{"gene":"EMC10","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2017,"finding":"Emc10 signals through small GTPases, p21-activated kinase (PAK), and the p38 MAPK–MK2 pathway to promote actin polymerization and endothelial cell migration; endothelial cell outgrowth from infarcted heart explants was also dependent on p38 MAPK–MK2 signaling downstream of Emc10.","method":"Cultured endothelial cell assays (migration, actin polymerization), infarcted heart explant outgrowth assay, Emc10-KO and bone marrow chimeric mice subjected to coronary artery ligation","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro signaling assays combined with KO mouse model and bone marrow chimera rescue, single lab","pmids":["28931551"],"is_preprint":false},{"year":2017,"finding":"Bone marrow-derived monocytes and macrophages are the predominant cellular sources of Emc10 in the infarcted murine heart; transplantation of wild-type bone marrow into Emc10-KO mice rescued the angiogenic defect and ameliorated left ventricular remodeling, establishing a bone marrow–heart axis.","method":"Emc10-KO mice, bone marrow chimera experiments (KO mice reconstituted with WT bone marrow), coronary artery ligation model","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal bone marrow chimera rescue with defined cellular phenotype, single lab","pmids":["28931551"],"is_preprint":false},{"year":2017,"finding":"Loss-of-function of Mirta22/Emc10 in the context of the 22q11.2 deletion mouse model rescues prepulse inhibition deficits, working memory impairment, social memory deficits, and synaptic/structural plasticity abnormalities in the prefrontal cortex, placing Emc10 up-regulation as a causal driver of these schizophrenia-related deficits downstream of 22q11.2-associated microRNA dysregulation.","method":"Genetic epistasis: Df(16)A+/− mice combined with homozygous Mirta22 LoF allele; behavioral tests (PPI, working memory, social memory); electrophysiology and structural plasticity assays in prefrontal cortex","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clear genetic epistasis with multiple orthogonal behavioral and cellular readouts, causal pathway established","pmids":["28696314"],"is_preprint":false},{"year":2018,"finding":"EMC10 deficiency in spermatozoa leads to inactivation of Na/K-ATPase, resulting in elevated intracellular Na+, decreased HCO3− entry, reduced cAMP-dependent PKA substrate phosphorylation, and reduced protein tyrosine phosphorylation, demonstrating that EMC10 maintains sperm ion balance (Na+ and HCO3−) required for motility, capacitation, and acrosome reaction.","method":"Emc10 KO mice; ion measurement (intracellular Na+, HCO3−); cAMP/PKA substrate phosphorylation assays; protein tyrosine phosphorylation assays; intracytoplasmic sperm injection (ICSI) rescue experiment","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model with multiple orthogonal biochemical mechanistic assays (ion balance, Na/K-ATPase activity, phosphorylation cascades) plus ICSI rescue","pmids":["29659949"],"is_preprint":false},{"year":2022,"finding":"The membrane-bound isoform of EMC10 (mEMC10), but not the secreted isoform (scEMC10), is required for sperm motility by positively regulating ATP1B3 (Na/K-ATPase β3 subunit) expression in germ cells; intra-testis mEMC10 overexpression rescued sperm motility defects in Emc10 KO mice whereas exogenous recombinant scEMC10 did not, establishing an mEMC10–Na,K/ATPase α4β3 axis for cytoplasmic Na+ homeostasis.","method":"Isoform-specific overexpression (intra-testis injection), Emc10 KO mice, recombinant scEMC10 treatment, ATP1B3 protein quantification, sperm motility assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific rescue experiment in KO background with defined molecular target (ATP1B3), single lab","pmids":["36077468"],"is_preprint":false},{"year":2022,"finding":"Secreted EMC10 (scEMC10) can be transported into cells where it binds to the catalytic subunit of PKA and inhibits PKA-stimulated CREB activity; ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets.","method":"Co-immunoprecipitation / binding assay (scEMC10 with PKA catalytic subunit), Emc10-KO mice and scEMC10-overexpressing mice, energy expenditure measurements, CREB activity assays, monoclonal antibody neutralization experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding interaction identified plus KO/OE mouse models with defined signaling readouts, single lab, abstract-level detail","pmids":["36443308"],"is_preprint":false},{"year":2024,"finding":"The two isoforms of EMC10 have opposing roles in hepatic ER stress: the secreted isoform (scEMC10) promotes, while the membrane-bound isoform (mEMC10) suppresses, activation of the PERK–eIF2α–ATF4 signaling pathway; Emc10 KO exacerbated hepatic ER stress and steatosis, whereas hepatic mEMC10 overexpression ameliorated them.","method":"Emc10 KO mice, hepatic mEMC10 overexpression, scEMC10 overexpression, scEMC10 neutralizing antibody treatment, methionine/choline-deficient diet and tunicamycin models, PERK–eIF2α–ATF4 pathway analysis in HepG2 cells","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific KO and overexpression with defined signaling pathway readouts across multiple mouse models, single lab","pmids":["38599383"],"is_preprint":false},{"year":2025,"finding":"Secreted EMC10 (scEMC10) suppresses muscle glucose uptake by inhibiting GLUT4 expression and membrane translocation, and by suppressing AMP-activated protein kinase activation and insulin signaling cascades; inhibition of scEMC10 via a neutralizing antibody enhanced GLUT4 membrane translocation and improved whole-body glucose homeostasis in mice.","method":"Emc10 KO mice, recombinant scEMC10 treatment, scEMC10 neutralizing antibody, myoblast cell studies, GLUT4 expression and membrane translocation assays, AMPK activation assays, muscle glucose uptake measurements","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO, recombinant protein, and antibody neutralization with multiple orthogonal biochemical readouts, single lab","pmids":["40441535"],"is_preprint":false},{"year":2009,"finding":"INM02 (EMC10) mRNA expression in MIN6 cells and intact isolated islets is upregulated more than threefold by high glucose (25 mM vs 5.5 mM), and secretion of INM02 protein is significantly augmented by high glucose in vitro, indicating glucose-regulated expression and secretion.","method":"RT-qPCR and ELISA in MIN6 cells and isolated pancreatic islets under varying glucose concentrations; recombinant protein production; serum detection by ELISA","journal":"The Journal of endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, expression and secretion assays only, no mechanistic pathway placed beyond glucose regulation","pmids":["19570817"],"is_preprint":false}],"current_model":"EMC10 encodes two isoforms — a membrane-bound form (mEMC10) and a secreted form (scEMC10) — with distinct, often opposing, mechanistic roles: mEMC10 maintains ER homeostasis (suppressing PERK–eIF2α–ATF4 signaling in the liver and supporting Na/K-ATPase α4β3 function to preserve sperm cytoplasmic Na+ homeostasis and motility), while scEMC10 acts as a circulating inhibitor that binds the PKA catalytic subunit to suppress thermogenesis in adipocytes, inhibits GLUT4 expression and membrane translocation via AMPK and insulin signaling suppression in muscle, and promotes hepatic ER stress; in the brain, Emc10 up-regulation (driven by 22q11.2-linked miRNA dysregulation) inhibits neuronal maturation and causes schizophrenia-related synaptic and behavioral deficits, and in the heart, monocyte/macrophage-derived Emc10 promotes post-infarction angiogenesis through small GTPases, PAK, and p38 MAPK–MK2-dependent actin polymerization and endothelial cell migration."},"narrative":{"mechanistic_narrative":"EMC10 is expressed as two functionally distinct isoforms — a membrane-bound form (mEMC10) and a secreted form (scEMC10) — that exert opposing control over endoplasmic reticulum homeostasis and metabolic and ion-transport signaling [PMID:36077468, PMID:38599383]. mEMC10 supports cellular homeostasis: it suppresses the PERK–eIF2α–ATF4 ER-stress pathway in liver, where mEMC10 overexpression ameliorates hepatic steatosis while scEMC10 promotes ER stress [PMID:38599383], and it sustains spermatozoa Na+/HCO3− balance by positively regulating the Na/K-ATPase β3 subunit ATP1B3, an mEMC10–Na,K-ATPase α4β3 axis required for sperm motility, cAMP/PKA-dependent phosphorylation, capacitation, and the acrosome reaction [PMID:29659949, PMID:36077468]. scEMC10 acts as a circulating inhibitor of metabolic signaling: it is internalized and binds the catalytic subunit of PKA to suppress PKA–CREB activity and thermogenesis in adipocytes [PMID:36443308], and it suppresses muscle glucose uptake by inhibiting GLUT4 expression and membrane translocation through dampened AMPK and insulin signaling [PMID:40441535]. In the brain, Emc10 up-regulation driven by 22q11.2-associated microRNA dysregulation is a causal driver of schizophrenia-related synaptic plasticity and behavioral deficits, as Emc10 loss-of-function rescues these phenotypes in the 22q11.2 deletion model [PMID:28696314]. In the infarcted heart, bone marrow-derived monocyte/macrophage Emc10 promotes angiogenesis and endothelial cell migration via small GTPases, PAK, and p38 MAPK–MK2-dependent actin polymerization [PMID:28931551].","teleology":[{"year":2009,"claim":"Established that EMC10 (INM02) is a glucose-responsive gene whose expression and protein secretion are induced by high glucose, first hinting at a secreted, metabolically regulated product.","evidence":"RT-qPCR and ELISA in MIN6 cells and isolated islets under varying glucose, with serum detection","pmids":["19570817"],"confidence":"Low","gaps":["No mechanistic pathway placed beyond glucose regulation","Did not distinguish isoforms or identify a molecular target","Secreted form's physiological action unknown"]},{"year":2017,"claim":"Defined a bone marrow–heart axis in which monocyte/macrophage-derived Emc10 drives post-infarction angiogenesis, answering where Emc10 acts and through which intracellular signaling it promotes endothelial migration.","evidence":"Emc10-KO and bone marrow chimeric mice with coronary artery ligation, endothelial migration and actin polymerization assays, infarct explant outgrowth","pmids":["28931551"],"confidence":"Medium","gaps":["Receptor or surface mediator linking Emc10 to small GTPase/PAK activation not identified","Whether the secreted isoform is the active species in this context not resolved","Human relevance untested"]},{"year":2017,"claim":"Placed Emc10 up-regulation as a causal node downstream of 22q11.2 microRNA dysregulation in schizophrenia-related circuit and behavioral deficits, establishing it as a disease-relevant effector.","evidence":"Genetic epistasis in Df(16)A+/− mice with Mirta22 LoF allele, behavioral and electrophysiological/structural plasticity readouts","pmids":["28696314"],"confidence":"High","gaps":["Molecular mechanism by which neuronal Emc10 inhibits maturation not defined","Isoform responsible in neurons unknown","Downstream synaptic effectors not identified"]},{"year":2018,"claim":"Connected EMC10 to ion homeostasis by showing its loss inactivates sperm Na/K-ATPase, raising intracellular Na+ and disrupting the HCO3−/cAMP/PKA/tyrosine-phosphorylation cascade required for fertility.","evidence":"Emc10 KO mice with ion measurements, PKA substrate and tyrosine phosphorylation assays, ICSI rescue","pmids":["29659949"],"confidence":"High","gaps":["Direct molecular interaction with the Na/K-ATPase not demonstrated","Whether EMC10 regulates pump expression or activity unresolved at this stage","Isoform contribution not yet dissected"]},{"year":2022,"claim":"Resolved that the membrane-bound isoform specifically maintains sperm ion balance by up-regulating the Na/K-ATPase β3 subunit ATP1B3, separating mEMC10 function from the secreted form.","evidence":"Isoform-specific intra-testis overexpression and recombinant scEMC10 treatment in Emc10 KO mice, ATP1B3 quantification, motility assays","pmids":["36077468"],"confidence":"Medium","gaps":["Mechanism by which mEMC10 regulates ATP1B3 expression unknown","Direct binding to the pump not shown","Single-lab isoform rescue"]},{"year":2022,"claim":"Identified scEMC10 as a circulating PKA inhibitor that is internalized and binds the PKA catalytic subunit to suppress CREB activity and adipocyte thermogenesis, giving the secreted isoform a defined molecular target.","evidence":"Co-IP/binding assay, Emc10 KO and scEMC10-overexpressing mice, energy expenditure and CREB assays, neutralizing antibody","pmids":["36443308"],"confidence":"Medium","gaps":["Mechanism of scEMC10 cellular uptake not defined","Structural basis of PKA binding unknown","Reciprocal/structural validation of interaction limited"]},{"year":2024,"claim":"Demonstrated the two isoforms have opposing effects on hepatic ER stress, with mEMC10 suppressing and scEMC10 promoting PERK–eIF2α–ATF4 signaling, unifying the isoform dichotomy in a metabolic disease context.","evidence":"Isoform-specific KO and hepatic overexpression mice, scEMC10 neutralizing antibody, MCD/tunicamycin models, pathway analysis in HepG2","pmids":["38599383"],"confidence":"Medium","gaps":["How mEMC10 mechanistically restrains PERK signaling not defined","Receptor mediating scEMC10's pro-ER-stress effect unknown","Single-lab models"]},{"year":2025,"claim":"Extended scEMC10's inhibitory metabolic role to skeletal muscle, showing it suppresses GLUT4 expression/translocation and AMPK/insulin signaling, positioning circulating scEMC10 as a regulator of whole-body glucose homeostasis.","evidence":"Emc10 KO mice, recombinant scEMC10 and neutralizing antibody, myoblast studies, GLUT4 translocation and AMPK assays, glucose uptake measurements","pmids":["40441535"],"confidence":"Medium","gaps":["Surface receptor for scEMC10 in muscle not identified","Whether PKA binding underlies the AMPK/insulin effects not connected","Single-lab study"]},{"year":null,"claim":"The cell-surface receptor(s) or uptake machinery through which secreted scEMC10 acts across tissues, and the molecular basis by which mEMC10 supports ER and ion-pump homeostasis, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No receptor identified for scEMC10 internalization","No structural model of EMC10 or its complexes","Mechanism linking mEMC10 to ATP1B3 and PERK pathway regulation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,8]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,5]}],"complexes":[],"partners":["PRKACA","ATP1B3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5UCC4","full_name":"ER membrane protein complex subunit 10","aliases":["Hematopoietic signal peptide-containing membrane domain-containing protein 1"],"length_aa":262,"mass_kda":27.3,"function":"Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins (PubMed:29242231, PubMed:29809151, PubMed:30415835, PubMed:32439656, PubMed:32459176). Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues (PubMed:29242231, PubMed:29809151, PubMed:30415835). Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices (PubMed:29809151, PubMed:30415835). It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes (PubMed:29242231, PubMed:29809151). By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors (PubMed:30415835). By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (Probable). Promotes angiogenesis and tissue repair in the heart after myocardial infarction. Stimulates cardiac endothelial cell migration and outgrowth via the activation of p38 MAPK, PAK and MAPK2 signaling pathways (PubMed:28931551)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q5UCC4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EMC10","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000161671","cell_line_id":"CID001936","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"CCDC47","stoichiometry":10.0},{"gene":"PRPF40A","stoichiometry":0.2},{"gene":"EMC4","stoichiometry":0.2},{"gene":"EMC7","stoichiometry":0.2},{"gene":"EMC3","stoichiometry":0.2},{"gene":"EMC2","stoichiometry":0.2},{"gene":"EMC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001936","total_profiled":1310},"omim":[{"mim_id":"621496","title":"ENDOPLASMIC RETICULUM MEMBRANE PROTEIN COMPLEX, SUBUNIT 9; EMC9","url":"https://www.omim.org/entry/621496"},{"mim_id":"620273","title":"ENDOPLASMIC RETICULUM MEMBRANE PROTEIN COMPLEX, SUBUNIT 3; EMC3","url":"https://www.omim.org/entry/620273"},{"mim_id":"619264","title":"NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND VARIABLE SEIZURES; NEDDFAS","url":"https://www.omim.org/entry/619264"},{"mim_id":"614545","title":"ENDOPLASMIC RETICULUM MEMBRANE PROTEIN COMPLEX, SUBUNIT 10; EMC10","url":"https://www.omim.org/entry/614545"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":173.6}],"url":"https://www.proteinatlas.org/search/EMC10"},"hgnc":{"alias_symbol":["INM02","HSS1","HSM1"],"prev_symbol":["C19orf63"]},"alphafold":{"accession":"Q5UCC4","domains":[{"cath_id":"-","chopping":"52-189","consensus_level":"high","plddt":92.1199,"start":52,"end":189}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5UCC4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5UCC4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5UCC4-F1-predicted_aligned_error_v6.png","plddt_mean":77.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EMC10","jax_strain_url":"https://www.jax.org/strain/search?query=EMC10"},"sequence":{"accession":"Q5UCC4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5UCC4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5UCC4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5UCC4"}},"corpus_meta":[{"pmid":"28931551","id":"PMC_28931551","title":"EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subunit 10) Is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction.","date":"2017","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/28931551","citation_count":44,"is_preprint":false},{"pmid":"28696314","id":"PMC_28696314","title":"Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28696314","citation_count":34,"is_preprint":false},{"pmid":"32869858","id":"PMC_32869858","title":"EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay.","date":"2020","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32869858","citation_count":32,"is_preprint":false},{"pmid":"29659949","id":"PMC_29659949","title":"EMC10 governs male fertility via maintaining sperm ion balance.","date":"2018","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29659949","citation_count":26,"is_preprint":false},{"pmid":"33531666","id":"PMC_33531666","title":"A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features.","date":"2021","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33531666","citation_count":22,"is_preprint":false},{"pmid":"38599383","id":"PMC_38599383","title":"EMC10 modulates hepatic ER stress and steatosis in an isoform-specific manner.","date":"2024","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/38599383","citation_count":15,"is_preprint":false},{"pmid":"36443308","id":"PMC_36443308","title":"Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36443308","citation_count":14,"is_preprint":false},{"pmid":"19570817","id":"PMC_19570817","title":"Molecular cloning of a novel secreted peptide, INM02, and regulation of its expression by glucose.","date":"2009","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19570817","citation_count":11,"is_preprint":false},{"pmid":"35684946","id":"PMC_35684946","title":"Biallelic loss of EMC10 leads to mild to severe intellectual disability.","date":"2022","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35684946","citation_count":11,"is_preprint":false},{"pmid":"40441535","id":"PMC_40441535","title":"Secreted EMC10 inhibits muscle GLUT4 activity and glucose uptake in mice.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40441535","citation_count":4,"is_preprint":false},{"pmid":"36077468","id":"PMC_36077468","title":"Membrane-Bound EMC10 Is Required for Sperm Motility via Maintaining the Homeostasis of Cytoplasm Sodium in Sperm.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36077468","citation_count":4,"is_preprint":false},{"pmid":"40150819","id":"PMC_40150819","title":"Case Report: Gingival Hyperplasia and Scoliosis as Additional Features of EMC10-Related Neurodevelopmental Disorder.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40150819","citation_count":1,"is_preprint":false},{"pmid":"40741735","id":"PMC_40741735","title":"EMC10 Gene Variants May Cause Dual Molecular Effects on the Neuropsychiatric Disease Pattern.","date":"2025","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40741735","citation_count":0,"is_preprint":false},{"pmid":"40102590","id":"PMC_40102590","title":"Serum secreted EMC10 (scEMC10) levels are inversely associated with metabolically active brown adipose tissue in humans.","date":"2025","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/40102590","citation_count":0,"is_preprint":false},{"pmid":"40232312","id":"PMC_40232312","title":"Chromosomal structural variation loci HSS1 and HSS6 lead to hybrid sterility in rice.","date":"2025","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/40232312","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10158,"output_tokens":2737,"usd":0.035764,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9981,"output_tokens":3401,"usd":0.067465,"stage2_stop_reason":"end_turn"},"total_usd":0.103229,"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\": 2017,\n      \"finding\": \"Emc10 signals through small GTPases, p21-activated kinase (PAK), and the p38 MAPK–MK2 pathway to promote actin polymerization and endothelial cell migration; endothelial cell outgrowth from infarcted heart explants was also dependent on p38 MAPK–MK2 signaling downstream of Emc10.\",\n      \"method\": \"Cultured endothelial cell assays (migration, actin polymerization), infarcted heart explant outgrowth assay, Emc10-KO and bone marrow chimeric mice subjected to coronary artery ligation\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro signaling assays combined with KO mouse model and bone marrow chimera rescue, single lab\",\n      \"pmids\": [\"28931551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Bone marrow-derived monocytes and macrophages are the predominant cellular sources of Emc10 in the infarcted murine heart; transplantation of wild-type bone marrow into Emc10-KO mice rescued the angiogenic defect and ameliorated left ventricular remodeling, establishing a bone marrow–heart axis.\",\n      \"method\": \"Emc10-KO mice, bone marrow chimera experiments (KO mice reconstituted with WT bone marrow), coronary artery ligation model\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal bone marrow chimera rescue with defined cellular phenotype, single lab\",\n      \"pmids\": [\"28931551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss-of-function of Mirta22/Emc10 in the context of the 22q11.2 deletion mouse model rescues prepulse inhibition deficits, working memory impairment, social memory deficits, and synaptic/structural plasticity abnormalities in the prefrontal cortex, placing Emc10 up-regulation as a causal driver of these schizophrenia-related deficits downstream of 22q11.2-associated microRNA dysregulation.\",\n      \"method\": \"Genetic epistasis: Df(16)A+/− mice combined with homozygous Mirta22 LoF allele; behavioral tests (PPI, working memory, social memory); electrophysiology and structural plasticity assays in prefrontal cortex\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clear genetic epistasis with multiple orthogonal behavioral and cellular readouts, causal pathway established\",\n      \"pmids\": [\"28696314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EMC10 deficiency in spermatozoa leads to inactivation of Na/K-ATPase, resulting in elevated intracellular Na+, decreased HCO3− entry, reduced cAMP-dependent PKA substrate phosphorylation, and reduced protein tyrosine phosphorylation, demonstrating that EMC10 maintains sperm ion balance (Na+ and HCO3−) required for motility, capacitation, and acrosome reaction.\",\n      \"method\": \"Emc10 KO mice; ion measurement (intracellular Na+, HCO3−); cAMP/PKA substrate phosphorylation assays; protein tyrosine phosphorylation assays; intracytoplasmic sperm injection (ICSI) rescue experiment\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model with multiple orthogonal biochemical mechanistic assays (ion balance, Na/K-ATPase activity, phosphorylation cascades) plus ICSI rescue\",\n      \"pmids\": [\"29659949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The membrane-bound isoform of EMC10 (mEMC10), but not the secreted isoform (scEMC10), is required for sperm motility by positively regulating ATP1B3 (Na/K-ATPase β3 subunit) expression in germ cells; intra-testis mEMC10 overexpression rescued sperm motility defects in Emc10 KO mice whereas exogenous recombinant scEMC10 did not, establishing an mEMC10–Na,K/ATPase α4β3 axis for cytoplasmic Na+ homeostasis.\",\n      \"method\": \"Isoform-specific overexpression (intra-testis injection), Emc10 KO mice, recombinant scEMC10 treatment, ATP1B3 protein quantification, sperm motility assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific rescue experiment in KO background with defined molecular target (ATP1B3), single lab\",\n      \"pmids\": [\"36077468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Secreted EMC10 (scEMC10) can be transported into cells where it binds to the catalytic subunit of PKA and inhibits PKA-stimulated CREB activity; ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets.\",\n      \"method\": \"Co-immunoprecipitation / binding assay (scEMC10 with PKA catalytic subunit), Emc10-KO mice and scEMC10-overexpressing mice, energy expenditure measurements, CREB activity assays, monoclonal antibody neutralization experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding interaction identified plus KO/OE mouse models with defined signaling readouts, single lab, abstract-level detail\",\n      \"pmids\": [\"36443308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The two isoforms of EMC10 have opposing roles in hepatic ER stress: the secreted isoform (scEMC10) promotes, while the membrane-bound isoform (mEMC10) suppresses, activation of the PERK–eIF2α–ATF4 signaling pathway; Emc10 KO exacerbated hepatic ER stress and steatosis, whereas hepatic mEMC10 overexpression ameliorated them.\",\n      \"method\": \"Emc10 KO mice, hepatic mEMC10 overexpression, scEMC10 overexpression, scEMC10 neutralizing antibody treatment, methionine/choline-deficient diet and tunicamycin models, PERK–eIF2α–ATF4 pathway analysis in HepG2 cells\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific KO and overexpression with defined signaling pathway readouts across multiple mouse models, single lab\",\n      \"pmids\": [\"38599383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Secreted EMC10 (scEMC10) suppresses muscle glucose uptake by inhibiting GLUT4 expression and membrane translocation, and by suppressing AMP-activated protein kinase activation and insulin signaling cascades; inhibition of scEMC10 via a neutralizing antibody enhanced GLUT4 membrane translocation and improved whole-body glucose homeostasis in mice.\",\n      \"method\": \"Emc10 KO mice, recombinant scEMC10 treatment, scEMC10 neutralizing antibody, myoblast cell studies, GLUT4 expression and membrane translocation assays, AMPK activation assays, muscle glucose uptake measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO, recombinant protein, and antibody neutralization with multiple orthogonal biochemical readouts, single lab\",\n      \"pmids\": [\"40441535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"INM02 (EMC10) mRNA expression in MIN6 cells and intact isolated islets is upregulated more than threefold by high glucose (25 mM vs 5.5 mM), and secretion of INM02 protein is significantly augmented by high glucose in vitro, indicating glucose-regulated expression and secretion.\",\n      \"method\": \"RT-qPCR and ELISA in MIN6 cells and isolated pancreatic islets under varying glucose concentrations; recombinant protein production; serum detection by ELISA\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, expression and secretion assays only, no mechanistic pathway placed beyond glucose regulation\",\n      \"pmids\": [\"19570817\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EMC10 encodes two isoforms — a membrane-bound form (mEMC10) and a secreted form (scEMC10) — with distinct, often opposing, mechanistic roles: mEMC10 maintains ER homeostasis (suppressing PERK–eIF2α–ATF4 signaling in the liver and supporting Na/K-ATPase α4β3 function to preserve sperm cytoplasmic Na+ homeostasis and motility), while scEMC10 acts as a circulating inhibitor that binds the PKA catalytic subunit to suppress thermogenesis in adipocytes, inhibits GLUT4 expression and membrane translocation via AMPK and insulin signaling suppression in muscle, and promotes hepatic ER stress; in the brain, Emc10 up-regulation (driven by 22q11.2-linked miRNA dysregulation) inhibits neuronal maturation and causes schizophrenia-related synaptic and behavioral deficits, and in the heart, monocyte/macrophage-derived Emc10 promotes post-infarction angiogenesis through small GTPases, PAK, and p38 MAPK–MK2-dependent actin polymerization and endothelial cell migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EMC10 is expressed as two functionally distinct isoforms — a membrane-bound form (mEMC10) and a secreted form (scEMC10) — that exert opposing control over endoplasmic reticulum homeostasis and metabolic and ion-transport signaling [#4, #6]. mEMC10 supports cellular homeostasis: it suppresses the PERK–eIF2\\u03b1–ATF4 ER-stress pathway in liver, where mEMC10 overexpression ameliorates hepatic steatosis while scEMC10 promotes ER stress [#6], and it sustains spermatozoa Na+/HCO3\\u2212 balance by positively regulating the Na/K-ATPase \\u03b23 subunit ATP1B3, an mEMC10–Na,K-ATPase \\u03b14\\u03b23 axis required for sperm motility, cAMP/PKA-dependent phosphorylation, capacitation, and the acrosome reaction [#3, #4]. scEMC10 acts as a circulating inhibitor of metabolic signaling: it is internalized and binds the catalytic subunit of PKA to suppress PKA–CREB activity and thermogenesis in adipocytes [#5], and it suppresses muscle glucose uptake by inhibiting GLUT4 expression and membrane translocation through dampened AMPK and insulin signaling [#7]. In the brain, Emc10 up-regulation driven by 22q11.2-associated microRNA dysregulation is a causal driver of schizophrenia-related synaptic plasticity and behavioral deficits, as Emc10 loss-of-function rescues these phenotypes in the 22q11.2 deletion model [#2]. In the infarcted heart, bone marrow-derived monocyte/macrophage Emc10 promotes angiogenesis and endothelial cell migration via small GTPases, PAK, and p38 MAPK–MK2-dependent actin polymerization [#0, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that EMC10 (INM02) is a glucose-responsive gene whose expression and protein secretion are induced by high glucose, first hinting at a secreted, metabolically regulated product.\",\n      \"evidence\": \"RT-qPCR and ELISA in MIN6 cells and isolated islets under varying glucose, with serum detection\",\n      \"pmids\": [\"19570817\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic pathway placed beyond glucose regulation\", \"Did not distinguish isoforms or identify a molecular target\", \"Secreted form's physiological action unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a bone marrow–heart axis in which monocyte/macrophage-derived Emc10 drives post-infarction angiogenesis, answering where Emc10 acts and through which intracellular signaling it promotes endothelial migration.\",\n      \"evidence\": \"Emc10-KO and bone marrow chimeric mice with coronary artery ligation, endothelial migration and actin polymerization assays, infarct explant outgrowth\",\n      \"pmids\": [\"28931551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor or surface mediator linking Emc10 to small GTPase/PAK activation not identified\", \"Whether the secreted isoform is the active species in this context not resolved\", \"Human relevance untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed Emc10 up-regulation as a causal node downstream of 22q11.2 microRNA dysregulation in schizophrenia-related circuit and behavioral deficits, establishing it as a disease-relevant effector.\",\n      \"evidence\": \"Genetic epistasis in Df(16)A+/\\u2212 mice with Mirta22 LoF allele, behavioral and electrophysiological/structural plasticity readouts\",\n      \"pmids\": [\"28696314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which neuronal Emc10 inhibits maturation not defined\", \"Isoform responsible in neurons unknown\", \"Downstream synaptic effectors not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected EMC10 to ion homeostasis by showing its loss inactivates sperm Na/K-ATPase, raising intracellular Na+ and disrupting the HCO3\\u2212/cAMP/PKA/tyrosine-phosphorylation cascade required for fertility.\",\n      \"evidence\": \"Emc10 KO mice with ion measurements, PKA substrate and tyrosine phosphorylation assays, ICSI rescue\",\n      \"pmids\": [\"29659949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular interaction with the Na/K-ATPase not demonstrated\", \"Whether EMC10 regulates pump expression or activity unresolved at this stage\", \"Isoform contribution not yet dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved that the membrane-bound isoform specifically maintains sperm ion balance by up-regulating the Na/K-ATPase \\u03b23 subunit ATP1B3, separating mEMC10 function from the secreted form.\",\n      \"evidence\": \"Isoform-specific intra-testis overexpression and recombinant scEMC10 treatment in Emc10 KO mice, ATP1B3 quantification, motility assays\",\n      \"pmids\": [\"36077468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which mEMC10 regulates ATP1B3 expression unknown\", \"Direct binding to the pump not shown\", \"Single-lab isoform rescue\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified scEMC10 as a circulating PKA inhibitor that is internalized and binds the PKA catalytic subunit to suppress CREB activity and adipocyte thermogenesis, giving the secreted isoform a defined molecular target.\",\n      \"evidence\": \"Co-IP/binding assay, Emc10 KO and scEMC10-overexpressing mice, energy expenditure and CREB assays, neutralizing antibody\",\n      \"pmids\": [\"36443308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of scEMC10 cellular uptake not defined\", \"Structural basis of PKA binding unknown\", \"Reciprocal/structural validation of interaction limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated the two isoforms have opposing effects on hepatic ER stress, with mEMC10 suppressing and scEMC10 promoting PERK–eIF2\\u03b1–ATF4 signaling, unifying the isoform dichotomy in a metabolic disease context.\",\n      \"evidence\": \"Isoform-specific KO and hepatic overexpression mice, scEMC10 neutralizing antibody, MCD/tunicamycin models, pathway analysis in HepG2\",\n      \"pmids\": [\"38599383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How mEMC10 mechanistically restrains PERK signaling not defined\", \"Receptor mediating scEMC10's pro-ER-stress effect unknown\", \"Single-lab models\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended scEMC10's inhibitory metabolic role to skeletal muscle, showing it suppresses GLUT4 expression/translocation and AMPK/insulin signaling, positioning circulating scEMC10 as a regulator of whole-body glucose homeostasis.\",\n      \"evidence\": \"Emc10 KO mice, recombinant scEMC10 and neutralizing antibody, myoblast studies, GLUT4 translocation and AMPK assays, glucose uptake measurements\",\n      \"pmids\": [\"40441535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Surface receptor for scEMC10 in muscle not identified\", \"Whether PKA binding underlies the AMPK/insulin effects not connected\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The cell-surface receptor(s) or uptake machinery through which secreted scEMC10 acts across tissues, and the molecular basis by which mEMC10 supports ER and ion-pump homeostasis, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor identified for scEMC10 internalization\", \"No structural model of EMC10 or its complexes\", \"Mechanism linking mEMC10 to ATP1B3 and PERK pathway regulation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008953897\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PRKACA\", \"ATP1B3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}