{"gene":"SEC11A","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2013,"finding":"SEC11A (SPC18) knockdown in gastric cancer cells reduced TGF-α levels in culture media, and forced expression of SPC18 increased cell growth in vitro and in vivo, establishing that SPC18 promotes cancer progression through promotion of TGF-α secretion.","method":"siRNA knockdown, forced overexpression, ELISA for TGF-α, MTT assay, Boyden chamber invasion assay, xenograft in SCID mice","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (ELISA, MTT, invasion, xenograft) in a single lab establishing secretion mechanism","pmids":["23995782"],"is_preprint":false},{"year":2017,"finding":"SEC11A (SPC18) knockdown in colorectal cancer cells reduced phosphorylated EGFR, Erk, and Akt levels, placing SPC18 upstream of EGFR/MAPK/PI3K signaling in CRC. SPC18 expression co-localized with β-catenin nuclear localization and MMP7 at the invasive front.","method":"siRNA knockdown, Western blotting for phospho-EGFR/Erk/Akt, immunohistochemistry co-localization, cell growth and invasion assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Western blot signaling, IHC co-localization, functional assays) in a single lab","pmids":["27859949"],"is_preprint":false},{"year":2021,"finding":"SEC11A is a direct target of miR-873-5p, confirmed by dual luciferase reporter assay; miR-873-5p overexpression downregulated SPC18 and EGFR pathway-related proteins, and the inhibitory effect on TSCC cell proliferation/migration/invasion was rescued by SEC11A overexpression, establishing miR-873-5p→SEC11A→EGFR pathway regulation.","method":"Dual luciferase reporter assay, Western blotting, CCK-8, wound healing, Transwell, flow cytometry, qRT-PCR","journal":"Oral diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by luciferase reporter plus rescue experiment, single lab","pmids":["33675129"],"is_preprint":false},{"year":2026,"finding":"SEC11A knockout cells showed greatly reduced HMPV replication, identifying SEC11A (the core catalytic subunit of the signal peptidase complex) as a critical host factor for human metapneumovirus infection. An exon-skipping alternative splicing event in SEC11A pre-mRNA was specifically induced by HMPV infection, occurring in the regulatory region upstream of the coding sequence.","method":"CRISPR/knockout cell lines, RNA sequencing of alternative splicing events, HMPV replication assay in knockout cells","journal":"Biosafety and health","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout cell lines with direct viral replication readout and RNA-seq characterization, single lab","pmids":["41743027"],"is_preprint":false},{"year":2019,"finding":"SEC11A knockdown inhibited bladder cancer cell growth and invasiveness, while forced SEC11A expression enhanced both, consistent with SPC18 functioning as a component of the signal peptidase complex that promotes secretion of growth-promoting factors.","method":"siRNA knockdown, SEC11A expression vector transfection, MTT assay, modified Boyden chamber invasion assay","journal":"Pathobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional cell assays in a single lab without identification of specific secreted substrate beyond prior work","pmids":["31163419"],"is_preprint":false},{"year":2023,"finding":"lentivirus-mediated SEC11A knockdown in HNSCC cell lines reduced cell proliferation, migration, and invasion in vitro, and inhibited tumor growth in xenograft models in vivo, with SEC11A protein localized predominantly in the cytoplasm.","method":"shRNA lentiviral knockdown, colony formation assay, CCK8, wound healing, Transwell, xenograft tumor assay, immunohistochemistry for subcellular localization","journal":"Heliyon","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays with loss-of-function but no new pathway mechanism identified, single lab","pmids":["37025806"],"is_preprint":false}],"current_model":"SEC11A encodes SPC18, the catalytic subunit of the eukaryotic signal peptidase complex (SPC) located in the endoplasmic reticulum, where it cleaves signal peptides from secretory proteins; experimentally, SPC18 drives secretion of TGF-α (and likely other EGFR ligands) to activate downstream EGFR/MAPK/PI3K signaling, is directly repressed by miR-873-5p, and is an essential host factor for human metapneumovirus replication, with HMPV infection inducing a specific exon-skipping event in SEC11A pre-mRNA."},"narrative":{"mechanistic_narrative":"SEC11A encodes SPC18, a catalytic subunit of the endoplasmic reticulum signal peptidase complex, and functions in cancer biology by promoting the secretion of growth-promoting factors that drive proliferation and invasion [PMID:23995782]. SPC18 promotes secretion of TGF-α, and its depletion reduces TGF-α in culture media while its overexpression enhances tumor cell growth in vitro and in vivo [PMID:23995782]. Downstream of this secretory output, SPC18 acts upstream of EGFR/MAPK/PI3K signaling: its knockdown lowers phosphorylated EGFR, Erk, and Akt, and its expression at the invasive front co-localizes with nuclear β-catenin and MMP7 [PMID:27859949]. SEC11A is directly repressed by miR-873-5p, and the anti-tumor effect of this microRNA proceeds through suppression of SEC11A and EGFR pathway proteins, with the phenotype rescued by SEC11A re-expression [PMID:33675129]. Beyond its role in tumor cell growth and invasion across multiple cancer types [PMID:23995782, PMID:27859949], SEC11A is an essential host factor for human metapneumovirus replication, and HMPV infection specifically induces an exon-skipping splicing event in the SEC11A regulatory region upstream of its coding sequence [PMID:41743027].","teleology":[{"year":2013,"claim":"Established that SPC18 promotes cancer progression not merely as a housekeeping peptidase but by driving secretion of the EGFR ligand TGF-α, linking signal-peptidase activity to a specific oncogenic secreted factor.","evidence":"siRNA knockdown and overexpression with TGF-α ELISA, proliferation/invasion assays, and xenografts in gastric cancer cells","pmids":["23995782"],"confidence":"Medium","gaps":["Direct enzymatic cleavage of the TGF-α signal peptide by SPC18 not biochemically reconstituted","Whether SPC18 selectively favors TGF-α over other secretory substrates unaddressed","Composition of the signal peptidase complex in these cells not characterized"]},{"year":2017,"claim":"Placed SPC18 upstream of a defined intracellular signaling cascade by showing its loss reduces EGFR/MAPK/PI3K phosphorylation, connecting its secretory role to downstream proliferative signaling and invasive-front markers.","evidence":"siRNA knockdown with phospho-EGFR/Erk/Akt Western blots and IHC co-localization with β-catenin and MMP7 in colorectal cancer","pmids":["27859949"],"confidence":"Medium","gaps":["Causal chain from SPC18 to phospho-EGFR not separated from general secretory defects","Identity of the secreted ligand mediating EGFR activation in CRC not established","Mechanism linking SPC18 to β-catenin nuclear localization unknown"]},{"year":2021,"claim":"Identified an upstream regulatory mechanism showing SEC11A is a direct miR-873-5p target, explaining how SEC11A levels are controlled and reinforcing the SEC11A→EGFR signaling axis through rescue.","evidence":"Dual luciferase reporter, Western blot, and SEC11A-overexpression rescue in tongue squamous cell carcinoma cells","pmids":["33675129"],"confidence":"Medium","gaps":["Physiological contexts in which miR-873-5p regulates SEC11A not defined","Whether other microRNAs co-regulate SEC11A unaddressed","Single-lab validation of the binding interaction"]},{"year":2023,"claim":"Extended the pro-tumor loss-of-function phenotype to HNSCC and reported predominantly cytoplasmic SPC18 localization, broadening the cancer-type generality of the secretory growth role.","evidence":"shRNA lentiviral knockdown with proliferation/migration/invasion assays, xenografts, and IHC localization in HNSCC","pmids":["37025806"],"confidence":"Low","gaps":["No new pathway mechanism identified beyond prior work","Secreted substrate mediating the HNSCC phenotype not identified","Cytoplasmic IHC signal not resolved to ER subcompartment"]},{"year":2026,"claim":"Revealed a host-pathogen role by showing SEC11A is required for human metapneumovirus replication and that HMPV reprograms SEC11A splicing, implicating signal-peptidase function in viral biology.","evidence":"CRISPR knockout cell lines with HMPV replication readout and RNA-seq detection of an infection-induced exon-skipping event","pmids":["41743027"],"confidence":"Medium","gaps":["Whether SEC11A acts by processing a viral protein or supporting host secretory machinery unknown","Functional consequence of the exon-skipping event on SPC18 activity not determined","Mechanism by which HMPV induces the splicing change uncharacterized"]},{"year":null,"claim":"The direct biochemical activity of SPC18 as the catalytic signal peptidase subunit, including its substrate repertoire and complex composition in human cells, remains uncharacterized in this corpus.","evidence":"No reconstitution or structural/biochemical assay of SPC18 catalysis present in the timeline","pmids":[],"confidence":"Low","gaps":["No direct demonstration of signal-peptide cleavage by human SPC18 in the corpus","Subunit partners of the signal peptidase complex not experimentally defined here","ER-membrane catalytic mechanism not addressed"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P67812","full_name":"Signal peptidase complex catalytic subunit SEC11A","aliases":["Endopeptidase SP18","Microsomal signal peptidase 18 kDa subunit","SPase 18 kDa subunit","SEC11 homolog A","SEC11-like protein 1","SPC18"],"length_aa":179,"mass_kda":20.6,"function":"Catalytic component of the signal peptidase complex (SPC) which catalyzes the cleavage of N-terminal signal sequences from nascent proteins as they are translocated into the lumen of the endoplasmic reticulum (PubMed:34388369). Specifically cleaves N-terminal signal peptides that contain a hydrophobic alpha-helix (h-region) shorter than 18-20 amino acids (PubMed:34388369)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P67812/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC11A","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SEC11A","total_profiled":1310},"omim":[{"mim_id":"618258","title":"SEC11 HOMOLOG A, SIGNAL PEPTIDASE COMPLEX SUBUNIT; SEC11A","url":"https://www.omim.org/entry/618258"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear membrane","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC11A"},"hgnc":{"alias_symbol":["SPC18","sid2895","SPCS4A"],"prev_symbol":["SEC11L1"]},"alphafold":{"accession":"P67812","domains":[{"cath_id":"2.10.109.10","chopping":"48-147","consensus_level":"high","plddt":93.2946,"start":48,"end":147},{"cath_id":"-","chopping":"151-176","consensus_level":"high","plddt":91.9492,"start":151,"end":176},{"cath_id":"1.20.5","chopping":"1-43","consensus_level":"medium","plddt":84.6767,"start":1,"end":43}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P67812","model_url":"https://alphafold.ebi.ac.uk/files/AF-P67812-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P67812-F1-predicted_aligned_error_v6.png","plddt_mean":90.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC11A","jax_strain_url":"https://www.jax.org/strain/search?query=SEC11A"},"sequence":{"accession":"P67812","fasta_url":"https://rest.uniprot.org/uniprotkb/P67812.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P67812/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P67812"}},"corpus_meta":[{"pmid":"32054332","id":"PMC_32054332","title":"Long non-coding RNA DDX11-AS1 facilitates gastric cancer progression by regulating miR-873-5p/SPC18 axis.","date":"2020","source":"Artificial cells, nanomedicine, and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32054332","citation_count":34,"is_preprint":false},{"pmid":"23995782","id":"PMC_23995782","title":"Signal peptidase complex 18, encoded by SEC11A, contributes to progression via TGF-α secretion in gastric cancer.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23995782","citation_count":32,"is_preprint":false},{"pmid":"16484202","id":"PMC_16484202","title":"Cloning, expression, and purification of functional Sec11a and Sec11b, type I signal peptidases of the archaeon Haloferax volcanii.","date":"2006","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/16484202","citation_count":29,"is_preprint":false},{"pmid":"18757567","id":"PMC_18757567","title":"Septal pore cap protein SPC18, isolated from the basidiomycetous fungus Rhizoctonia solani, also resides in pore plugs.","date":"2008","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/18757567","citation_count":19,"is_preprint":false},{"pmid":"27859949","id":"PMC_27859949","title":"Clinicopathological significance of SPC18 in colorectal cancer: SPC18 participates in tumor progression.","date":"2017","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/27859949","citation_count":16,"is_preprint":false},{"pmid":"31163419","id":"PMC_31163419","title":"SEC11A Expression Is Associated with Basal-Like Bladder Cancer and Predicts Patient Survival.","date":"2019","source":"Pathobiology : journal of immunopathology, molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31163419","citation_count":7,"is_preprint":false},{"pmid":"33675129","id":"PMC_33675129","title":"MiR-873-5p modulates progression of tongue squamous cell carcinoma via targeting SEC11A.","date":"2021","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33675129","citation_count":5,"is_preprint":false},{"pmid":"37025806","id":"PMC_37025806","title":"SEC11A contributes to tumour progression of head and neck squamous cell carcinoma.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37025806","citation_count":4,"is_preprint":false},{"pmid":"36456166","id":"PMC_36456166","title":"Clinical Significance of SEC11A Expression in Patients With Locally Advanced Gastric Cancer.","date":"2022","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36456166","citation_count":1,"is_preprint":false},{"pmid":"41743027","id":"PMC_41743027","title":"SEC11A identified as a critical host factor for HMPV through virus-induced alternative splicing.","date":"2026","source":"Biosafety and health","url":"https://pubmed.ncbi.nlm.nih.gov/41743027","citation_count":0,"is_preprint":false},{"pmid":"37484429","id":"PMC_37484429","title":"Corrigendum to \"SEC11A contributes to tumour progression of head and neck squamous cell carcinoma\" [Heliyon 9(4) (April 2023) e14958].","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37484429","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7230,"output_tokens":1493,"usd":0.022042,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8260,"output_tokens":2245,"usd":0.048712,"stage2_stop_reason":"end_turn"},"total_usd":0.070754,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"SEC11A (SPC18) knockdown in gastric cancer cells reduced TGF-α levels in culture media, and forced expression of SPC18 increased cell growth in vitro and in vivo, establishing that SPC18 promotes cancer progression through promotion of TGF-α secretion.\",\n      \"method\": \"siRNA knockdown, forced overexpression, ELISA for TGF-α, MTT assay, Boyden chamber invasion assay, xenograft in SCID mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (ELISA, MTT, invasion, xenograft) in a single lab establishing secretion mechanism\",\n      \"pmids\": [\"23995782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SEC11A (SPC18) knockdown in colorectal cancer cells reduced phosphorylated EGFR, Erk, and Akt levels, placing SPC18 upstream of EGFR/MAPK/PI3K signaling in CRC. SPC18 expression co-localized with β-catenin nuclear localization and MMP7 at the invasive front.\",\n      \"method\": \"siRNA knockdown, Western blotting for phospho-EGFR/Erk/Akt, immunohistochemistry co-localization, cell growth and invasion assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Western blot signaling, IHC co-localization, functional assays) in a single lab\",\n      \"pmids\": [\"27859949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC11A is a direct target of miR-873-5p, confirmed by dual luciferase reporter assay; miR-873-5p overexpression downregulated SPC18 and EGFR pathway-related proteins, and the inhibitory effect on TSCC cell proliferation/migration/invasion was rescued by SEC11A overexpression, establishing miR-873-5p→SEC11A→EGFR pathway regulation.\",\n      \"method\": \"Dual luciferase reporter assay, Western blotting, CCK-8, wound healing, Transwell, flow cytometry, qRT-PCR\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by luciferase reporter plus rescue experiment, single lab\",\n      \"pmids\": [\"33675129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC11A knockout cells showed greatly reduced HMPV replication, identifying SEC11A (the core catalytic subunit of the signal peptidase complex) as a critical host factor for human metapneumovirus infection. An exon-skipping alternative splicing event in SEC11A pre-mRNA was specifically induced by HMPV infection, occurring in the regulatory region upstream of the coding sequence.\",\n      \"method\": \"CRISPR/knockout cell lines, RNA sequencing of alternative splicing events, HMPV replication assay in knockout cells\",\n      \"journal\": \"Biosafety and health\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout cell lines with direct viral replication readout and RNA-seq characterization, single lab\",\n      \"pmids\": [\"41743027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SEC11A knockdown inhibited bladder cancer cell growth and invasiveness, while forced SEC11A expression enhanced both, consistent with SPC18 functioning as a component of the signal peptidase complex that promotes secretion of growth-promoting factors.\",\n      \"method\": \"siRNA knockdown, SEC11A expression vector transfection, MTT assay, modified Boyden chamber invasion assay\",\n      \"journal\": \"Pathobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cell assays in a single lab without identification of specific secreted substrate beyond prior work\",\n      \"pmids\": [\"31163419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"lentivirus-mediated SEC11A knockdown in HNSCC cell lines reduced cell proliferation, migration, and invasion in vitro, and inhibited tumor growth in xenograft models in vivo, with SEC11A protein localized predominantly in the cytoplasm.\",\n      \"method\": \"shRNA lentiviral knockdown, colony formation assay, CCK8, wound healing, Transwell, xenograft tumor assay, immunohistochemistry for subcellular localization\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays with loss-of-function but no new pathway mechanism identified, single lab\",\n      \"pmids\": [\"37025806\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC11A encodes SPC18, the catalytic subunit of the eukaryotic signal peptidase complex (SPC) located in the endoplasmic reticulum, where it cleaves signal peptides from secretory proteins; experimentally, SPC18 drives secretion of TGF-α (and likely other EGFR ligands) to activate downstream EGFR/MAPK/PI3K signaling, is directly repressed by miR-873-5p, and is an essential host factor for human metapneumovirus replication, with HMPV infection inducing a specific exon-skipping event in SEC11A pre-mRNA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC11A encodes SPC18, a catalytic subunit of the endoplasmic reticulum signal peptidase complex, and functions in cancer biology by promoting the secretion of growth-promoting factors that drive proliferation and invasion [#0]. SPC18 promotes secretion of TGF-\\u03b1, and its depletion reduces TGF-\\u03b1 in culture media while its overexpression enhances tumor cell growth in vitro and in vivo [#0]. Downstream of this secretory output, SPC18 acts upstream of EGFR/MAPK/PI3K signaling: its knockdown lowers phosphorylated EGFR, Erk, and Akt, and its expression at the invasive front co-localizes with nuclear \\u03b2-catenin and MMP7 [#1]. SEC11A is directly repressed by miR-873-5p, and the anti-tumor effect of this microRNA proceeds through suppression of SEC11A and EGFR pathway proteins, with the phenotype rescued by SEC11A re-expression [#2]. Beyond its role in tumor cell growth and invasion across multiple cancer types [#0, #1], SEC11A is an essential host factor for human metapneumovirus replication, and HMPV infection specifically induces an exon-skipping splicing event in the SEC11A regulatory region upstream of its coding sequence [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that SPC18 promotes cancer progression not merely as a housekeeping peptidase but by driving secretion of the EGFR ligand TGF-\\u03b1, linking signal-peptidase activity to a specific oncogenic secreted factor.\",\n      \"evidence\": \"siRNA knockdown and overexpression with TGF-\\u03b1 ELISA, proliferation/invasion assays, and xenografts in gastric cancer cells\",\n      \"pmids\": [\"23995782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct enzymatic cleavage of the TGF-\\u03b1 signal peptide by SPC18 not biochemically reconstituted\",\n        \"Whether SPC18 selectively favors TGF-\\u03b1 over other secretory substrates unaddressed\",\n        \"Composition of the signal peptidase complex in these cells not characterized\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed SPC18 upstream of a defined intracellular signaling cascade by showing its loss reduces EGFR/MAPK/PI3K phosphorylation, connecting its secretory role to downstream proliferative signaling and invasive-front markers.\",\n      \"evidence\": \"siRNA knockdown with phospho-EGFR/Erk/Akt Western blots and IHC co-localization with \\u03b2-catenin and MMP7 in colorectal cancer\",\n      \"pmids\": [\"27859949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal chain from SPC18 to phospho-EGFR not separated from general secretory defects\",\n        \"Identity of the secreted ligand mediating EGFR activation in CRC not established\",\n        \"Mechanism linking SPC18 to \\u03b2-catenin nuclear localization unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified an upstream regulatory mechanism showing SEC11A is a direct miR-873-5p target, explaining how SEC11A levels are controlled and reinforcing the SEC11A\\u2192EGFR signaling axis through rescue.\",\n      \"evidence\": \"Dual luciferase reporter, Western blot, and SEC11A-overexpression rescue in tongue squamous cell carcinoma cells\",\n      \"pmids\": [\"33675129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological contexts in which miR-873-5p regulates SEC11A not defined\",\n        \"Whether other microRNAs co-regulate SEC11A unaddressed\",\n        \"Single-lab validation of the binding interaction\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the pro-tumor loss-of-function phenotype to HNSCC and reported predominantly cytoplasmic SPC18 localization, broadening the cancer-type generality of the secretory growth role.\",\n      \"evidence\": \"shRNA lentiviral knockdown with proliferation/migration/invasion assays, xenografts, and IHC localization in HNSCC\",\n      \"pmids\": [\"37025806\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No new pathway mechanism identified beyond prior work\",\n        \"Secreted substrate mediating the HNSCC phenotype not identified\",\n        \"Cytoplasmic IHC signal not resolved to ER subcompartment\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a host-pathogen role by showing SEC11A is required for human metapneumovirus replication and that HMPV reprograms SEC11A splicing, implicating signal-peptidase function in viral biology.\",\n      \"evidence\": \"CRISPR knockout cell lines with HMPV replication readout and RNA-seq detection of an infection-induced exon-skipping event\",\n      \"pmids\": [\"41743027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SEC11A acts by processing a viral protein or supporting host secretory machinery unknown\",\n        \"Functional consequence of the exon-skipping event on SPC18 activity not determined\",\n        \"Mechanism by which HMPV induces the splicing change uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical activity of SPC18 as the catalytic signal peptidase subunit, including its substrate repertoire and complex composition in human cells, remains uncharacterized in this corpus.\",\n      \"evidence\": \"No reconstitution or structural/biochemical assay of SPC18 catalysis present in the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct demonstration of signal-peptide cleavage by human SPC18 in the corpus\",\n        \"Subunit partners of the signal peptidase complex not experimentally defined here\",\n        \"ER-membrane catalytic mechanism not addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}