{"gene":"COLEC10","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1999,"finding":"CL-L1 (COLEC10 protein) is a collectin with an N-terminal cysteine-rich domain, collagen-like domain, neck domain, and carbohydrate recognition domain; it is present mainly in liver as a cytosolic protein; expression of fusion proteins lacking the collagen and N-terminal domains demonstrated that CL-L1 binds mannose weakly but does not bind to mannan columns.","method":"cDNA cloning, Northern blot, Western blot, RT-PCR, chromosomal localization, E. coli fusion protein expression with carbohydrate-binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — original cloning and direct in vitro carbohydrate-binding assay with recombinant protein; foundational paper with 126 citations","pmids":["10224141"],"is_preprint":false},{"year":2012,"finding":"CL-L1 (COLEC10) preferentially binds d-mannose, d-fucose, N-acetylglucosamine, and d-galactose via its CRD, while CL-K1 (COLEC11) binds most avidly to l-fucose and d-mannose; CL-L1 appears restricted to the cytosol of hepatocytes, whereas CL-K1 is a serum protein; CL-K1 is found in circulating complexes with MASP-1/3.","method":"Specificity analyses of carbohydrate recognition domains, biochemical fractionation, binding assays","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding specificity characterization and localization, single review/analysis paper but with multiple orthogonal observations","pmids":["22475410"],"is_preprint":false},{"year":2016,"finding":"CL-L1 (COLEC10) and CL-K1 (COLEC11) form heteromeric complexes (CL-LK) in circulation, which activate the lectin complement pathway via MASPs upon binding to microbial high mannose-like glycoconjugates.","method":"Biochemical characterization, complement activation assays, review of interaction data","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 — functional characterization of heteromeric complex formation and complement activation, replicated across multiple labs","pmids":["27377710"],"is_preprint":false},{"year":2017,"finding":"COLEC10 is expressed in the basement membrane of the palate during murine embryonic development; loss-of-function mutations in COLEC10 (c.25C>T p.Arg9Ter, c.226delA p.Gly77Glufs*66, c.528C>G p.Cys176Trp) impair the expression and/or secretion of CL-L1, disrupting morphogenesis of craniofacial structures (3MC syndrome); CL-L1 (COLEC10 protein) and CL-K1 (COLEC11 protein) form heteromeric complexes.","method":"In situ expression analysis in murine embryos, functional characterization of patient mutations by expression/secretion assays, genetic linkage in 3MC families","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — direct mutation functional assays showing impaired secretion, direct embryonic localization, replicated across multiple 3MC families","pmids":["28301481"],"is_preprint":false},{"year":2018,"finding":"CL-L1 (COLEC10) and CL-K1 (COLEC11) have widespread and nearly identical tissue distribution with high co-expression in secretory epithelial cells of endo-/exocrine secretory tissues and mucosa; local synthesis in peripheral tissues is responsible for heteromeric CL-LK complex formation, as demonstrated by concordance between mRNA and protein localization.","method":"Immunohistochemistry with monoclonal antibodies on human tissues, mRNA in situ localization","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional implications for complex formation, single lab but multiple tissue types","pmids":["30108587"],"is_preprint":false},{"year":2021,"finding":"A COLEC10 frameshift variant (c.807_810delCTGT; p.Cys270Serfs*33) that removes a conserved cysteine residue does not affect CL-L1 transcription or secretion (plasma levels normal), but impairs the chemoattractive function of CL-L1: HeLa cells migrate significantly less in response to the mutant protein compared to wild-type.","method":"Sanger sequencing, plasma CL-L1 level measurement, cell migration assay (wound healing/chemotaxis with wild-type vs. mutant CL-L1)","journal":"European journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay showing loss of chemoattractant activity for the mutant protein, single lab","pmids":["34740859"],"is_preprint":false},{"year":2023,"finding":"COLEC10 directly binds GRP78 (78-kDa glucose-regulated protein) via its C-terminal carbohydrate recognition domain in the endoplasmic reticulum; this interaction occupies GRP78 and releases/activates ER stress transducers (PERK, IRE1α), triggering the unfolded protein response (UPR) and inducing ER dilation and fragmentation, thereby inhibiting HCC cell growth and migration.","method":"Co-immunoprecipitation, domain-deletion constructs, Western blot for ER stress markers (p-PERK, p-IRE1α, ATF4, DDIT3, XBP1s), electron microscopy of ER morphology, ROS measurement, in vitro and in vivo growth assays","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding shown by Co-IP with domain mapping, multiple orthogonal ER stress readouts, in vitro and in vivo functional validation","pmids":["36925047"],"is_preprint":false},{"year":2023,"finding":"COLEC10 is predominantly produced by quiescent hepatic stellate cells (not hepatocytes) in mouse and human liver; overexpression of COLEC10 in LX-2 hepatic stellate cells promotes mRNA expression of extracellular matrix components COL1A1, COL1A2, COL3A1 and the matrix metalloproteinase MMP2, implicating COLEC10 in liver fibrosis pathogenesis.","method":"Single-cell RNA sequencing re-analysis, pseudotime trajectory inference, lentiviral COLEC10 overexpression in LX-2 cells, bulk RNA sequencing, RT-qPCR","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — direct overexpression experiment with transcriptomic readout of ECM genes, scRNA-seq for cell-type assignment, single lab","pmids":["38036508"],"is_preprint":false},{"year":2024,"finding":"COLEC10 inhibits HCC stemness by suppressing Wnt/β-catenin signaling: COLEC10 overexpression upregulates the Wnt inhibitory factor WIF1, reduces cytoplasmic β-catenin levels, and promotes the interaction of β-catenin with the destruction complex component CK1α; additionally, the E3 ligase adaptor KLHL22 facilitates COLEC10 monoubiquitination and degradation.","method":"Wnt/β-catenin reporter assay, co-immunoprecipitation, colony/sphere formation assays, side population assay, limiting dilution tumor initiation assay in vivo, Western blot","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — direct Co-IP showing β-catenin/CK1α interaction promoted by COLEC10, Wnt reporter assay, in vitro and in vivo functional readouts; single lab","pmids":["39080215"],"is_preprint":false}],"current_model":"COLEC10 encodes CL-L1, a collectin with a C-type carbohydrate recognition domain (CRD) that binds mannose and related sugars, forms heteromeric complexes (CL-LK) with CL-K1/COLEC11 to activate the lectin complement pathway via MASPs, acts as a chemoattractant for neural crest cell migration during craniofacial development (loss-of-function causing 3MC syndrome), is predominantly produced by hepatic stellate cells in the liver, and within cells directly binds GRP78 via its CRD to trigger ER stress/UPR and suppresses Wnt/β-catenin signaling by promoting β-catenin interaction with the CK1α destruction complex—with KLHL22 acting as an E3 ligase adaptor for COLEC10 monoubiquitination."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of CL-L1 as a novel collectin family member resolved the gene's domain architecture and established its liver-enriched expression, but the weak mannose-binding observed with truncated fusion proteins left the physiological ligand specificity uncertain.","evidence":"cDNA cloning, Northern blot, E. coli fusion protein carbohydrate-binding assays","pmids":["10224141"],"confidence":"High","gaps":["Full-length protein binding specificity not tested","Biological function unknown","Secretion vs. intracellular retention unclear"]},{"year":2012,"claim":"Detailed CRD specificity profiling clarified that CL-L1 preferentially binds mannose, fucose, GlcNAc, and galactose, and revealed an apparent cytosolic restriction of CL-L1 distinct from the secreted CL-K1, raising questions about how the two collectins interact.","evidence":"Carbohydrate specificity analyses and biochemical fractionation of hepatocytes","pmids":["22475410"],"confidence":"Medium","gaps":["Mechanism of intracellular retention not defined","Heteromeric complex formation with CL-K1 not yet demonstrated directly"]},{"year":2016,"claim":"Demonstration that CL-L1 and CL-K1 form circulating CL-LK heteromeric complexes that activate the lectin complement pathway via MASPs established the functional unit for innate immune pattern recognition.","evidence":"Biochemical characterization and complement activation assays","pmids":["27377710"],"confidence":"Medium","gaps":["Stoichiometry and structure of CL-LK complex unresolved","Relative contribution of CL-L1 vs. CL-K1 CRDs to ligand recognition unknown"]},{"year":2017,"claim":"Linking COLEC10 loss-of-function mutations to 3MC syndrome and showing impaired CL-L1 secretion established a direct developmental role for the gene in craniofacial morphogenesis, independent of complement activation.","evidence":"Functional characterization of patient mutations (expression/secretion assays), in situ hybridization in murine embryonic palate, genetic linkage in 3MC families","pmids":["28301481"],"confidence":"High","gaps":["Downstream signaling pathway driving neural crest migration not identified","Whether complement activation is required for the developmental phenotype unclear"]},{"year":2018,"claim":"Immunohistochemical mapping across human tissues showed widespread CL-L1/CL-K1 co-expression in secretory epithelia, demonstrating that local peripheral synthesis—not solely hepatic production—generates CL-LK complexes.","evidence":"Monoclonal antibody immunohistochemistry and mRNA in situ on human tissue panels","pmids":["30108587"],"confidence":"Medium","gaps":["Functional relevance of extrahepatic CL-LK production not tested","Whether tissue-specific CL-LK activates complement locally unknown"]},{"year":2021,"claim":"A COLEC10 frameshift variant that preserves secretion but abolishes chemoattractant activity demonstrated that the CRD-containing C-terminus is required for CL-L1's role as a cell migration guidance cue, mechanistically separating secretion from biological function.","evidence":"Cell migration/chemotaxis assay with wild-type vs. mutant recombinant CL-L1, plasma level measurement","pmids":["34740859"],"confidence":"Medium","gaps":["Receptor mediating chemoattractant response unidentified","Whether this variant causes 3MC in homozygous state not confirmed"]},{"year":2023,"claim":"Discovery that intracellular COLEC10 directly binds GRP78 via its CRD to release ER stress transducers PERK and IRE1α revealed a cell-autonomous tumor-suppressive mechanism through UPR activation and ER structural disruption in HCC cells.","evidence":"Co-immunoprecipitation with domain-deletion constructs, Western blot for p-PERK/p-IRE1α/ATF4/DDIT3/XBP1s, electron microscopy, in vivo xenograft assays","pmids":["36925047"],"confidence":"High","gaps":["Whether CRD-GRP78 interaction is carbohydrate-dependent or protein-protein unknown","Relevance of this mechanism outside HCC not tested"]},{"year":2023,"claim":"Single-cell transcriptomics reassigned COLEC10's primary hepatic source to quiescent hepatic stellate cells rather than hepatocytes, and overexpression experiments linked COLEC10 to induction of fibrosis-associated ECM genes.","evidence":"scRNA-seq re-analysis, lentiviral overexpression in LX-2 stellate cells, RT-qPCR for COL1A1/COL1A2/COL3A1/MMP2","pmids":["38036508"],"confidence":"Medium","gaps":["Stellate cell activation state dependency not established","Whether endogenous COLEC10 knockdown reduces fibrosis not tested","In vivo fibrosis model lacking"]},{"year":2024,"claim":"Mechanistic dissection of COLEC10's tumor-suppressive role showed it inhibits Wnt/β-catenin signaling by upregulating WIF1 and promoting β-catenin association with the CK1α destruction complex, while KLHL22 was identified as the E3 ligase adaptor mediating COLEC10 monoubiquitination and turnover.","evidence":"Wnt/β-catenin reporter assay, Co-IP for β-catenin–CK1α, sphere formation and limiting dilution xenograft assays, Western blot for ubiquitination","pmids":["39080215"],"confidence":"Medium","gaps":["Direct binding site on β-catenin/CK1α not mapped","Whether Wnt suppression and GRP78-mediated ER stress are independent or connected pathways unknown","KLHL22 ubiquitination site on COLEC10 not identified"]},{"year":null,"claim":"The receptor or co-receptor through which secreted CL-L1 exerts its chemoattractant function during embryonic development remains unidentified, and the relationship between the extracellular complement-activating role and the intracellular ER-stress/Wnt-suppressive mechanisms has not been integrated.","evidence":"","pmids":[],"confidence":"Low","gaps":["No chemoattractant receptor identified","No structural model of CL-LK heteromer","Interplay between complement activation, ER stress induction, and Wnt pathway suppression unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,8]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,3,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6]}],"complexes":["CL-LK (CL-L1/CL-K1 heteromer)","CL-LK–MASP complex"],"partners":["COLEC11","HSPA5","KLHL22","CSNK1A1","CTNNB1"],"other_free_text":[]},"mechanistic_narrative":"COLEC10 encodes collectin liver 1 (CL-L1), a pattern-recognition molecule of the innate immune system that also serves critical roles in embryonic morphogenesis and hepatocellular homeostasis. CL-L1 contains an N-terminal cysteine-rich domain, a collagen-like domain, a neck domain, and a C-type carbohydrate recognition domain (CRD) that binds mannose, fucose, N-acetylglucosamine, and galactose; it hetero-oligomerizes with CL-K1 (COLEC11) to form circulating CL-LK complexes that activate the lectin complement pathway via MASPs [PMID:10224141, PMID:27377710]. Loss-of-function mutations in COLEC10 cause 3MC syndrome, a Mendelian craniofacial dysostosis, by impairing CL-L1 secretion and its chemoattractant activity for migrating cells during palate and craniofacial development [PMID:28301481, PMID:34740859]. Intracellularly, COLEC10 directly binds the ER chaperone GRP78 through its CRD, sequestering GRP78 and thereby activating PERK- and IRE1α-dependent ER stress responses that suppress hepatocellular carcinoma cell growth; it also inhibits Wnt/β-catenin signaling by upregulating WIF1 and promoting β-catenin interaction with the CK1α destruction complex, with KLHL22 acting as an E3 ligase adaptor that monoubiquitinates and destabilizes COLEC10 [PMID:36925047, PMID:39080215]."},"prefetch_data":{"uniprot":{"accession":"Q9Y6Z7","full_name":"Collectin-10","aliases":["Collectin liver protein 1","CL-L1","Collectin-34","CL-34"],"length_aa":277,"mass_kda":30.7,"function":"Lectin that binds to various sugars: galactose > mannose = fucose > N-acetylglucosamine > N-acetylgalactosamine (PubMed:10224141). Acts as a chemoattractant, probably involved in the regulation of cell migration (PubMed:28301481)","subcellular_location":"Secreted; Golgi apparatus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9Y6Z7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COLEC10","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/COLEC10","total_profiled":1310},"omim":[{"mim_id":"612502","title":"COLLECTIN 11; COLEC11","url":"https://www.omim.org/entry/612502"},{"mim_id":"607620","title":"COLLECTIN 10; COLEC10","url":"https://www.omim.org/entry/607620"},{"mim_id":"265050","title":"3MC SYNDROME 2; 3MC2","url":"https://www.omim.org/entry/265050"},{"mim_id":"257920","title":"3MC SYNDROME 1; 3MC1","url":"https://www.omim.org/entry/257920"},{"mim_id":"248340","title":"3MC SYNDROME 3; 3MC3","url":"https://www.omim.org/entry/248340"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":61.4}],"url":"https://www.proteinatlas.org/search/COLEC10"},"hgnc":{"alias_symbol":["CL-L1","CL-10"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6Z7","domains":[{"cath_id":"3.10.100.10","chopping":"159-274","consensus_level":"high","plddt":96.4328,"start":159,"end":274}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Z7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Z7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Z7-F1-predicted_aligned_error_v6.png","plddt_mean":80.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COLEC10","jax_strain_url":"https://www.jax.org/strain/search?query=COLEC10"},"sequence":{"accession":"Q9Y6Z7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6Z7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6Z7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Z7"}},"corpus_meta":[{"pmid":"10224141","id":"PMC_10224141","title":"Molecular cloning of a novel human collectin from liver (CL-L1).","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10224141","citation_count":126,"is_preprint":false},{"pmid":"22475410","id":"PMC_22475410","title":"Structure and function of collectin liver 1 (CL-L1) and collectin 11 (CL-11, CL-K1).","date":"2012","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/22475410","citation_count":79,"is_preprint":false},{"pmid":"27377710","id":"PMC_27377710","title":"The collectins CL-L1, CL-K1 and CL-P1, and their roles in complement and innate immunity.","date":"2016","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27377710","citation_count":70,"is_preprint":false},{"pmid":"28301481","id":"PMC_28301481","title":"COLEC10 is mutated in 3MC patients and regulates early craniofacial development.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28301481","citation_count":61,"is_preprint":false},{"pmid":"30108587","id":"PMC_30108587","title":"CL-L1 and CL-K1 Exhibit Widespread Tissue Distribution With High and Co-Localized Expression in Secretory Epithelia and Mucosa.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30108587","citation_count":29,"is_preprint":false},{"pmid":"25710878","id":"PMC_25710878","title":"Genetic variation of COLEC10 and COLEC11 and association with serum levels of collectin liver 1 (CL-L1) and collectin kidney 1 (CL-K1).","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25710878","citation_count":28,"is_preprint":false},{"pmid":"32751929","id":"PMC_32751929","title":"Association of Polymorphisms of MASP1/3, COLEC10, and COLEC11 Genes with 3MC Syndrome.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32751929","citation_count":25,"is_preprint":false},{"pmid":"33565325","id":"PMC_33565325","title":"MiR-452-5p mediates the proliferation, migration and invasion of hepatocellular carcinoma cells via targeting COLEC10.","date":"2021","source":"Personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33565325","citation_count":17,"is_preprint":false},{"pmid":"34636477","id":"PMC_34636477","title":"Whole-exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34636477","citation_count":12,"is_preprint":false},{"pmid":"38036508","id":"PMC_38036508","title":"The C-type lectin COLEC10 is predominantly produced by hepatic stellate cells and involved in the pathogenesis of liver fibrosis.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38036508","citation_count":9,"is_preprint":false},{"pmid":"30756438","id":"PMC_30756438","title":"Two-Step Structure Phase Transition, Dielectric Anomalies, and Thermochromic Luminescence Behavior in a Direct Band Gap 2D Corrugated Layer Lead Chloride Hybrid of [(CH3 )4 N]4 Pb3 Cl10.","date":"2019","source":"Chemistry (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/30756438","citation_count":9,"is_preprint":false},{"pmid":"36925047","id":"PMC_36925047","title":"COLEC10 Induces Endoplasmic Reticulum Stress by Occupying GRP78 and Inhibits Hepatocellular Carcinoma.","date":"2023","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36925047","citation_count":8,"is_preprint":false},{"pmid":"34740859","id":"PMC_34740859","title":"A novel COLEC10 mutation in a child with 3MC syndrome.","date":"2021","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34740859","citation_count":6,"is_preprint":false},{"pmid":"39080215","id":"PMC_39080215","title":"COLEC10 inhibits the stemness of hepatocellular carcinoma by suppressing the activity of β-catenin signaling.","date":"2024","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/39080215","citation_count":4,"is_preprint":false},{"pmid":"35943032","id":"PMC_35943032","title":"Expanding the phenotypic spectrum of COLEC10-Related 3MC syndrome: A glimpse into COLEC10-Related 3MC syndrome in the Ashkenazi Jewish population.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/35943032","citation_count":2,"is_preprint":false},{"pmid":"40010397","id":"PMC_40010397","title":"Adaptation and conservation of CL-10/11 in avian lungs: implications for their role in pulmonary innate immune protection.","date":"2025","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40010397","citation_count":2,"is_preprint":false},{"pmid":"39495851","id":"PMC_39495851","title":"HCC control by lycorine-based restraining of the MiR-224-5p/COLEC10 axis.","date":"2024","source":"Pakistan journal of pharmaceutical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39495851","citation_count":1,"is_preprint":false},{"pmid":"41578380","id":"PMC_41578380","title":"COLEC10 and COLEC11 are new serum biomarkers of chronic liver disease.","date":"2026","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41578380","citation_count":0,"is_preprint":false},{"pmid":"40545641","id":"PMC_40545641","title":"Circularly Polarized Luminescence in Chiral Antimony(III) Chloride [Sb2Cl10]4- Dimers Induced by Asymmetric Hydrogen Bonding.","date":"2025","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40545641","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11360,"output_tokens":2530,"usd":0.036015},"stage2":{"model":"claude-opus-4-6","input_tokens":5874,"output_tokens":2686,"usd":0.14478},"total_usd":0.180795,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"CL-L1 (COLEC10 protein) is a collectin with an N-terminal cysteine-rich domain, collagen-like domain, neck domain, and carbohydrate recognition domain; it is present mainly in liver as a cytosolic protein; expression of fusion proteins lacking the collagen and N-terminal domains demonstrated that CL-L1 binds mannose weakly but does not bind to mannan columns.\",\n      \"method\": \"cDNA cloning, Northern blot, Western blot, RT-PCR, chromosomal localization, E. coli fusion protein expression with carbohydrate-binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning and direct in vitro carbohydrate-binding assay with recombinant protein; foundational paper with 126 citations\",\n      \"pmids\": [\"10224141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CL-L1 (COLEC10) preferentially binds d-mannose, d-fucose, N-acetylglucosamine, and d-galactose via its CRD, while CL-K1 (COLEC11) binds most avidly to l-fucose and d-mannose; CL-L1 appears restricted to the cytosol of hepatocytes, whereas CL-K1 is a serum protein; CL-K1 is found in circulating complexes with MASP-1/3.\",\n      \"method\": \"Specificity analyses of carbohydrate recognition domains, biochemical fractionation, binding assays\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding specificity characterization and localization, single review/analysis paper but with multiple orthogonal observations\",\n      \"pmids\": [\"22475410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CL-L1 (COLEC10) and CL-K1 (COLEC11) form heteromeric complexes (CL-LK) in circulation, which activate the lectin complement pathway via MASPs upon binding to microbial high mannose-like glycoconjugates.\",\n      \"method\": \"Biochemical characterization, complement activation assays, review of interaction data\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization of heteromeric complex formation and complement activation, replicated across multiple labs\",\n      \"pmids\": [\"27377710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COLEC10 is expressed in the basement membrane of the palate during murine embryonic development; loss-of-function mutations in COLEC10 (c.25C>T p.Arg9Ter, c.226delA p.Gly77Glufs*66, c.528C>G p.Cys176Trp) impair the expression and/or secretion of CL-L1, disrupting morphogenesis of craniofacial structures (3MC syndrome); CL-L1 (COLEC10 protein) and CL-K1 (COLEC11 protein) form heteromeric complexes.\",\n      \"method\": \"In situ expression analysis in murine embryos, functional characterization of patient mutations by expression/secretion assays, genetic linkage in 3MC families\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct mutation functional assays showing impaired secretion, direct embryonic localization, replicated across multiple 3MC families\",\n      \"pmids\": [\"28301481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CL-L1 (COLEC10) and CL-K1 (COLEC11) have widespread and nearly identical tissue distribution with high co-expression in secretory epithelial cells of endo-/exocrine secretory tissues and mucosa; local synthesis in peripheral tissues is responsible for heteromeric CL-LK complex formation, as demonstrated by concordance between mRNA and protein localization.\",\n      \"method\": \"Immunohistochemistry with monoclonal antibodies on human tissues, mRNA in situ localization\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional implications for complex formation, single lab but multiple tissue types\",\n      \"pmids\": [\"30108587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A COLEC10 frameshift variant (c.807_810delCTGT; p.Cys270Serfs*33) that removes a conserved cysteine residue does not affect CL-L1 transcription or secretion (plasma levels normal), but impairs the chemoattractive function of CL-L1: HeLa cells migrate significantly less in response to the mutant protein compared to wild-type.\",\n      \"method\": \"Sanger sequencing, plasma CL-L1 level measurement, cell migration assay (wound healing/chemotaxis with wild-type vs. mutant CL-L1)\",\n      \"journal\": \"European journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay showing loss of chemoattractant activity for the mutant protein, single lab\",\n      \"pmids\": [\"34740859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COLEC10 directly binds GRP78 (78-kDa glucose-regulated protein) via its C-terminal carbohydrate recognition domain in the endoplasmic reticulum; this interaction occupies GRP78 and releases/activates ER stress transducers (PERK, IRE1α), triggering the unfolded protein response (UPR) and inducing ER dilation and fragmentation, thereby inhibiting HCC cell growth and migration.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion constructs, Western blot for ER stress markers (p-PERK, p-IRE1α, ATF4, DDIT3, XBP1s), electron microscopy of ER morphology, ROS measurement, in vitro and in vivo growth assays\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding shown by Co-IP with domain mapping, multiple orthogonal ER stress readouts, in vitro and in vivo functional validation\",\n      \"pmids\": [\"36925047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COLEC10 is predominantly produced by quiescent hepatic stellate cells (not hepatocytes) in mouse and human liver; overexpression of COLEC10 in LX-2 hepatic stellate cells promotes mRNA expression of extracellular matrix components COL1A1, COL1A2, COL3A1 and the matrix metalloproteinase MMP2, implicating COLEC10 in liver fibrosis pathogenesis.\",\n      \"method\": \"Single-cell RNA sequencing re-analysis, pseudotime trajectory inference, lentiviral COLEC10 overexpression in LX-2 cells, bulk RNA sequencing, RT-qPCR\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct overexpression experiment with transcriptomic readout of ECM genes, scRNA-seq for cell-type assignment, single lab\",\n      \"pmids\": [\"38036508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COLEC10 inhibits HCC stemness by suppressing Wnt/β-catenin signaling: COLEC10 overexpression upregulates the Wnt inhibitory factor WIF1, reduces cytoplasmic β-catenin levels, and promotes the interaction of β-catenin with the destruction complex component CK1α; additionally, the E3 ligase adaptor KLHL22 facilitates COLEC10 monoubiquitination and degradation.\",\n      \"method\": \"Wnt/β-catenin reporter assay, co-immunoprecipitation, colony/sphere formation assays, side population assay, limiting dilution tumor initiation assay in vivo, Western blot\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct Co-IP showing β-catenin/CK1α interaction promoted by COLEC10, Wnt reporter assay, in vitro and in vivo functional readouts; single lab\",\n      \"pmids\": [\"39080215\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COLEC10 encodes CL-L1, a collectin with a C-type carbohydrate recognition domain (CRD) that binds mannose and related sugars, forms heteromeric complexes (CL-LK) with CL-K1/COLEC11 to activate the lectin complement pathway via MASPs, acts as a chemoattractant for neural crest cell migration during craniofacial development (loss-of-function causing 3MC syndrome), is predominantly produced by hepatic stellate cells in the liver, and within cells directly binds GRP78 via its CRD to trigger ER stress/UPR and suppresses Wnt/β-catenin signaling by promoting β-catenin interaction with the CK1α destruction complex—with KLHL22 acting as an E3 ligase adaptor for COLEC10 monoubiquitination.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"COLEC10 encodes collectin liver 1 (CL-L1), a pattern-recognition molecule of the innate immune system that also serves critical roles in embryonic morphogenesis and hepatocellular homeostasis. CL-L1 contains an N-terminal cysteine-rich domain, a collagen-like domain, a neck domain, and a C-type carbohydrate recognition domain (CRD) that binds mannose, fucose, N-acetylglucosamine, and galactose; it hetero-oligomerizes with CL-K1 (COLEC11) to form circulating CL-LK complexes that activate the lectin complement pathway via MASPs [PMID:10224141, PMID:27377710]. Loss-of-function mutations in COLEC10 cause 3MC syndrome, a Mendelian craniofacial dysostosis, by impairing CL-L1 secretion and its chemoattractant activity for migrating cells during palate and craniofacial development [PMID:28301481, PMID:34740859]. Intracellularly, COLEC10 directly binds the ER chaperone GRP78 through its CRD, sequestering GRP78 and thereby activating PERK- and IRE1α-dependent ER stress responses that suppress hepatocellular carcinoma cell growth; it also inhibits Wnt/β-catenin signaling by upregulating WIF1 and promoting β-catenin interaction with the CK1α destruction complex, with KLHL22 acting as an E3 ligase adaptor that monoubiquitinates and destabilizes COLEC10 [PMID:36925047, PMID:39080215].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of CL-L1 as a novel collectin family member resolved the gene's domain architecture and established its liver-enriched expression, but the weak mannose-binding observed with truncated fusion proteins left the physiological ligand specificity uncertain.\",\n      \"evidence\": \"cDNA cloning, Northern blot, E. coli fusion protein carbohydrate-binding assays\",\n      \"pmids\": [\"10224141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length protein binding specificity not tested\", \"Biological function unknown\", \"Secretion vs. intracellular retention unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Detailed CRD specificity profiling clarified that CL-L1 preferentially binds mannose, fucose, GlcNAc, and galactose, and revealed an apparent cytosolic restriction of CL-L1 distinct from the secreted CL-K1, raising questions about how the two collectins interact.\",\n      \"evidence\": \"Carbohydrate specificity analyses and biochemical fractionation of hepatocytes\",\n      \"pmids\": [\"22475410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of intracellular retention not defined\", \"Heteromeric complex formation with CL-K1 not yet demonstrated directly\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that CL-L1 and CL-K1 form circulating CL-LK heteromeric complexes that activate the lectin complement pathway via MASPs established the functional unit for innate immune pattern recognition.\",\n      \"evidence\": \"Biochemical characterization and complement activation assays\",\n      \"pmids\": [\"27377710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structure of CL-LK complex unresolved\", \"Relative contribution of CL-L1 vs. CL-K1 CRDs to ligand recognition unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking COLEC10 loss-of-function mutations to 3MC syndrome and showing impaired CL-L1 secretion established a direct developmental role for the gene in craniofacial morphogenesis, independent of complement activation.\",\n      \"evidence\": \"Functional characterization of patient mutations (expression/secretion assays), in situ hybridization in murine embryonic palate, genetic linkage in 3MC families\",\n      \"pmids\": [\"28301481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway driving neural crest migration not identified\", \"Whether complement activation is required for the developmental phenotype unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Immunohistochemical mapping across human tissues showed widespread CL-L1/CL-K1 co-expression in secretory epithelia, demonstrating that local peripheral synthesis—not solely hepatic production—generates CL-LK complexes.\",\n      \"evidence\": \"Monoclonal antibody immunohistochemistry and mRNA in situ on human tissue panels\",\n      \"pmids\": [\"30108587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional relevance of extrahepatic CL-LK production not tested\", \"Whether tissue-specific CL-LK activates complement locally unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A COLEC10 frameshift variant that preserves secretion but abolishes chemoattractant activity demonstrated that the CRD-containing C-terminus is required for CL-L1's role as a cell migration guidance cue, mechanistically separating secretion from biological function.\",\n      \"evidence\": \"Cell migration/chemotaxis assay with wild-type vs. mutant recombinant CL-L1, plasma level measurement\",\n      \"pmids\": [\"34740859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating chemoattractant response unidentified\", \"Whether this variant causes 3MC in homozygous state not confirmed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that intracellular COLEC10 directly binds GRP78 via its CRD to release ER stress transducers PERK and IRE1α revealed a cell-autonomous tumor-suppressive mechanism through UPR activation and ER structural disruption in HCC cells.\",\n      \"evidence\": \"Co-immunoprecipitation with domain-deletion constructs, Western blot for p-PERK/p-IRE1α/ATF4/DDIT3/XBP1s, electron microscopy, in vivo xenograft assays\",\n      \"pmids\": [\"36925047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CRD-GRP78 interaction is carbohydrate-dependent or protein-protein unknown\", \"Relevance of this mechanism outside HCC not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Single-cell transcriptomics reassigned COLEC10's primary hepatic source to quiescent hepatic stellate cells rather than hepatocytes, and overexpression experiments linked COLEC10 to induction of fibrosis-associated ECM genes.\",\n      \"evidence\": \"scRNA-seq re-analysis, lentiviral overexpression in LX-2 stellate cells, RT-qPCR for COL1A1/COL1A2/COL3A1/MMP2\",\n      \"pmids\": [\"38036508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stellate cell activation state dependency not established\", \"Whether endogenous COLEC10 knockdown reduces fibrosis not tested\", \"In vivo fibrosis model lacking\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mechanistic dissection of COLEC10's tumor-suppressive role showed it inhibits Wnt/β-catenin signaling by upregulating WIF1 and promoting β-catenin association with the CK1α destruction complex, while KLHL22 was identified as the E3 ligase adaptor mediating COLEC10 monoubiquitination and turnover.\",\n      \"evidence\": \"Wnt/β-catenin reporter assay, Co-IP for β-catenin–CK1α, sphere formation and limiting dilution xenograft assays, Western blot for ubiquitination\",\n      \"pmids\": [\"39080215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding site on β-catenin/CK1α not mapped\", \"Whether Wnt suppression and GRP78-mediated ER stress are independent or connected pathways unknown\", \"KLHL22 ubiquitination site on COLEC10 not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor or co-receptor through which secreted CL-L1 exerts its chemoattractant function during embryonic development remains unidentified, and the relationship between the extracellular complement-activating role and the intracellular ER-stress/Wnt-suppressive mechanisms has not been integrated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No chemoattractant receptor identified\", \"No structural model of CL-LK heteromer\", \"Interplay between complement activation, ER stress induction, and Wnt pathway suppression unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"CL-LK (CL-L1/CL-K1 heteromer)\",\n      \"CL-LK–MASP complex\"\n    ],\n    \"partners\": [\n      \"COLEC11\",\n      \"HSPA5\",\n      \"KLHL22\",\n      \"CSNK1A1\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}