-of-function and gain-of-function, RNA sequencing, rescue assays, IL-6 ELISA, Western blot for NF-κB pathway\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with in vivo validation and rescue; mechanistic pathway (EMP1→NF-κB→IL-6→CAF) identified by multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40016223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EMP1 promotes osteosarcoma malignant progression by upregulating IRX2 and subsequently MMP9. Knockdown of EMP1 inhibited migration and invasion; overexpression of EMP1 increased IRX2 and MMP9 protein levels; rescue experiments confirmed IRX2 is involved in EMP1-regulated osteosarcoma progression.\",\n      \"method\": \"Transwell and wound healing migration/invasion assays, EMP1 knockdown/overexpression, Western blot for IRX2 and MMP9, rescue experiments with IRX2\",\n      \"journal\": \"Panminerva medica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, axis assignment by Western blot and partial rescue, no direct binding or promoter experiments\",\n      \"pmids\": [\"32716150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In metastatic colorectal cancer, KRAS-G12D inhibition converts EMP1+ tumor cells to a WNT-driven LGR5+ stem cell-like state through a shift in transcription factor usage with limited chromatin remodeling, occurring within hours of treatment. Genetic ablation of the LGR5+ population after forced conversion reduced metastatic burden and prolonged survival.\",\n      \"method\": \"Preclinical colorectal cancer mouse models, RMC-9945 RAS(ON) inhibitor treatment, transcriptomic cell-state profiling, genetic ablation of LGR5+ cells, chromatin remodeling analysis\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic experiments with cell-state tracking, mechanistic cell plasticity pathway established, single lab\",\n      \"pmids\": [\"41128661\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EMP1 (also known as TMP/CL-20) is an integral tetraspan membrane glycoprotein (PMP22 family, four transmembrane domains) whose expression is transcriptionally driven by c-Myc (via a first-intron CACGTG E-box) and by the SOS1/Ras/MEK/ERK pathway (which induces EMP1 to enable tight junction assembly in airway epithelium), and is epigenetically silenced by SMYD3-mediated H4K20me3; it localizes to epithelial junctions in the liver, where it marks a high-relapse colorectal cancer cell state (HRC/EMP1+) that transitions to LGR5+ stem-like cells under KRAS inhibition, and it exerts context-dependent tumor-suppressive or oncogenic effects in various cancers by modulating the PI3K/AKT, MAPK, and NF-κB pathways, as well as PPARG-driven ferroptosis resistance and IL-6-mediated cancer-associated fibroblast infiltration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EMP1 (TMP/CL-20) is a tetraspan integral membrane glycoprotein of the PMP22 family that functions at epithelial cell junctions and as a regulator of epithelial proliferation, cell-state plasticity, and cancer progression [#1, #3]. It localizes to intercellular borders and epithelial junctions, including bile duct epithelia and bile canaliculi, marking it as a junctional protein [#3], and it is indispensable for tight junction assembly during airway morphogenesis downstream of SOS1/Ras/MEK/ERK signaling [#4]. EMP1 transcription is controlled at multiple levels: it is a direct c-Myc-Max target through a CACGTG E-box in its first intron, conferring tumorigenic activity when overexpressed [#0]; it is induced by ETV4 [#13]; and it is silenced epigenetically by SMYD3-mediated H4K20me3 deposition and post-transcriptionally by miR-95-3p and miR-34a [#12, #14, #15]. EMP1 exerts context-dependent effects on tumor behavior by modulating the PI3K/AKT/mTOR, RAS/RAF/MAPK, and NF-\\u03baB pathways: it activates PI3K-AKT and CD44-linked stemness in glioma [#7], drives RAS/RAF/MAPK/c-JUN-dependent proliferation and EMT in ovarian cancer [#6], and promotes IL-6 secretion via NF-\\u03baB to recruit cancer-associated fibroblasts in triple-negative breast cancer [#16], while opposing AKT signaling and proliferation in gastric cancer [#12]. EMP1 loss confers ferroptosis resistance through PPARG-driven upregulation of pFAK and SLC7A11 in bladder cancer [#5]. In microsatellite-stable colorectal cancer, EMP1 marks a high-relapse residual tumor cell state whose genetic ablation prevents metastatic recurrence, and these EMP1+ cells convert to WNT-driven LGR5+ stem-like cells, including rapidly upon KRAS-G12D inhibition [#11, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the molecular identity of EMP1 as a four-transmembrane PMP22-family membrane protein, providing the structural framework for all later functional work.\",\n      \"evidence\": \"cDNA cloning/sequencing, Northern analysis, and FISH mapping in human bronchial epithelial cells\",\n      \"pmids\": [\"9126480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No membrane topology confirmed experimentally\", \"Function of the protein not addressed\", \"Binding partners unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Confirmed EMP1 as part of a duplicated mammalian membrane glycoprotein family expressed in proliferative cells, hinting at a proliferation-linked role.\",\n      \"evidence\": \"cDNA isolation and chromosomal mapping by linkage and FISH in mouse\",\n      \"pmids\": [\"9615230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlation with proliferation not mechanistically tested\", \"No functional assay\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Answered how EMP1 connects to oncogenic transcription by showing it is a direct c-Myc target with intrinsic tumorigenic activity.\",\n      \"evidence\": \"Reporter assays, EMSA for c-Myc-Max binding to an intronic E-box, inducible MycER activation, and nude mouse xenografts\",\n      \"pmids\": [\"10207076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream mechanism of tumorigenicity not defined\", \"Did not address normal physiological role\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined EMP1 as a bona fide junctional protein by localizing it to epithelial cell-cell borders and bile canaliculi.\",\n      \"evidence\": \"Immunofluorescence/IHC with anti-EMP1 antiserum and co-localization with dipeptidyl peptidase IV in liver tissue and a liver stem cell line\",\n      \"pmids\": [\"16036215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role at junctions not tested\", \"No interacting junctional proteins identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided a physiological function by placing EMP1 downstream of SOS1/Ras/MEK/ERK as an essential factor for tight junction assembly.\",\n      \"evidence\": \"GEF RNAi screen, microarray identification of EMP1 as pathway target, and EMP1 knockdown with tight junction readouts in two human airway cell lines\",\n      \"pmids\": [\"25394671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which EMP1 promotes junction assembly unknown\", \"Direct junctional partners not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed EMP1 can act oncogenically through PI3K-AKT signaling and stemness, broadening its role beyond junction biology.\",\n      \"evidence\": \"EMP1 siRNA knockdown in glioma cells with proliferation/invasion assays and PI3K-AKT and CD44 readouts\",\n      \"pmids\": [\"31111534\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct link between EMP1 and PI3K-AKT components\", \"Gain-of-function not included\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended EMP1 oncogenic signaling to the RAS/RAF/MAPK/c-JUN axis driving proliferation, invasion, and EMT.\",\n      \"evidence\": \"siRNA and overexpression in ovarian cancer cells with phenotypic assays and Western blot of pathway components\",\n      \"pmids\": [\"32210572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway activation inferred from protein levels, not direct binding\", \"Tissue specificity of the axis unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified EMP1 as a functional marker of high-relapse residual tumor cells whose elimination prevents metastatic recurrence.\",\n      \"evidence\": \"Single-cell transcriptomics, genetic ablation of EMP1-high cells, and in vivo tracking in a microsatellite-stable CRC mouse model\",\n      \"pmids\": [\"36352230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EMP1 protein is causal or merely a marker not resolved\", \"Mechanism of EMP1+ to LGR5+ transition not defined here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed epigenetic control of EMP1 by SMYD3 and a tumor-suppressive output via AKT, illustrating its context-dependent role.\",\n      \"evidence\": \"ChIP for H4K20me3 at the EMP1 locus, SMYD3 knockdown, and EMP1 gain-of-function/rescue with p-Akt readout in gastric cancer cells\",\n      \"pmids\": [\"37386026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How EMP1 suppresses AKT mechanistically unknown\", \"Reconciliation with oncogenic PI3K-AKT activation in other tissues unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined transcriptional and post-transcriptional regulators of EMP1 (ETV4, miR-95-3p, miR-34a) linking its expression to PI3K/AKT-driven phenotypes and drug resistance.\",\n      \"evidence\": \"Luciferase reporter and ChIP for ETV4, dual-luciferase miRNA-target validation, and rescue experiments with downstream pathway readouts in GBM and gastric cancer\",\n      \"pmids\": [\"34976153\", \"33714198\", \"31450568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing directions of EMP1 effect across these studies not unified\", \"Direct effectors downstream of EMP1 not isolated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked EMP1 loss to ferroptosis resistance and migration through a PPARG-pFAK-SLC7A11 program.\",\n      \"evidence\": \"EMP1 knockdown/overexpression in bladder cancer cells with ferroptosis and migration assays, PPARG ligand treatment, and FABP4 siRNA rescue\",\n      \"pmids\": [\"35850179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EMP1 restrains PPARG unknown\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed EMP1 shapes the tumor microenvironment by driving NF-\\u03baB-dependent IL-6 secretion and CAF infiltration.\",\n      \"evidence\": \"Co-culture, xenografts, loss/gain-of-function, RNA-seq, IL-6 ELISA, and NF-\\u03baB Western blot in TNBC\",\n      \"pmids\": [\"40016223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a tetraspan membrane protein activates NF-\\u03baB not defined\", \"Direct EMP1 signaling partners unidentified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated that EMP1+ tumor cells undergo rapid KRAS-inhibition-driven conversion to LGR5+ stem-like cells via transcription factor rewiring, identifying a plasticity mechanism underlying relapse.\",\n      \"evidence\": \"Preclinical CRC mouse models, RAS(ON) inhibitor treatment, transcriptomic cell-state profiling, chromatin analysis, and genetic ablation of LGR5+ cells\",\n      \"pmids\": [\"41128661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of EMP1 protein itself in the conversion not isolated\", \"Transcription factors driving the switch not fully enumerated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what direct molecular partners EMP1 engages at the membrane to transduce its signaling and junctional functions, and how the same protein produces opposing tumor-suppressive and oncogenic outputs across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct physical interactor or receptor identified\", \"No structural model of the tetraspan protein in complex\", \"Context-determinant of suppressor-vs-oncogene switch unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 7, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 11, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}