{"gene":"TMED2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1996,"finding":"p24A (TMED2) is a type I transmembrane protein localized in microsomal membranes, zymogen granule membranes, and the plasma membrane, containing a KKXX ER retention/retrieval motif in its cytoplasmic tail, and is homologous to yeast Emp24p involved in ER-to-Golgi vesicular transport, identifying it as a member of the p24 family implicated in vesicular targeting and protein transport.","method":"Protein isolation, cloning, sequence analysis, subcellular fractionation, Northern blotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cloning plus direct subcellular fractionation and sequence-based functional inference; single lab but multiple orthogonal approaches","pmids":["8663407"],"is_preprint":false},{"year":1999,"finding":"p24A (TMED2) cycles continuously between the intermediate compartment (IC) and the cis-Golgi network via large microtubule-dependent pre-Golgi carriers, and overexpression of GFP-p24A causes partial relocalization to ER elements; AlF4- (G-protein activator) blocks peripheral pre-Golgi movements and inhibits FRAP in the Golgi, indicating G-protein-dependent trafficking.","method":"GFP tagging + live-cell imaging, FRAP, AlF4- treatment, immunofluorescence localization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging with GFP fusions, FRAP, pharmacological perturbation, and immunolocalization; multiple orthogonal methods in one study","pmids":["9914165"],"is_preprint":false},{"year":2007,"finding":"p24A (TMED2) associates with PAR-2 at the Golgi apparatus via its N-terminal GOLD domain (residues 1–105) binding the second extracellular loop of PAR-2; after receptor activation, ARF1 regulates dissociation of PAR-2 from p24A and initiates PAR-2 trafficking to the plasma membrane; overexpression of the p24A GOLD domain fragment arrests PAR-2 at the Golgi and prevents resensitization.","method":"Co-immunoprecipitation, deletion/mutant constructs, ARF1 perturbation, trafficking assays, resensitization assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, domain-mapping mutagenesis, dominant-negative approach, and functional resensitization readout; multiple orthogonal methods","pmids":["17693410"],"is_preprint":false},{"year":2010,"finding":"p24A (TMED2) interacts with the calcium sensing receptor (CaSR) via the CaSR carboxyl terminus; only the immaturely glycosylated (ER) form of CaSR binds p24A; interaction occurs in the ER/ERGIC and dissociates before the trans-Golgi; p24A and p24A(ΔGOLD) increase total and plasma membrane CaSR protein, but the p24A(FF/AA) mutant does not, indicating that p24A promotes CaSR stability and plasma membrane targeting in the early secretory pathway.","method":"Yeast two-hybrid screen, co-immunoprecipitation in HEK293 cells, glycosylation analysis, mutant constructs, plasma membrane expression assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus mutagenesis; single lab, multiple methods","pmids":["20361938"],"is_preprint":false},{"year":2010,"finding":"Loss of TMED2/p24β1 protein (due to a point mutation in its signal sequence) in homozygous 99J mice results in concurrent loss of its oligomerization partners TMED7/p24γ3 and TMED10/p24δ1, demonstrating that TMED2 regulates the protein levels of its hetero-oligomeric complex partners; TMED2 is required for mouse embryo morphogenesis and placental labyrinth formation.","method":"ENU mutagenesis screen, Western blotting, immunofluorescence, mouse genetics (homozygous mutant embryo analysis)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct genetic loss-of-function in vivo with multiple protein-level readouts and orthogonal methods; demonstrates complex stability dependency","pmids":["20178780"],"is_preprint":false},{"year":2011,"finding":"p24A (TMED2) binds multiple GPCRs including PAR-1, P2Y1, P2Y2, P2Y4, P2Y11, and μ-opioid receptor 1B via acidic residues (Glu/Asp) in their second extracellular loops; p24A and p23 arrest these GPCRs at intracellular compartments; overexpression of the N-terminal p24A fragment impairs PAR-2 resensitization in primary rat astrocytes.","method":"Co-immunoprecipitation, dominant-negative fragment overexpression, trafficking assays in HEK293 cells and primary rat astrocytes","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with multiple receptors plus domain mapping plus native cell functional assay; single lab","pmids":["21219331"],"is_preprint":false},{"year":2018,"finding":"TMED2 associates with MITA/STING specifically upon viral stimulation (HSV-1 infection), reinforces MITA dimerization, and facilitates MITA trafficking from the ER to perinuclear vesicles; TMED2 suppression or deletion markedly impairs type I IFN production and increases HSV-1 viral load.","method":"Co-immunoprecipitation (stimulus-dependent), TMED2 knockdown/knockout, IFN production assays, viral load measurement, MITA dimerization assays, trafficking assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — stimulus-dependent co-IP, genetic KO, multiple functional readouts (IFN production, dimerization, trafficking, viral load); multiple orthogonal methods","pmids":["30540941"],"is_preprint":false},{"year":2018,"finding":"TMED2 is required cell-autonomously in the chorion for chorioallantoic attachment; Fibronectin is abnormally retained in the ER of Tmed2 homozygous mutant allantoises, identifying Fibronectin as a cargo protein of TMED2 in the early secretory pathway.","method":"Conditional/tissue-specific genetic analysis, ex vivo chorion-allantois recombination assay, immunostaining for ER retention of Fibronectin, gene expression analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with ex vivo tissue recombination and direct cargo retention evidence; single lab","pmids":["30236446"],"is_preprint":false},{"year":2022,"finding":"TMED2 and TMED10 are essential components of a supercomplex that mediates exchange of cholesterol and ceramides at ER-Golgi membrane contact sites; loss of TMED2 or TMED10 impairs plasma membrane lipid nanodomain (raft) formation by disrupting lipid compositional remodeling at ER-Golgi interfaces.","method":"Genetic screen (anthrax toxin intoxication), biochemical fractionation, morphological analysis, lipid composition analysis, TMED2/TMED10 KO cell lines","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genetic screen followed by biochemical, morphological, and mechanistic analyses with KO cells; multiple orthogonal methods","pmids":["36174556"],"is_preprint":false},{"year":2022,"finding":"TMED2 binds to Smoothened (SMO) and retains it in the ER and Golgi compartments, preventing SMO localization to the plasma membrane; mutation of TMED2 allows SMO accumulation at the plasma membrane, recapitulating early events of Hedgehog (HH) stimulation; TMED2 functions to repress HH signaling strength during neural differentiation.","method":"Haploid ESC genetic screen, super-resolution microscopy, co-immunoprecipitation/binding assay, TMED2 mutant analysis, neural differentiation assay","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genetic screen, super-resolution imaging, binding interaction, functional rescue/overexpression in multiple cell types; multiple orthogonal methods","pmids":["35353806"],"is_preprint":false},{"year":2023,"finding":"TMED2 interacts with TLR2, TLR4, and TLR3 (but not TLR5, TLR9 at the tested conditions) and is required for ER-to-Golgi export of both plasma membrane and endosomal TLRs; dominant-negative forms of TMED2 impair ER export of TLRs.","method":"Protein interaction studies (co-immunoprecipitation/pulldown), dominant-negative constructs, trafficking assays","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction studies plus dominant-negative functional assay; single lab, two orthogonal methods","pmids":["37491993"],"is_preprint":false},{"year":2023,"finding":"TMED2 promotes cisplatin resistance in breast cancer cells by facilitating ubiquitination of KEAP1, thereby relieving KEAP1-mediated inhibition of Nrf2 and increasing expression of downstream drug resistance genes HO-1 and NQO1.","method":"Western blotting, RT-PCR, CCK-8 and TUNEL assays, TMED2 overexpression/knockdown in MCF-7 and MDA-MB-231 cells, ubiquitination assay","journal":"Current medical science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, western blot-based mechanistic inference without reconstitution or structural validation; moderate evidence for KEAP1 ubiquitination involvement","pmids":["37615927"],"is_preprint":false},{"year":2024,"finding":"TMED2 enhances EGFR-AKT signaling in glioma by facilitating EGFR recycling to the plasma membrane, identifying a role for TMED2 in membrane receptor recycling in addition to its known anterograde trafficking function.","method":"TMED2 knockdown/overexpression in glioma cell lines, EGFR trafficking/recycling assays, AKT signaling readouts, xenograft mouse model","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with signaling readouts, recycling assay without biochemical reconstitution; limited mechanistic depth","pmids":["38354922"],"is_preprint":false},{"year":2025,"finding":"TMED2 promotes osteosarcoma progression via activation of the MAPK/MEK/ERK signaling pathway, with CKAP4 identified as a downstream effector of TMED2; TMED2 knockdown suppresses MEK/ERK activation and promotes M1 macrophage polarization.","method":"shRNA knockdown, Western blotting, xenograft mouse model, CKAP4 knockdown epistasis","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD + Western blot; downstream effector identified by co-knockdown without direct biochemical interaction validation","pmids":["42165997"],"is_preprint":false}],"current_model":"TMED2 (p24A/p24β1) is a type I transmembrane p24-family cargo receptor that cycles between the ER, ERGIC, and cis-Golgi via microtubule-dependent carriers, where it forms hetero-oligomeric complexes with TMED7 and TMED10 to facilitate anterograde trafficking of specific cargo proteins—including multiple GPCRs (PAR-1, PAR-2, P2Y receptors, μ-opioid receptor), TLRs, the calcium sensing receptor, Fibronectin, and Smoothened—by binding their extracellular loops and releasing them in an ARF1-dependent manner; TMED2 also forms part of an ER-Golgi supercomplex that exchanges cholesterol and ceramides at membrane contact sites to control plasma membrane lipid nanodomain composition, and upon viral infection specifically associates with MITA/STING to reinforce its dimerization and trafficking required for innate immune signaling."},"narrative":{"mechanistic_narrative":"TMED2 (p24A/p24β1) is a type I transmembrane p24-family cargo receptor that operates in the early secretory pathway, cycling between the ER, intermediate compartment, and cis-Golgi via large microtubule-dependent pre-Golgi carriers in a G-protein-dependent manner [PMID:8663407, PMID:9914165]. It functions as a hetero-oligomer whose integrity it controls: loss of TMED2 in vivo concurrently destabilizes its partners TMED7 and TMED10, and TMED2 is required for mouse embryo morphogenesis and placental labyrinth formation [PMID:20178780]. Through its N-terminal GOLD domain, TMED2 binds the second extracellular loop of client receptors—engaging acidic residues in the extracellular loops of multiple GPCRs (PAR-1, PAR-2, P2Y receptors, μ-opioid receptor)—and then releases them in an ARF1-dependent manner to permit anterograde trafficking, so that dominant-negative GOLD fragments arrest cargo at intracellular compartments and block receptor resensitization [PMID:17693410, PMID:21219331]. This receptor-chaperoning role extends to the calcium-sensing receptor, whose immature ER form it stabilizes and routes to the plasma membrane [PMID:20361938], to Toll-like receptors TLR2/3/4 whose ER-to-Golgi export it mediates [PMID:37491993], and to Fibronectin, which is retained in the ER upon TMED2 loss [PMID:30236446]. TMED2 also acts as a negative regulator of trafficking for Smoothened, retaining SMO in the ER and Golgi to repress Hedgehog signaling strength during neural differentiation [PMID:35353806]. Beyond discrete cargo handling, TMED2 together with TMED10 forms a supercomplex that exchanges cholesterol and ceramides at ER-Golgi membrane contact sites, controlling plasma membrane lipid nanodomain composition [PMID:36174556], and upon viral infection it associates with MITA/STING to reinforce its dimerization and ER-to-vesicle trafficking required for type I interferon production [PMID:30540941].","teleology":[{"year":1996,"claim":"Established TMED2 as a p24-family transmembrane protein of the secretory pathway, framing it as a candidate vesicular transport factor rather than an uncharacterized membrane protein.","evidence":"Protein isolation, cloning, sequence analysis, and subcellular fractionation identifying a KKXX ER retrieval motif and homology to yeast Emp24p","pmids":["8663407"],"confidence":"Medium","gaps":["No direct cargo identified","Functional role in transport inferred from homology, not demonstrated"]},{"year":1999,"claim":"Defined how and where TMED2 moves, showing it continuously cycles between the intermediate compartment and cis-Golgi on microtubule-dependent carriers under G-protein control.","evidence":"GFP-fusion live imaging, FRAP, and AlF4- pharmacological perturbation in cultured cells","pmids":["9914165"],"confidence":"High","gaps":["Identity of the regulating G-protein not resolved","Cargo carried during cycling not defined"]},{"year":2007,"claim":"Provided the first mechanistic cargo model, demonstrating GOLD-domain binding to a receptor extracellular loop and ARF1-dependent release as the basis for regulated anterograde trafficking.","evidence":"Reciprocal co-IP, GOLD domain-mapping mutagenesis, ARF1 perturbation, and PAR-2 resensitization assays","pmids":["17693410"],"confidence":"High","gaps":["Mechanism of ARF1-triggered release not structurally resolved","Generality across receptor classes not yet tested"]},{"year":2010,"claim":"Extended the cargo-chaperone role to receptor biogenesis, showing TMED2 stabilizes the immature ER form of CaSR and promotes its plasma membrane delivery.","evidence":"Yeast two-hybrid, co-IP, glycosylation analysis, and mutant plasma membrane expression assays in HEK293 cells","pmids":["20361938"],"confidence":"Medium","gaps":["FF/AA motif role in release not mechanistically explained","Single-lab interaction data"]},{"year":2010,"claim":"Demonstrated in vivo that TMED2 maintains the protein levels of its hetero-oligomeric partners and is essential for embryonic and placental morphogenesis, establishing functional interdependence of the p24 complex.","evidence":"ENU point-mutant mice, Western blotting, immunofluorescence, and mutant embryo analysis","pmids":["20178780"],"confidence":"High","gaps":["Cargo responsible for morphogenesis defects not identified at this stage","Mechanism linking complex loss to placental failure unresolved"]},{"year":2011,"claim":"Generalized the GOLD-domain receptor interaction to a broad GPCR clientele, identifying acidic extracellular-loop residues as the shared recognition determinant.","evidence":"Co-IP with multiple GPCRs, dominant-negative fragment overexpression, and trafficking assays in HEK293 cells and primary astrocytes","pmids":["21219331"],"confidence":"Medium","gaps":["Selectivity rules among receptors not defined","Quantitative binding affinities not measured"]},{"year":2018,"claim":"Revealed a stimulus-specific signaling role, showing TMED2 is recruited to MITA/STING upon viral infection to reinforce dimerization and trafficking needed for type I IFN responses.","evidence":"Stimulus-dependent co-IP, TMED2 knockdown/knockout, IFN and viral load assays, and MITA dimerization/trafficking readouts","pmids":["30540941"],"confidence":"High","gaps":["How viral stimulus triggers the TMED2-MITA association is unknown","Whether the p24 complex partners participate not addressed"]},{"year":2018,"claim":"Connected the in vivo morphogenesis phenotype to a specific cargo by identifying Fibronectin as ER-retained upon TMED2 loss in the chorion.","evidence":"Tissue-specific genetic analysis, ex vivo chorion-allantois recombination, and Fibronectin ER-retention immunostaining","pmids":["30236446"],"confidence":"Medium","gaps":["Direct TMED2-Fibronectin binding not shown","Whether other cargo contribute to the defect unresolved"]},{"year":2022,"claim":"Uncovered a lipid-transfer function distinct from cargo handling, placing TMED2 with TMED10 in a supercomplex that exchanges cholesterol and ceramides at ER-Golgi contact sites to shape plasma membrane nanodomains.","evidence":"Anthrax-toxin genetic screen, biochemical fractionation, lipid composition analysis, and KO cell lines","pmids":["36174556"],"confidence":"High","gaps":["Direct lipid-transfer activity of TMED2 vs. scaffolding role not distinguished","Structure of the supercomplex unknown"]},{"year":2022,"claim":"Established TMED2 as a negative trafficking regulator, retaining Smoothened in the ER/Golgi to dampen Hedgehog signaling during neural differentiation.","evidence":"Haploid ESC genetic screen, super-resolution microscopy, binding assay, and neural differentiation assays","pmids":["35353806"],"confidence":"High","gaps":["Mechanism of SMO release under Hedgehog stimulation not defined","Whether retention uses the GOLD domain not tested here"]},{"year":2023,"claim":"Broadened the cargo repertoire to innate immune receptors, showing TMED2 mediates ER-to-Golgi export of TLR2/3/4.","evidence":"Co-IP/pulldown, dominant-negative constructs, and trafficking assays","pmids":["37491993"],"confidence":"Medium","gaps":["Recognition motif on TLRs not mapped","Selectivity excluding TLR5/TLR9 not mechanistically explained"]},{"year":2023,"claim":"Proposed a disease-associated role in which TMED2 supports cisplatin resistance by promoting KEAP1 ubiquitination and relieving inhibition of Nrf2.","evidence":"Overexpression/knockdown in breast cancer lines, ubiquitination assay, and viability/apoptosis readouts","pmids":["37615927"],"confidence":"Low","gaps":["Western-blot-based mechanistic inference without reconstitution or structural validation","Direct TMED2-KEAP1 interaction not established","Link to TMED2's trafficking function unclear"]},{"year":2024,"claim":"Suggested a recycling role beyond anterograde transport, with TMED2 promoting EGFR return to the plasma membrane to enhance EGFR-AKT signaling in glioma.","evidence":"Knockdown/overexpression in glioma lines, recycling and AKT readouts, and xenograft model","pmids":["38354922"],"confidence":"Low","gaps":["Recycling mechanism not biochemically reconstituted","Direct EGFR engagement not demonstrated","Single-lab study"]},{"year":2025,"claim":"Implicated TMED2 in tumor progression via MAPK/MEK/ERK activation with CKAP4 as a downstream effector in osteosarcoma.","evidence":"shRNA knockdown, Western blotting, xenograft model, and CKAP4 epistasis","pmids":["42165997"],"confidence":"Low","gaps":["Downstream effector identified by co-knockdown without direct interaction validation","Connection to TMED2 trafficking activity not established"]},{"year":null,"claim":"How a single GOLD-domain receptor selects among its diverse cargo and switches between promoting versus restraining their surface delivery remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of GOLD-cargo recognition","Rules distinguishing anterograde export from ER retention not defined","Mechanistic basis of stimulus-dependent partner selection (e.g. STING) unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,3,5,7,9,10]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,3,7,9]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,2,7,10]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,9]}],"complexes":["TMED2/TMED7/TMED10 p24 hetero-oligomer","ER-Golgi lipid-exchange supercomplex (TMED2/TMED10)"],"partners":["TMED7","TMED10","PAR-2","CASR","SMO","STING/MITA","TLR4","FIBRONECTIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15363","full_name":"Transmembrane emp24 domain-containing protein 2","aliases":["Membrane protein p24A","p24","p24 family protein beta-1","p24beta1"],"length_aa":201,"mass_kda":22.8,"function":"Involved in vesicular protein trafficking. Mainly functions in the early secretory pathway but also in post-Golgi membranes. Thought to act as cargo receptor at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and to be involved in vesicle coat formation at the cytoplasmic side. In COPII vesicle-mediated anterograde transport involved in the transport of GPI-anchored proteins and proposed to act together with TMED10 as their cargo receptor; the function specifically implies SEC24C and SEC24D of the COPII vesicle coat and lipid raft-like microdomains of the ER. Recognizes GPI anchors structural remodeled in the ER by PGAP1 and MPPE1. In COPI vesicle-mediated retrograde transport inhibits the GTPase-activating activity of ARFGAP1 towards ARF1 thus preventing immature uncoating and allowing cargo selection to take place. Involved in trafficking of G protein-coupled receptors (GPCRs). Regulates F2RL1, OPRM1 and P2RY4 exocytic trafficking from the Golgi to the plasma membrane thus contributing to receptor resensitization. Facilitates CASR maturation and stabilization in the early secretory pathway and increases CASR plasma membrane targeting. Proposed to be involved in organization of intracellular membranes such as the maintenance of the Golgi apparatus. May also play a role in the biosynthesis of secreted cargo such as eventual processing","subcellular_location":"Cytoplasmic vesicle membrane; Cytoplasmic vesicle, COPI-coated vesicle membrane; Golgi apparatus, cis-Golgi network membrane; Golgi apparatus, Golgi stack membrane; Endoplasmic reticulum membrane; Endoplasmic reticulum-Golgi intermediate compartment membrane","url":"https://www.uniprot.org/uniprotkb/Q15363/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TMED2","classification":"Common Essential","n_dependent_lines":837,"n_total_lines":1208,"dependency_fraction":0.6928807947019867},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000086598","cell_line_id":"CID000907","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"MYBBP1A","stoichiometry":10.0},{"gene":"TMED10","stoichiometry":10.0},{"gene":"TMED7-TICAM2;TMED7","stoichiometry":10.0},{"gene":"TMED9","stoichiometry":10.0},{"gene":"TMED1","stoichiometry":10.0},{"gene":"TMED4","stoichiometry":10.0},{"gene":"LMAN2","stoichiometry":4.0},{"gene":"RAB2A","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"COPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000907","total_profiled":1310},"omim":[{"mim_id":"620437","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 3; TMED3","url":"https://www.omim.org/entry/620437"},{"mim_id":"620436","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 9; TMED9","url":"https://www.omim.org/entry/620436"},{"mim_id":"619990","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 7; TMED7","url":"https://www.omim.org/entry/619990"},{"mim_id":"619642","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 2; TMED2","url":"https://www.omim.org/entry/619642"},{"mim_id":"605406","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 10; TMED10","url":"https://www.omim.org/entry/605406"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMED2"},"hgnc":{"alias_symbol":["RNP24","P24A","p24beta1","p24b1"],"prev_symbol":[]},"alphafold":{"accession":"Q15363","domains":[{"cath_id":"2.60.120.680","chopping":"19-116","consensus_level":"medium","plddt":89.615,"start":19,"end":116},{"cath_id":"1.20.5","chopping":"123-201","consensus_level":"medium","plddt":86.5724,"start":123,"end":201}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15363","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15363-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15363-F1-predicted_aligned_error_v6.png","plddt_mean":87.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMED2","jax_strain_url":"https://www.jax.org/strain/search?query=TMED2"},"sequence":{"accession":"Q15363","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15363.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15363/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15363"}},"corpus_meta":[{"pmid":"8663407","id":"PMC_8663407","title":"Tmp21 and p24A, two type I proteins enriched in pancreatic microsomal membranes, are members of a protein family involved in vesicular trafficking.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8663407","citation_count":89,"is_preprint":false},{"pmid":"9914165","id":"PMC_9914165","title":"Intracellular localization and in vivo trafficking of p24A and p23.","date":"1999","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9914165","citation_count":84,"is_preprint":false},{"pmid":"30540941","id":"PMC_30540941","title":"TMED2 Potentiates Cellular IFN Responses to DNA Viruses by Reinforcing MITA Dimerization and Facilitating Its Trafficking.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30540941","citation_count":80,"is_preprint":false},{"pmid":"20178780","id":"PMC_20178780","title":"The trafficking protein Tmed2/p24beta(1) is required for morphogenesis of the mouse embryo and placenta.","date":"2010","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20178780","citation_count":57,"is_preprint":false},{"pmid":"17693410","id":"PMC_17693410","title":"p24A, a type I transmembrane protein, controls ARF1-dependent resensitization of protease-activated receptor-2 by influence on receptor trafficking.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17693410","citation_count":50,"is_preprint":false},{"pmid":"36174556","id":"PMC_36174556","title":"ER-Golgi-localized proteins TMED2 and TMED10 control the formation of plasma membrane lipid nanodomains.","date":"2022","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/36174556","citation_count":35,"is_preprint":false},{"pmid":"34707394","id":"PMC_34707394","title":"Multi-Omics Analysis Identified TMED2 as a Shared Potential Biomarker in Six Subtypes of Human Cancer.","date":"2021","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34707394","citation_count":32,"is_preprint":false},{"pmid":"28797121","id":"PMC_28797121","title":"Non-alcoholic fatty liver disease in mice with heterozygous mutation in TMED2.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28797121","citation_count":31,"is_preprint":false},{"pmid":"21219331","id":"PMC_21219331","title":"Proteinase-activated receptors, nucleotide P2Y receptors, and μ-opioid receptor-1B are under the control of the type I transmembrane proteins p23 and p24A in post-Golgi trafficking.","date":"2011","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21219331","citation_count":27,"is_preprint":false},{"pmid":"29212217","id":"PMC_29212217","title":"TMED2 promotes epithelial ovarian cancer growth.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29212217","citation_count":24,"is_preprint":false},{"pmid":"32293333","id":"PMC_32293333","title":"The circular RNA CDR1as regulate cell proliferation via TMED2 and TMED10.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32293333","citation_count":23,"is_preprint":false},{"pmid":"20361938","id":"PMC_20361938","title":"The cargo receptor p24A facilitates calcium sensing receptor maturation and stabilization in the early secretory pathway.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20361938","citation_count":18,"is_preprint":false},{"pmid":"35353806","id":"PMC_35353806","title":"TMED2 binding restricts SMO to the ER and Golgi compartments.","date":"2022","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/35353806","citation_count":15,"is_preprint":false},{"pmid":"22212250","id":"PMC_22212250","title":"TMED2/p24β1 is expressed in all gestational stages of human placentas and in choriocarcinoma cell lines.","date":"2011","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/22212250","citation_count":14,"is_preprint":false},{"pmid":"30236446","id":"PMC_30236446","title":"TMED2/emp24 is required in both the chorion and the allantois for placental labyrinth layer development.","date":"2018","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/30236446","citation_count":14,"is_preprint":false},{"pmid":"33364837","id":"PMC_33364837","title":"Expression and Importance of TMED2 in Multiple Myeloma Cells.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33364837","citation_count":12,"is_preprint":false},{"pmid":"38354922","id":"PMC_38354922","title":"TMED2 promotes glioma tumorigenesis by being involved in EGFR recycling transport.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38354922","citation_count":9,"is_preprint":false},{"pmid":"33210454","id":"PMC_33210454","title":"Circular RNA circ_0008305 aggravates hepatocellular carcinoma growth through binding to miR-186 and inducing TMED2.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33210454","citation_count":8,"is_preprint":false},{"pmid":"37391589","id":"PMC_37391589","title":"VIRMA facilitates intrahepatic cholangiocarcinoma progression through epigenetic augmentation of TMED2 and PARD3B mRNA stabilization.","date":"2023","source":"Journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/37391589","citation_count":7,"is_preprint":false},{"pmid":"37615927","id":"PMC_37615927","title":"TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the KEAP1-Nrf2 Pathway.","date":"2023","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/37615927","citation_count":5,"is_preprint":false},{"pmid":"36618780","id":"PMC_36618780","title":"Screening of the novel immune-suppressive biomarkers of TMED family and whether knockdown of TMED2/3/4/9 inhibits cell migration and invasion in breast cancer.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36618780","citation_count":5,"is_preprint":false},{"pmid":"39694382","id":"PMC_39694382","title":"Study on the role and mechanism of TMED2 in oral squamous cell carcinoma.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39694382","citation_count":2,"is_preprint":false},{"pmid":"37491993","id":"PMC_37491993","title":"Anterograde trafficking of Toll-like receptors requires the cargo sorting adaptors TMED-2 and 7.","date":"2023","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/37491993","citation_count":2,"is_preprint":false},{"pmid":"41581626","id":"PMC_41581626","title":"TMED2 promotes thyroid cancer tumorigenesis by being involved in mTORC1-mediated fatty acid metabolism.","date":"2026","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/41581626","citation_count":1,"is_preprint":false},{"pmid":"42165997","id":"PMC_42165997","title":"TMED2 regulates macrophage polarization through MEK/ERK signaling pathway for osteosarcoma progression promotion.","date":"2026","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42165997","citation_count":0,"is_preprint":false},{"pmid":"42147235","id":"PMC_42147235","title":"Silencing TMED2 suppresses cell growth and tumor progression in diffuse large B-cell lymphoma via inducing G0/G1 cell cycle arrest.","date":"2026","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42147235","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15108,"output_tokens":3680,"usd":0.050262,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11317,"output_tokens":4474,"usd":0.084218,"stage2_stop_reason":"end_turn"},"total_usd":0.13448,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"p24A (TMED2) is a type I transmembrane protein localized in microsomal membranes, zymogen granule membranes, and the plasma membrane, containing a KKXX ER retention/retrieval motif in its cytoplasmic tail, and is homologous to yeast Emp24p involved in ER-to-Golgi vesicular transport, identifying it as a member of the p24 family implicated in vesicular targeting and protein transport.\",\n      \"method\": \"Protein isolation, cloning, sequence analysis, subcellular fractionation, Northern blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cloning plus direct subcellular fractionation and sequence-based functional inference; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"8663407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"p24A (TMED2) cycles continuously between the intermediate compartment (IC) and the cis-Golgi network via large microtubule-dependent pre-Golgi carriers, and overexpression of GFP-p24A causes partial relocalization to ER elements; AlF4- (G-protein activator) blocks peripheral pre-Golgi movements and inhibits FRAP in the Golgi, indicating G-protein-dependent trafficking.\",\n      \"method\": \"GFP tagging + live-cell imaging, FRAP, AlF4- treatment, immunofluorescence localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging with GFP fusions, FRAP, pharmacological perturbation, and immunolocalization; multiple orthogonal methods in one study\",\n      \"pmids\": [\"9914165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p24A (TMED2) associates with PAR-2 at the Golgi apparatus via its N-terminal GOLD domain (residues 1–105) binding the second extracellular loop of PAR-2; after receptor activation, ARF1 regulates dissociation of PAR-2 from p24A and initiates PAR-2 trafficking to the plasma membrane; overexpression of the p24A GOLD domain fragment arrests PAR-2 at the Golgi and prevents resensitization.\",\n      \"method\": \"Co-immunoprecipitation, deletion/mutant constructs, ARF1 perturbation, trafficking assays, resensitization assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, domain-mapping mutagenesis, dominant-negative approach, and functional resensitization readout; multiple orthogonal methods\",\n      \"pmids\": [\"17693410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p24A (TMED2) interacts with the calcium sensing receptor (CaSR) via the CaSR carboxyl terminus; only the immaturely glycosylated (ER) form of CaSR binds p24A; interaction occurs in the ER/ERGIC and dissociates before the trans-Golgi; p24A and p24A(ΔGOLD) increase total and plasma membrane CaSR protein, but the p24A(FF/AA) mutant does not, indicating that p24A promotes CaSR stability and plasma membrane targeting in the early secretory pathway.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation in HEK293 cells, glycosylation analysis, mutant constructs, plasma membrane expression assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus mutagenesis; single lab, multiple methods\",\n      \"pmids\": [\"20361938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of TMED2/p24β1 protein (due to a point mutation in its signal sequence) in homozygous 99J mice results in concurrent loss of its oligomerization partners TMED7/p24γ3 and TMED10/p24δ1, demonstrating that TMED2 regulates the protein levels of its hetero-oligomeric complex partners; TMED2 is required for mouse embryo morphogenesis and placental labyrinth formation.\",\n      \"method\": \"ENU mutagenesis screen, Western blotting, immunofluorescence, mouse genetics (homozygous mutant embryo analysis)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct genetic loss-of-function in vivo with multiple protein-level readouts and orthogonal methods; demonstrates complex stability dependency\",\n      \"pmids\": [\"20178780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"p24A (TMED2) binds multiple GPCRs including PAR-1, P2Y1, P2Y2, P2Y4, P2Y11, and μ-opioid receptor 1B via acidic residues (Glu/Asp) in their second extracellular loops; p24A and p23 arrest these GPCRs at intracellular compartments; overexpression of the N-terminal p24A fragment impairs PAR-2 resensitization in primary rat astrocytes.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative fragment overexpression, trafficking assays in HEK293 cells and primary rat astrocytes\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with multiple receptors plus domain mapping plus native cell functional assay; single lab\",\n      \"pmids\": [\"21219331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMED2 associates with MITA/STING specifically upon viral stimulation (HSV-1 infection), reinforces MITA dimerization, and facilitates MITA trafficking from the ER to perinuclear vesicles; TMED2 suppression or deletion markedly impairs type I IFN production and increases HSV-1 viral load.\",\n      \"method\": \"Co-immunoprecipitation (stimulus-dependent), TMED2 knockdown/knockout, IFN production assays, viral load measurement, MITA dimerization assays, trafficking assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — stimulus-dependent co-IP, genetic KO, multiple functional readouts (IFN production, dimerization, trafficking, viral load); multiple orthogonal methods\",\n      \"pmids\": [\"30540941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMED2 is required cell-autonomously in the chorion for chorioallantoic attachment; Fibronectin is abnormally retained in the ER of Tmed2 homozygous mutant allantoises, identifying Fibronectin as a cargo protein of TMED2 in the early secretory pathway.\",\n      \"method\": \"Conditional/tissue-specific genetic analysis, ex vivo chorion-allantois recombination assay, immunostaining for ER retention of Fibronectin, gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with ex vivo tissue recombination and direct cargo retention evidence; single lab\",\n      \"pmids\": [\"30236446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMED2 and TMED10 are essential components of a supercomplex that mediates exchange of cholesterol and ceramides at ER-Golgi membrane contact sites; loss of TMED2 or TMED10 impairs plasma membrane lipid nanodomain (raft) formation by disrupting lipid compositional remodeling at ER-Golgi interfaces.\",\n      \"method\": \"Genetic screen (anthrax toxin intoxication), biochemical fractionation, morphological analysis, lipid composition analysis, TMED2/TMED10 KO cell lines\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genetic screen followed by biochemical, morphological, and mechanistic analyses with KO cells; multiple orthogonal methods\",\n      \"pmids\": [\"36174556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMED2 binds to Smoothened (SMO) and retains it in the ER and Golgi compartments, preventing SMO localization to the plasma membrane; mutation of TMED2 allows SMO accumulation at the plasma membrane, recapitulating early events of Hedgehog (HH) stimulation; TMED2 functions to repress HH signaling strength during neural differentiation.\",\n      \"method\": \"Haploid ESC genetic screen, super-resolution microscopy, co-immunoprecipitation/binding assay, TMED2 mutant analysis, neural differentiation assay\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genetic screen, super-resolution imaging, binding interaction, functional rescue/overexpression in multiple cell types; multiple orthogonal methods\",\n      \"pmids\": [\"35353806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMED2 interacts with TLR2, TLR4, and TLR3 (but not TLR5, TLR9 at the tested conditions) and is required for ER-to-Golgi export of both plasma membrane and endosomal TLRs; dominant-negative forms of TMED2 impair ER export of TLRs.\",\n      \"method\": \"Protein interaction studies (co-immunoprecipitation/pulldown), dominant-negative constructs, trafficking assays\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction studies plus dominant-negative functional assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"37491993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMED2 promotes cisplatin resistance in breast cancer cells by facilitating ubiquitination of KEAP1, thereby relieving KEAP1-mediated inhibition of Nrf2 and increasing expression of downstream drug resistance genes HO-1 and NQO1.\",\n      \"method\": \"Western blotting, RT-PCR, CCK-8 and TUNEL assays, TMED2 overexpression/knockdown in MCF-7 and MDA-MB-231 cells, ubiquitination assay\",\n      \"journal\": \"Current medical science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, western blot-based mechanistic inference without reconstitution or structural validation; moderate evidence for KEAP1 ubiquitination involvement\",\n      \"pmids\": [\"37615927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMED2 enhances EGFR-AKT signaling in glioma by facilitating EGFR recycling to the plasma membrane, identifying a role for TMED2 in membrane receptor recycling in addition to its known anterograde trafficking function.\",\n      \"method\": \"TMED2 knockdown/overexpression in glioma cell lines, EGFR trafficking/recycling assays, AKT signaling readouts, xenograft mouse model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with signaling readouts, recycling assay without biochemical reconstitution; limited mechanistic depth\",\n      \"pmids\": [\"38354922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMED2 promotes osteosarcoma progression via activation of the MAPK/MEK/ERK signaling pathway, with CKAP4 identified as a downstream effector of TMED2; TMED2 knockdown suppresses MEK/ERK activation and promotes M1 macrophage polarization.\",\n      \"method\": \"shRNA knockdown, Western blotting, xenograft mouse model, CKAP4 knockdown epistasis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD + Western blot; downstream effector identified by co-knockdown without direct biochemical interaction validation\",\n      \"pmids\": [\"42165997\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMED2 (p24A/p24β1) is a type I transmembrane p24-family cargo receptor that cycles between the ER, ERGIC, and cis-Golgi via microtubule-dependent carriers, where it forms hetero-oligomeric complexes with TMED7 and TMED10 to facilitate anterograde trafficking of specific cargo proteins—including multiple GPCRs (PAR-1, PAR-2, P2Y receptors, μ-opioid receptor), TLRs, the calcium sensing receptor, Fibronectin, and Smoothened—by binding their extracellular loops and releasing them in an ARF1-dependent manner; TMED2 also forms part of an ER-Golgi supercomplex that exchanges cholesterol and ceramides at membrane contact sites to control plasma membrane lipid nanodomain composition, and upon viral infection specifically associates with MITA/STING to reinforce its dimerization and trafficking required for innate immune signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMED2 (p24A/p24\\u03b21) is a type I transmembrane p24-family cargo receptor that operates in the early secretory pathway, cycling between the ER, intermediate compartment, and cis-Golgi via large microtubule-dependent pre-Golgi carriers in a G-protein-dependent manner [#0, #1]. It functions as a hetero-oligomer whose integrity it controls: loss of TMED2 in vivo concurrently destabilizes its partners TMED7 and TMED10, and TMED2 is required for mouse embryo morphogenesis and placental labyrinth formation [#4]. Through its N-terminal GOLD domain, TMED2 binds the second extracellular loop of client receptors\\u2014engaging acidic residues in the extracellular loops of multiple GPCRs (PAR-1, PAR-2, P2Y receptors, \\u03bc-opioid receptor)\\u2014and then releases them in an ARF1-dependent manner to permit anterograde trafficking, so that dominant-negative GOLD fragments arrest cargo at intracellular compartments and block receptor resensitization [#2, #5]. This receptor-chaperoning role extends to the calcium-sensing receptor, whose immature ER form it stabilizes and routes to the plasma membrane [#3], to Toll-like receptors TLR2/3/4 whose ER-to-Golgi export it mediates [#10], and to Fibronectin, which is retained in the ER upon TMED2 loss [#7]. TMED2 also acts as a negative regulator of trafficking for Smoothened, retaining SMO in the ER and Golgi to repress Hedgehog signaling strength during neural differentiation [#9]. Beyond discrete cargo handling, TMED2 together with TMED10 forms a supercomplex that exchanges cholesterol and ceramides at ER-Golgi membrane contact sites, controlling plasma membrane lipid nanodomain composition [#8], and upon viral infection it associates with MITA/STING to reinforce its dimerization and ER-to-vesicle trafficking required for type I interferon production [#6].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established TMED2 as a p24-family transmembrane protein of the secretory pathway, framing it as a candidate vesicular transport factor rather than an uncharacterized membrane protein.\",\n      \"evidence\": \"Protein isolation, cloning, sequence analysis, and subcellular fractionation identifying a KKXX ER retrieval motif and homology to yeast Emp24p\",\n      \"pmids\": [\"8663407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct cargo identified\", \"Functional role in transport inferred from homology, not demonstrated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined how and where TMED2 moves, showing it continuously cycles between the intermediate compartment and cis-Golgi on microtubule-dependent carriers under G-protein control.\",\n      \"evidence\": \"GFP-fusion live imaging, FRAP, and AlF4- pharmacological perturbation in cultured cells\",\n      \"pmids\": [\"9914165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the regulating G-protein not resolved\", \"Cargo carried during cycling not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Provided the first mechanistic cargo model, demonstrating GOLD-domain binding to a receptor extracellular loop and ARF1-dependent release as the basis for regulated anterograde trafficking.\",\n      \"evidence\": \"Reciprocal co-IP, GOLD domain-mapping mutagenesis, ARF1 perturbation, and PAR-2 resensitization assays\",\n      \"pmids\": [\"17693410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ARF1-triggered release not structurally resolved\", \"Generality across receptor classes not yet tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the cargo-chaperone role to receptor biogenesis, showing TMED2 stabilizes the immature ER form of CaSR and promotes its plasma membrane delivery.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, glycosylation analysis, and mutant plasma membrane expression assays in HEK293 cells\",\n      \"pmids\": [\"20361938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FF/AA motif role in release not mechanistically explained\", \"Single-lab interaction data\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated in vivo that TMED2 maintains the protein levels of its hetero-oligomeric partners and is essential for embryonic and placental morphogenesis, establishing functional interdependence of the p24 complex.\",\n      \"evidence\": \"ENU point-mutant mice, Western blotting, immunofluorescence, and mutant embryo analysis\",\n      \"pmids\": [\"20178780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo responsible for morphogenesis defects not identified at this stage\", \"Mechanism linking complex loss to placental failure unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Generalized the GOLD-domain receptor interaction to a broad GPCR clientele, identifying acidic extracellular-loop residues as the shared recognition determinant.\",\n      \"evidence\": \"Co-IP with multiple GPCRs, dominant-negative fragment overexpression, and trafficking assays in HEK293 cells and primary astrocytes\",\n      \"pmids\": [\"21219331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity rules among receptors not defined\", \"Quantitative binding affinities not measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a stimulus-specific signaling role, showing TMED2 is recruited to MITA/STING upon viral infection to reinforce dimerization and trafficking needed for type I IFN responses.\",\n      \"evidence\": \"Stimulus-dependent co-IP, TMED2 knockdown/knockout, IFN and viral load assays, and MITA dimerization/trafficking readouts\",\n      \"pmids\": [\"30540941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How viral stimulus triggers the TMED2-MITA association is unknown\", \"Whether the p24 complex partners participate not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected the in vivo morphogenesis phenotype to a specific cargo by identifying Fibronectin as ER-retained upon TMED2 loss in the chorion.\",\n      \"evidence\": \"Tissue-specific genetic analysis, ex vivo chorion-allantois recombination, and Fibronectin ER-retention immunostaining\",\n      \"pmids\": [\"30236446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TMED2-Fibronectin binding not shown\", \"Whether other cargo contribute to the defect unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a lipid-transfer function distinct from cargo handling, placing TMED2 with TMED10 in a supercomplex that exchanges cholesterol and ceramides at ER-Golgi contact sites to shape plasma membrane nanodomains.\",\n      \"evidence\": \"Anthrax-toxin genetic screen, biochemical fractionation, lipid composition analysis, and KO cell lines\",\n      \"pmids\": [\"36174556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lipid-transfer activity of TMED2 vs. scaffolding role not distinguished\", \"Structure of the supercomplex unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established TMED2 as a negative trafficking regulator, retaining Smoothened in the ER/Golgi to dampen Hedgehog signaling during neural differentiation.\",\n      \"evidence\": \"Haploid ESC genetic screen, super-resolution microscopy, binding assay, and neural differentiation assays\",\n      \"pmids\": [\"35353806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of SMO release under Hedgehog stimulation not defined\", \"Whether retention uses the GOLD domain not tested here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened the cargo repertoire to innate immune receptors, showing TMED2 mediates ER-to-Golgi export of TLR2/3/4.\",\n      \"evidence\": \"Co-IP/pulldown, dominant-negative constructs, and trafficking assays\",\n      \"pmids\": [\"37491993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recognition motif on TLRs not mapped\", \"Selectivity excluding TLR5/TLR9 not mechanistically explained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proposed a disease-associated role in which TMED2 supports cisplatin resistance by promoting KEAP1 ubiquitination and relieving inhibition of Nrf2.\",\n      \"evidence\": \"Overexpression/knockdown in breast cancer lines, ubiquitination assay, and viability/apoptosis readouts\",\n      \"pmids\": [\"37615927\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Western-blot-based mechanistic inference without reconstitution or structural validation\", \"Direct TMED2-KEAP1 interaction not established\", \"Link to TMED2's trafficking function unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Suggested a recycling role beyond anterograde transport, with TMED2 promoting EGFR return to the plasma membrane to enhance EGFR-AKT signaling in glioma.\",\n      \"evidence\": \"Knockdown/overexpression in glioma lines, recycling and AKT readouts, and xenograft model\",\n      \"pmids\": [\"38354922\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Recycling mechanism not biochemically reconstituted\", \"Direct EGFR engagement not demonstrated\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated TMED2 in tumor progression via MAPK/MEK/ERK activation with CKAP4 as a downstream effector in osteosarcoma.\",\n      \"evidence\": \"shRNA knockdown, Western blotting, xenograft model, and CKAP4 epistasis\",\n      \"pmids\": [\"42165997\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Downstream effector identified by co-knockdown without direct interaction validation\", \"Connection to TMED2 trafficking activity not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single GOLD-domain receptor selects among its diverse cargo and switches between promoting versus restraining their surface delivery remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of GOLD-cargo recognition\", \"Rules distinguishing anterograde export from ER retention not defined\", \"Mechanistic basis of stimulus-dependent partner selection (e.g. STING) unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 3, 5, 7, 9, 10]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 3, 7, 9]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 2, 7, 10]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"complexes\": [\n      \"TMED2/TMED7/TMED10 p24 hetero-oligomer\",\n      \"ER-Golgi lipid-exchange supercomplex (TMED2/TMED10)\"\n    ],\n    \"partners\": [\n      \"TMED7\",\n      \"TMED10\",\n      \"PAR-2\",\n      \"CaSR\",\n      \"SMO\",\n      \"STING/MITA\",\n      \"TLR4\",\n      \"Fibronectin\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}