{"gene":"ELAPOR1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2010,"finding":"EIG121 (ELAPOR1) is a transmembrane protein localized in plasma membrane–late endosome–lysosome compartments; deletion of the putative transmembrane domain abolished membrane association. Overexpression caused accumulation of cytoplasmic vacuoles, translocation of autophagosome marker LC3 to punctate structures, marked increase in autophagosomes by electron microscopy, increased acidic vesicles, and lysosomal degradation of long-lived proteins. Knockdown of EIG121 blocked starvation-induced LC3 degradation and, combined with starvation or cytotoxic agents, greatly increased apoptosis, indicating EIG121 promotes cell survival under stress via the autophagy pathway.","method":"Tetracycline-inducible overexpression system, subcellular fractionation, immunofluorescence, electron microscopy, transmembrane domain deletion mutants, siRNA knockdown, lysosomal protein degradation assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, EM, mutagenesis of transmembrane domain, LC3 assay, knockdown) in a single focused study with rigorous controls","pmids":["21072319"],"is_preprint":false},{"year":2015,"finding":"KIAA1324 (ELAPOR1) physically interacts with the oncoprotein GRP78 (glucose-regulated protein 78 kDa), identified by protein interaction (co-immunoprecipitation) analysis. KIAA1324 blocked GRP78 oncogenic activity by (1) inhibiting GRP78–caspase-7 interaction and (2) suppressing GRP78-mediated AKT activation, thereby inducing apoptosis in gastric cancer cells.","method":"Protein interaction analysis (co-immunoprecipitation), xenograft tumor model, proliferation/invasion/apoptosis assays, AKT activation measurement","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying binding partner plus functional rescue in xenograft, single lab with two orthogonal readouts","pmids":["26045166"],"is_preprint":false},{"year":2021,"finding":"ELAPOR1 is a MIST1 (BHLHA15) transcriptional target containing a mannose-6-phosphate receptor (M6PR) domain. In cultured cells, ELAPOR1 traffics with cis-Golgi resident proteins and with the trans-Golgi/late endosome protein CI-M6PR. Truncation mutants disrupted secretory vesicle trafficking. Mass spectrometric analysis of co-immunoprecipitated proteins showed ELAPOR1 and CI-M6PR share many binding partners, but CI-M6PR co-immunoprecipitated more lysosomal proteins. In Elapor1 knockout mice, secretory granule maturation was defective in gastric zymogenic cells, establishing ELAPOR1 as required for normal secretory granule maturation.","method":"Co-immunoprecipitation with mass spectrometry, truncation mutant expression, in vivo Elapor1 knockout mouse, immunofluorescence co-localization with Golgi/endosome markers","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with mass spectrometry, truncation mutagenesis affecting trafficking, and in vivo KO mouse with defined secretory granule phenotype in a single study","pmids":["34816763"],"is_preprint":false},{"year":2023,"finding":"N-linked glycosylation of KIAA1324 (ELAPOR1) is an essential post-translational modification for its tumor-suppressive functions in gastric cancer. Loss of N-linked glycosylation (by mutagenesis) eliminated suppression of cancer cell proliferation and migration, blocked KIAA1324-induced apoptosis, altered subcellular localization, caused rapid proteasomal degradation (reduced protein stability), and abolished inhibition of GRP78–caspase-7 interaction. KIAA1324 also undergoes fucosylation (a modification of the N-glycan mediated by fucosyltransferase); inhibition of fucosylation suppressed KIAA1324-induced cell growth inhibition and apoptosis.","method":"N-glycosylation site mutagenesis, fucosyltransferase inhibition, apoptosis assays, subcellular localization microscopy, proteasomal degradation assay, RNA sequencing, co-immunoprecipitation","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-directed mutagenesis of glycosylation sites with multiple orthogonal functional readouts (localization, stability, apoptosis, protein interaction), single lab with rigorous controls","pmids":["37612293"],"is_preprint":false},{"year":2017,"finding":"EIG121 (ELAPOR1) exerts dual functions in the regulation of both autophagy and stemness in endometrial carcinoma JEC cells, including in cancer stem cell subpopulations. Autophagy inhibition decreased cancer stem cell properties and enhanced sensitivity to paclitaxel, and EIG121 regulation was linked to both pathways.","method":"EIG121 overexpression/knockdown in JEC spheres, autophagy inhibition assays, stemness marker analysis, paclitaxel sensitivity assay","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional cell-based assays but limited mechanistic detail in abstract, single lab, single study","pmids":["28656197"],"is_preprint":false},{"year":2025,"finding":"ELAPOR1 forms a square planar homodimer in cis, which assembles into a trans-tetramer via head-to-head homophilic interactions dependent on copper chelation, as determined by cryo-electron microscopy. ELAPOR1 exhibits dual membrane orientation: a predicted Nin–Cout topology and a noncanonical Nout–Cin topology in vesicles. The noncanonical topology enables ELAPOR1 to function as a tethering factor bridging proacrosomal vesicles (PAVs) through head-to-head homophilic interactions. A copper chelation-deficient mutant (ELAPOR14HA) forms cis homodimers but fails to mediate homophilic interactions in vitro and causes defective PAV fusion in mice, phenocopying Elapor1-null mice. ELAPOR1 interacts with the SNARE protein STX12; conditional knockout of Stx12 in germ cells caused similar acrosome biogenesis defects. Male Elapor1-/- mice are infertile with defective acrosome biogenesis and a globozoospermia-like phenotype.","method":"Cryo-electron microscopy, copper chelation mutant (ELAPOR14HA) in vitro and in vivo, Elapor1 knockout mice, conditional Stx12 knockout mice, in vitro tethering assays, co-immunoprecipitation with STX12","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with mutagenesis validation in vitro and in vivo, multiple orthogonal methods, KO phenotype, binding partner identification","pmids":["40737321"],"is_preprint":false},{"year":2026,"finding":"ELAPOR1 interacts with VPS54 and regulates VPS54-associated assembly of the GARP complex in the testis, thereby controlling the transport of Golgi and early endosome-related vesicles and fusion of proacrosomal vesicles during acrosome biogenesis. Elapor1 germ cell-specific knockout mice produced deformed sperm with impaired motility and defective fertilization. ELAPOR1 protein colocalized with the acrosome during early acrosome formation.","method":"Germ cell-specific Elapor1 knockout mice, mass spectrometry, co-immunoprecipitation, proximity labeling, immunofluorescence, transmission electron microscopy","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus proximity labeling identifying VPS54/GARP binding, supported by KO mouse with defined acrosome phenotype and TEM, single lab with multiple orthogonal methods","pmids":["41993632"],"is_preprint":false},{"year":2026,"finding":"In neurons with pathological TDP-43 (nuclear-cleared and cytoplasmic phosphorylated TDP-43), KIAA1324/ELAPOR1 protein was significantly decreased despite increased KIAA1324 mRNA in iPSC-derived neurons with TDP-43 depletion, potentially due to alternative polyadenylation of KIAA1324 mRNA detected upon TDP-43 depletion which may affect translation efficiency. Mass spectrometry of KIAA1324-overexpressing SH-SY5Y cells revealed that KIAA1324 protein affects a network of mitochondrial proteins.","method":"Immunohistochemistry of post-mortem ALS brain tissue, immunocytochemistry of iPSC-derived neurons, mass spectrometry of KIAA1324-overexpressing SH-SY5Y cells, image analysis","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mass spectrometry interactome plus IHC/ICC correlative data in human tissue and iPSC neurons; translation efficiency mechanism is hypothesized, not directly tested","pmids":["41668214"],"is_preprint":false},{"year":2024,"finding":"ELAPOR1 transgene expression in PDAC cells inhibited migration and invasion and induced gene expression characteristics of the classical/progenitor subtype. Metabolome analysis linked ELAPOR1 upregulation to a metabolic program characterized by upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide (an oncometabolite derived from S-adenosylmethionine) was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro.","method":"ELAPOR1 transgene overexpression in PDAC cell lines, transcriptome profiling, metabolome analysis of patient tumors and cell lines, in vitro migration/invasion assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgene overexpression with defined transcriptome and metabolome readouts, single lab, in vitro and patient cohort validation","pmids":["38630934"],"is_preprint":false}],"current_model":"ELAPOR1 (EIG121/KIAA1324) is an evolutionarily conserved transmembrane protein containing a mannose-6-phosphate receptor domain that localizes to the trans-Golgi network, late endosomes, and lysosomes; it functions as a copper-dependent tethering factor that forms trans-tetramers via head-to-head homophilic interactions to drive vesicle fusion (including proacrosomal vesicle fusion during acrosome biogenesis), regulates secretory granule maturation downstream of the transcription factor MIST1, promotes autophagy by facilitating lysosomal degradation (protecting cells from stress-induced death), suppresses oncogenic GRP78–caspase-7 and GRP78–AKT signaling, and requires N-linked glycosylation and fucosylation for protein stability, proper localization, and anti-tumor activity; additionally, ELAPOR1 interacts with the SNARE STX12 and the GARP complex component VPS54 to coordinate vesicular trafficking."},"narrative":{"mechanistic_narrative":"ELAPOR1 (EIG121/KIAA1324) is an evolutionarily conserved transmembrane protein with a mannose-6-phosphate receptor domain that organizes vesicular trafficking across the trans-Golgi/late endosome/lysosome axis and acts as a tumor suppressor in multiple epithelial cancers [PMID:21072319, PMID:34816763]. Structurally, it forms a square-planar cis homodimer that assembles into a trans-tetramer through copper chelation-dependent head-to-head homophilic interactions, allowing it to function as a membrane tethering factor; a copper chelation-deficient mutant retains cis dimerization but fails to bridge vesicles [PMID:40737321]. This tethering activity drives proacrosomal vesicle fusion during acrosome biogenesis, and Elapor1-null males are infertile with a globozoospermia-like phenotype; ELAPOR1 coordinates this trafficking through the SNARE STX12 and through VPS54-dependent assembly of the GARP complex [PMID:40737321, PMID:41993632]. As a transcriptional target of MIST1, ELAPOR1 is required for normal secretory granule maturation in gastric zymogenic cells, where it traffics alongside cis-Golgi proteins and CI-M6PR [PMID:34816763]. In the autophagy pathway, ELAPOR1 promotes lysosomal degradation of long-lived proteins and supports cell survival under starvation and cytotoxic stress [PMID:21072319]. Its anti-tumor activity operates through physical interaction with GRP78, blocking GRP78–caspase-7 binding and GRP78-driven AKT activation to induce apoptosis, and these functions depend on N-linked glycosylation and fucosylation that maintain its stability and proper localization [PMID:26045166, PMID:37612293].","teleology":[{"year":2010,"claim":"Established ELAPOR1's first cellular function by showing it is an endolysosomal transmembrane protein that drives autophagy and protects cells from stress-induced death.","evidence":"Inducible overexpression, fractionation, EM, transmembrane-domain deletion, LC3 degradation assays and siRNA knockdown in cultured cells","pmids":["21072319"],"confidence":"High","gaps":["No molecular partners or trafficking machinery identified","Mechanism by which an endolysosomal protein nucleates autophagosome formation undefined"]},{"year":2015,"claim":"Identified a molecular basis for ELAPOR1's tumor-suppressive activity through physical interaction with the oncoprotein GRP78.","evidence":"Co-immunoprecipitation, xenograft tumor model, and AKT/apoptosis readouts in gastric cancer cells","pmids":["26045166"],"confidence":"Medium","gaps":["Interaction shown by co-IP without structural mapping of the binding interface","Connection between GRP78 inhibition and the earlier autophagy role unresolved"]},{"year":2017,"claim":"Linked ELAPOR1-regulated autophagy to cancer stemness and chemoresistance in endometrial carcinoma.","evidence":"Overexpression/knockdown in JEC spheres with stemness markers and paclitaxel sensitivity assays","pmids":["28656197"],"confidence":"Low","gaps":["Limited mechanistic detail; correlative cell-based assays only","No molecular link established between ELAPOR1 and stemness regulators"]},{"year":2021,"claim":"Placed ELAPOR1 in a defined secretory trafficking pathway as a MIST1 target required for secretory granule maturation, and related it functionally to the M6P receptor CI-M6PR.","evidence":"Co-IP/mass spectrometry, truncation mutants, Golgi/endosome co-localization, and Elapor1 knockout mouse gastric phenotype","pmids":["34816763"],"confidence":"High","gaps":["Whether ELAPOR1 binds M6P-tagged cargo like CI-M6PR not determined","Mechanism of granule maturation defect not resolved at molecular level"]},{"year":2023,"claim":"Showed that N-glycosylation and fucosylation are required post-translational modifications controlling ELAPOR1 stability, localization, and tumor-suppressive function.","evidence":"Glycosylation-site mutagenesis, fucosyltransferase inhibition, proteasomal degradation, localization, and apoptosis assays in gastric cancer cells","pmids":["37612293"],"confidence":"High","gaps":["Identity of the responsible fucosyltransferase not pinpointed","How glycosylation enforces correct localization mechanistically unclear"]},{"year":2025,"claim":"Defined the structural mechanism of ELAPOR1 as a copper-dependent membrane tethering factor and established its essential role in acrosome biogenesis.","evidence":"Cryo-EM, copper-chelation-deficient mutant in vitro and in vivo, Elapor1 and conditional Stx12 knockout mice, in vitro tethering assays, co-IP with STX12","pmids":["40737321"],"confidence":"High","gaps":["Physiological source/role of copper at the tethering interface unresolved","Functional significance of dual membrane topology beyond PAV tethering unclear"]},{"year":2026,"claim":"Connected ELAPOR1 to the GARP complex, showing it regulates VPS54-associated GARP assembly to control Golgi/endosome vesicle transport and proacrosomal vesicle fusion.","evidence":"Germ cell-specific Elapor1 knockout mice, mass spectrometry, co-IP, proximity labeling, immunofluorescence, and TEM","pmids":["41993632"],"confidence":"High","gaps":["How ELAPOR1 tethering activity and GARP-dependent transport are mechanistically coupled not defined","Whether GARP regulation generalizes beyond testis unknown"]},{"year":2026,"claim":"Implicated ELAPOR1 in TDP-43 proteinopathy and a mitochondrial protein network, expanding its relevance to neurodegeneration.","evidence":"IHC of ALS brain, iPSC-derived neurons with TDP-43 depletion, and mass spectrometry of KIAA1324-overexpressing SH-SY5Y cells","pmids":["41668214"],"confidence":"Medium","gaps":["Alternative polyadenylation/translation mechanism hypothesized but not directly tested","Functional consequence of the mitochondrial protein association not established"]},{"year":null,"claim":"It remains unknown how ELAPOR1's structural tethering activity, M6P-receptor domain, and post-translational modifications mechanistically converge to coordinate its diverse roles in autophagy, secretory granule maturation, acrosome biogenesis, and tumor suppression.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking cargo recognition to tethering function","Whether copper-dependent tetramerization operates outside germ cells untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,5,6]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,0]}],"complexes":[],"partners":["GRP78","STX12","VPS54","CI-M6PR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UXG2","full_name":"Endosome/lysosome-associated apoptosis and autophagy regulator 1","aliases":["Estrogen-induced gene 121 protein"],"length_aa":1013,"mass_kda":111.4,"function":"May protect cells from cell death by inducing cytosolic vacuolization and up-regulating the autophagy pathway (PubMed:21072319). May play a role in apoptosis and cell proliferation through its interaction with HSPA5 (PubMed:26045166)","subcellular_location":"Cell membrane; Late endosome membrane; Golgi apparatus, trans-Golgi network membrane; Lysosome membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6UXG2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELAPOR1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ELAPOR1","total_profiled":1310},"omim":[{"mim_id":"616366","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 32; DEE32","url":"https://www.omim.org/entry/616366"},{"mim_id":"614048","title":"ENDOSOME-LYSOSOME-ASSOCIATED APOPTOSIS AND AUTOPHAGY REGULATOR 2; ELAPOR2","url":"https://www.omim.org/entry/614048"},{"mim_id":"611298","title":"ENDOSOME-LYSOSOME-ASSOCIATED APOPTOSIS AND AUTOPHAGY REGULATOR 1; ELAPOR1","url":"https://www.omim.org/entry/611298"},{"mim_id":"176262","title":"POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER 2; KCNA2","url":"https://www.omim.org/entry/176262"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":147.7},{"tissue":"salivary gland","ntpm":156.2},{"tissue":"stomach 1","ntpm":83.2}],"url":"https://www.proteinatlas.org/search/ELAPOR1"},"hgnc":{"alias_symbol":["maba1","EIG121"],"prev_symbol":["KIAA1324"]},"alphafold":{"accession":"Q6UXG2","domains":[{"cath_id":"-","chopping":"55-111","consensus_level":"medium","plddt":84.4872,"start":55,"end":111},{"cath_id":"2.60.120.200","chopping":"122-141_156-270","consensus_level":"high","plddt":79.8907,"start":122,"end":270},{"cath_id":"2.60.120.200","chopping":"336-588","consensus_level":"medium","plddt":83.6328,"start":336,"end":588},{"cath_id":"-","chopping":"592-656","consensus_level":"medium","plddt":81.5998,"start":592,"end":656},{"cath_id":"2.70.130.10","chopping":"668-721_731-856","consensus_level":"high","plddt":84.0562,"start":668,"end":856},{"cath_id":"-","chopping":"865-902","consensus_level":"high","plddt":87.6308,"start":865,"end":902}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXG2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXG2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXG2-F1-predicted_aligned_error_v6.png","plddt_mean":77.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELAPOR1","jax_strain_url":"https://www.jax.org/strain/search?query=ELAPOR1"},"sequence":{"accession":"Q6UXG2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXG2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXG2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXG2"}},"corpus_meta":[{"pmid":"21072319","id":"PMC_21072319","title":"The novel estrogen-induced gene EIG121 regulates autophagy and promotes cell survival under stress.","date":"2010","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/21072319","citation_count":77,"is_preprint":false},{"pmid":"16322283","id":"PMC_16322283","title":"Identification of a novel estrogen-regulated gene, EIG121, induced by hormone replacement therapy and differentially expressed in type I and type II endometrial cancer.","date":"2005","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/16322283","citation_count":51,"is_preprint":false},{"pmid":"26045166","id":"PMC_26045166","title":"KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26045166","citation_count":42,"is_preprint":false},{"pmid":"21102415","id":"PMC_21102415","title":"Molecular clustering based on ERα and EIG121 predicts survival in high-grade serous carcinoma of the ovary/peritoneum.","date":"2010","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/21102415","citation_count":40,"is_preprint":false},{"pmid":"28656197","id":"PMC_28656197","title":"Autophagy plays an important role in stemness mediation and the novel dual function of EIG121 in both autophagy and stemness regulation of endometrial carcinoma JEC cells.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28656197","citation_count":27,"is_preprint":false},{"pmid":"37612293","id":"PMC_37612293","title":"N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37612293","citation_count":17,"is_preprint":false},{"pmid":"34816763","id":"PMC_34816763","title":"ELAPOR1 is a secretory granule maturation-promoting factor that is lost during paligenosis.","date":"2021","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34816763","citation_count":16,"is_preprint":false},{"pmid":"14767521","id":"PMC_14767521","title":"Different transcriptional expression of KIAA1324 and its splicing variants in human carcinoma cell lines with different metastatic capacity.","date":"2004","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/14767521","citation_count":13,"is_preprint":false},{"pmid":"38630934","id":"PMC_38630934","title":"ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer.","date":"2024","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38630934","citation_count":11,"is_preprint":false},{"pmid":"32377505","id":"PMC_32377505","title":"Altered Expression of Three EGFR Posttranslational Regulators MDGI, MIG6, and EIG121 in Invasive Breast Carcinomas.","date":"2020","source":"Analytical cellular pathology (Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/32377505","citation_count":7,"is_preprint":false},{"pmid":"40737321","id":"PMC_40737321","title":"ELAPOR1 is a copper-dependent tethering factor driving proacrosomal vesicle fusion during acrosome biogenesis.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/40737321","citation_count":4,"is_preprint":false},{"pmid":"27230222","id":"PMC_27230222","title":"A novel polymorphic repeat in the upstream regulatory region of the estrogen-induced gene EIG121 is not associated with the risk of developing breast or endometrial cancer.","date":"2016","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/27230222","citation_count":1,"is_preprint":false},{"pmid":"41668214","id":"PMC_41668214","title":"Lost in translation: absence of KIAA1324/ELAPOR1 protein in pathological TDP-43-affected neurons in ALS/FTD.","date":"2026","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/41668214","citation_count":0,"is_preprint":false},{"pmid":"41993632","id":"PMC_41993632","title":"ELAPOR1 regulates VPS54-mediated GARP complex formation and proacrosomal vesicle fusion during spermatogenesis.","date":"2026","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/41993632","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.26.656141","title":"Coordinated adaptive changes in insulin, insulin receptor, and inceptor genes in hystricognath rodents","date":"2025-05-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.26.656141","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10438,"output_tokens":3211,"usd":0.039739,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10703,"output_tokens":3126,"usd":0.065833,"stage2_stop_reason":"end_turn"},"total_usd":0.105572,"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\": 2010,\n      \"finding\": \"EIG121 (ELAPOR1) is a transmembrane protein localized in plasma membrane–late endosome–lysosome compartments; deletion of the putative transmembrane domain abolished membrane association. Overexpression caused accumulation of cytoplasmic vacuoles, translocation of autophagosome marker LC3 to punctate structures, marked increase in autophagosomes by electron microscopy, increased acidic vesicles, and lysosomal degradation of long-lived proteins. Knockdown of EIG121 blocked starvation-induced LC3 degradation and, combined with starvation or cytotoxic agents, greatly increased apoptosis, indicating EIG121 promotes cell survival under stress via the autophagy pathway.\",\n      \"method\": \"Tetracycline-inducible overexpression system, subcellular fractionation, immunofluorescence, electron microscopy, transmembrane domain deletion mutants, siRNA knockdown, lysosomal protein degradation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, EM, mutagenesis of transmembrane domain, LC3 assay, knockdown) in a single focused study with rigorous controls\",\n      \"pmids\": [\"21072319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KIAA1324 (ELAPOR1) physically interacts with the oncoprotein GRP78 (glucose-regulated protein 78 kDa), identified by protein interaction (co-immunoprecipitation) analysis. KIAA1324 blocked GRP78 oncogenic activity by (1) inhibiting GRP78–caspase-7 interaction and (2) suppressing GRP78-mediated AKT activation, thereby inducing apoptosis in gastric cancer cells.\",\n      \"method\": \"Protein interaction analysis (co-immunoprecipitation), xenograft tumor model, proliferation/invasion/apoptosis assays, AKT activation measurement\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying binding partner plus functional rescue in xenograft, single lab with two orthogonal readouts\",\n      \"pmids\": [\"26045166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELAPOR1 is a MIST1 (BHLHA15) transcriptional target containing a mannose-6-phosphate receptor (M6PR) domain. In cultured cells, ELAPOR1 traffics with cis-Golgi resident proteins and with the trans-Golgi/late endosome protein CI-M6PR. Truncation mutants disrupted secretory vesicle trafficking. Mass spectrometric analysis of co-immunoprecipitated proteins showed ELAPOR1 and CI-M6PR share many binding partners, but CI-M6PR co-immunoprecipitated more lysosomal proteins. In Elapor1 knockout mice, secretory granule maturation was defective in gastric zymogenic cells, establishing ELAPOR1 as required for normal secretory granule maturation.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, truncation mutant expression, in vivo Elapor1 knockout mouse, immunofluorescence co-localization with Golgi/endosome markers\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with mass spectrometry, truncation mutagenesis affecting trafficking, and in vivo KO mouse with defined secretory granule phenotype in a single study\",\n      \"pmids\": [\"34816763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"N-linked glycosylation of KIAA1324 (ELAPOR1) is an essential post-translational modification for its tumor-suppressive functions in gastric cancer. Loss of N-linked glycosylation (by mutagenesis) eliminated suppression of cancer cell proliferation and migration, blocked KIAA1324-induced apoptosis, altered subcellular localization, caused rapid proteasomal degradation (reduced protein stability), and abolished inhibition of GRP78–caspase-7 interaction. KIAA1324 also undergoes fucosylation (a modification of the N-glycan mediated by fucosyltransferase); inhibition of fucosylation suppressed KIAA1324-induced cell growth inhibition and apoptosis.\",\n      \"method\": \"N-glycosylation site mutagenesis, fucosyltransferase inhibition, apoptosis assays, subcellular localization microscopy, proteasomal degradation assay, RNA sequencing, co-immunoprecipitation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-directed mutagenesis of glycosylation sites with multiple orthogonal functional readouts (localization, stability, apoptosis, protein interaction), single lab with rigorous controls\",\n      \"pmids\": [\"37612293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EIG121 (ELAPOR1) exerts dual functions in the regulation of both autophagy and stemness in endometrial carcinoma JEC cells, including in cancer stem cell subpopulations. Autophagy inhibition decreased cancer stem cell properties and enhanced sensitivity to paclitaxel, and EIG121 regulation was linked to both pathways.\",\n      \"method\": \"EIG121 overexpression/knockdown in JEC spheres, autophagy inhibition assays, stemness marker analysis, paclitaxel sensitivity assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cell-based assays but limited mechanistic detail in abstract, single lab, single study\",\n      \"pmids\": [\"28656197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELAPOR1 forms a square planar homodimer in cis, which assembles into a trans-tetramer via head-to-head homophilic interactions dependent on copper chelation, as determined by cryo-electron microscopy. ELAPOR1 exhibits dual membrane orientation: a predicted Nin–Cout topology and a noncanonical Nout–Cin topology in vesicles. The noncanonical topology enables ELAPOR1 to function as a tethering factor bridging proacrosomal vesicles (PAVs) through head-to-head homophilic interactions. A copper chelation-deficient mutant (ELAPOR14HA) forms cis homodimers but fails to mediate homophilic interactions in vitro and causes defective PAV fusion in mice, phenocopying Elapor1-null mice. ELAPOR1 interacts with the SNARE protein STX12; conditional knockout of Stx12 in germ cells caused similar acrosome biogenesis defects. Male Elapor1-/- mice are infertile with defective acrosome biogenesis and a globozoospermia-like phenotype.\",\n      \"method\": \"Cryo-electron microscopy, copper chelation mutant (ELAPOR14HA) in vitro and in vivo, Elapor1 knockout mice, conditional Stx12 knockout mice, in vitro tethering assays, co-immunoprecipitation with STX12\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with mutagenesis validation in vitro and in vivo, multiple orthogonal methods, KO phenotype, binding partner identification\",\n      \"pmids\": [\"40737321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ELAPOR1 interacts with VPS54 and regulates VPS54-associated assembly of the GARP complex in the testis, thereby controlling the transport of Golgi and early endosome-related vesicles and fusion of proacrosomal vesicles during acrosome biogenesis. Elapor1 germ cell-specific knockout mice produced deformed sperm with impaired motility and defective fertilization. ELAPOR1 protein colocalized with the acrosome during early acrosome formation.\",\n      \"method\": \"Germ cell-specific Elapor1 knockout mice, mass spectrometry, co-immunoprecipitation, proximity labeling, immunofluorescence, transmission electron microscopy\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus proximity labeling identifying VPS54/GARP binding, supported by KO mouse with defined acrosome phenotype and TEM, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41993632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In neurons with pathological TDP-43 (nuclear-cleared and cytoplasmic phosphorylated TDP-43), KIAA1324/ELAPOR1 protein was significantly decreased despite increased KIAA1324 mRNA in iPSC-derived neurons with TDP-43 depletion, potentially due to alternative polyadenylation of KIAA1324 mRNA detected upon TDP-43 depletion which may affect translation efficiency. Mass spectrometry of KIAA1324-overexpressing SH-SY5Y cells revealed that KIAA1324 protein affects a network of mitochondrial proteins.\",\n      \"method\": \"Immunohistochemistry of post-mortem ALS brain tissue, immunocytochemistry of iPSC-derived neurons, mass spectrometry of KIAA1324-overexpressing SH-SY5Y cells, image analysis\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mass spectrometry interactome plus IHC/ICC correlative data in human tissue and iPSC neurons; translation efficiency mechanism is hypothesized, not directly tested\",\n      \"pmids\": [\"41668214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELAPOR1 transgene expression in PDAC cells inhibited migration and invasion and induced gene expression characteristics of the classical/progenitor subtype. Metabolome analysis linked ELAPOR1 upregulation to a metabolic program characterized by upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide (an oncometabolite derived from S-adenosylmethionine) was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro.\",\n      \"method\": \"ELAPOR1 transgene overexpression in PDAC cell lines, transcriptome profiling, metabolome analysis of patient tumors and cell lines, in vitro migration/invasion assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgene overexpression with defined transcriptome and metabolome readouts, single lab, in vitro and patient cohort validation\",\n      \"pmids\": [\"38630934\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELAPOR1 (EIG121/KIAA1324) is an evolutionarily conserved transmembrane protein containing a mannose-6-phosphate receptor domain that localizes to the trans-Golgi network, late endosomes, and lysosomes; it functions as a copper-dependent tethering factor that forms trans-tetramers via head-to-head homophilic interactions to drive vesicle fusion (including proacrosomal vesicle fusion during acrosome biogenesis), regulates secretory granule maturation downstream of the transcription factor MIST1, promotes autophagy by facilitating lysosomal degradation (protecting cells from stress-induced death), suppresses oncogenic GRP78–caspase-7 and GRP78–AKT signaling, and requires N-linked glycosylation and fucosylation for protein stability, proper localization, and anti-tumor activity; additionally, ELAPOR1 interacts with the SNARE STX12 and the GARP complex component VPS54 to coordinate vesicular trafficking.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELAPOR1 (EIG121/KIAA1324) is an evolutionarily conserved transmembrane protein with a mannose-6-phosphate receptor domain that organizes vesicular trafficking across the trans-Golgi/late endosome/lysosome axis and acts as a tumor suppressor in multiple epithelial cancers [#0, #2]. Structurally, it forms a square-planar cis homodimer that assembles into a trans-tetramer through copper chelation-dependent head-to-head homophilic interactions, allowing it to function as a membrane tethering factor; a copper chelation-deficient mutant retains cis dimerization but fails to bridge vesicles [#5]. This tethering activity drives proacrosomal vesicle fusion during acrosome biogenesis, and Elapor1-null males are infertile with a globozoospermia-like phenotype; ELAPOR1 coordinates this trafficking through the SNARE STX12 and through VPS54-dependent assembly of the GARP complex [#5, #6]. As a transcriptional target of MIST1, ELAPOR1 is required for normal secretory granule maturation in gastric zymogenic cells, where it traffics alongside cis-Golgi proteins and CI-M6PR [#2]. In the autophagy pathway, ELAPOR1 promotes lysosomal degradation of long-lived proteins and supports cell survival under starvation and cytotoxic stress [#0]. Its anti-tumor activity operates through physical interaction with GRP78, blocking GRP78\\u2013caspase-7 binding and GRP78-driven AKT activation to induce apoptosis, and these functions depend on N-linked glycosylation and fucosylation that maintain its stability and proper localization [#1, #3].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established ELAPOR1's first cellular function by showing it is an endolysosomal transmembrane protein that drives autophagy and protects cells from stress-induced death.\",\n      \"evidence\": \"Inducible overexpression, fractionation, EM, transmembrane-domain deletion, LC3 degradation assays and siRNA knockdown in cultured cells\",\n      \"pmids\": [\"21072319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular partners or trafficking machinery identified\", \"Mechanism by which an endolysosomal protein nucleates autophagosome formation undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a molecular basis for ELAPOR1's tumor-suppressive activity through physical interaction with the oncoprotein GRP78.\",\n      \"evidence\": \"Co-immunoprecipitation, xenograft tumor model, and AKT/apoptosis readouts in gastric cancer cells\",\n      \"pmids\": [\"26045166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction shown by co-IP without structural mapping of the binding interface\", \"Connection between GRP78 inhibition and the earlier autophagy role unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked ELAPOR1-regulated autophagy to cancer stemness and chemoresistance in endometrial carcinoma.\",\n      \"evidence\": \"Overexpression/knockdown in JEC spheres with stemness markers and paclitaxel sensitivity assays\",\n      \"pmids\": [\"28656197\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic detail; correlative cell-based assays only\", \"No molecular link established between ELAPOR1 and stemness regulators\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed ELAPOR1 in a defined secretory trafficking pathway as a MIST1 target required for secretory granule maturation, and related it functionally to the M6P receptor CI-M6PR.\",\n      \"evidence\": \"Co-IP/mass spectrometry, truncation mutants, Golgi/endosome co-localization, and Elapor1 knockout mouse gastric phenotype\",\n      \"pmids\": [\"34816763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ELAPOR1 binds M6P-tagged cargo like CI-M6PR not determined\", \"Mechanism of granule maturation defect not resolved at molecular level\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that N-glycosylation and fucosylation are required post-translational modifications controlling ELAPOR1 stability, localization, and tumor-suppressive function.\",\n      \"evidence\": \"Glycosylation-site mutagenesis, fucosyltransferase inhibition, proteasomal degradation, localization, and apoptosis assays in gastric cancer cells\",\n      \"pmids\": [\"37612293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible fucosyltransferase not pinpointed\", \"How glycosylation enforces correct localization mechanistically unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the structural mechanism of ELAPOR1 as a copper-dependent membrane tethering factor and established its essential role in acrosome biogenesis.\",\n      \"evidence\": \"Cryo-EM, copper-chelation-deficient mutant in vitro and in vivo, Elapor1 and conditional Stx12 knockout mice, in vitro tethering assays, co-IP with STX12\",\n      \"pmids\": [\"40737321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological source/role of copper at the tethering interface unresolved\", \"Functional significance of dual membrane topology beyond PAV tethering unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected ELAPOR1 to the GARP complex, showing it regulates VPS54-associated GARP assembly to control Golgi/endosome vesicle transport and proacrosomal vesicle fusion.\",\n      \"evidence\": \"Germ cell-specific Elapor1 knockout mice, mass spectrometry, co-IP, proximity labeling, immunofluorescence, and TEM\",\n      \"pmids\": [\"41993632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ELAPOR1 tethering activity and GARP-dependent transport are mechanistically coupled not defined\", \"Whether GARP regulation generalizes beyond testis unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated ELAPOR1 in TDP-43 proteinopathy and a mitochondrial protein network, expanding its relevance to neurodegeneration.\",\n      \"evidence\": \"IHC of ALS brain, iPSC-derived neurons with TDP-43 depletion, and mass spectrometry of KIAA1324-overexpressing SH-SY5Y cells\",\n      \"pmids\": [\"41668214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Alternative polyadenylation/translation mechanism hypothesized but not directly tested\", \"Functional consequence of the mitochondrial protein association not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how ELAPOR1's structural tethering activity, M6P-receptor domain, and post-translational modifications mechanistically converge to coordinate its diverse roles in autophagy, secretory granule maturation, acrosome biogenesis, and tumor suppression.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking cargo recognition to tethering function\", \"Whether copper-dependent tetramerization operates outside germ cells untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GRP78\", \"STX12\", \"VPS54\", \"CI-M6PR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}