{"gene":"COLEC10","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1999,"finding":"CL-L1 (COLEC10) was cloned and found to encode a collectin with an N-terminal cysteine-rich domain, collagen-like domain, neck domain, and carbohydrate recognition domain (CRD). Expression studies of recombinant fusion proteins lacking the collagen and N-terminal domains showed that CL-L1 binds mannose weakly but does not bind to mannan columns. CL-L1 was identified as a cytosolic protein predominantly expressed in liver.","method":"cDNA cloning, Northern blot, Western blot, RT-PCR, recombinant fusion protein expression in E. coli with carbohydrate-binding assay, chromosomal localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (molecular cloning, recombinant protein functional assay, blotting), single lab","pmids":["10224141"],"is_preprint":false},{"year":2012,"finding":"CL-L1 (COLEC10) shows preference for d-mannose, d-fucose, N-acetylglucosamine, and d-galactose via its carbohydrate recognition domain, whereas CL-L1 appears restricted to the cytosol of hepatocytes rather than being a serum protein like CL-K1 (CL-11).","method":"Specificity analyses of CRDs, cellular localization studies (review synthesizing primary experimental data)","journal":"Immunobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper synthesizing prior experimental findings; no new primary experiments described in this abstract","pmids":["22475410"],"is_preprint":false},{"year":2016,"finding":"CL-L1 (COLEC10) and CL-K1 (COLEC11) form heteromeric complexes in circulation (known as CL-LK), which activate the lectin complement pathway via MASPs, implicating COLEC10 in complement-mediated innate immunity.","method":"Biochemical characterization of circulating complexes, complement activation assays (review synthesizing primary experimental data)","journal":"Immunobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper summarizing experimental findings from other groups; no new primary experiments described in this abstract","pmids":["27377710"],"is_preprint":false},{"year":2015,"finding":"CL-L1 serum levels strongly correlate with CL-K1 serum levels (ρ=0.74, P<0.0001), suggesting a large proportion exists as heterooligomers or are co-regulated. The COLEC10 Arg125Trp variant was associated with increased CL-L1 serum levels.","method":"Gene sequencing of COLEC10 and COLEC11, serum concentration measurement by ELISA, statistical correlation analysis","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, association-based, no direct biochemical reconstitution of heterooligomer formation","pmids":["25710878"],"is_preprint":false},{"year":2017,"finding":"COLEC10 is mutated in 3MC syndrome patients (mutations c.25C>T; p.Arg9Ter, c.226delA; p.Gly77Glufs*66, and c.528C>G; p.Cys176Trp), and these mutations impair the expression and/or secretion of CL-L1. COLEC10 is expressed in the basement membrane of the palate during murine embryo development, and CL-L1 and CL-K1 form heteromeric complexes. Loss of COLEC10 function is linked to craniofacial developmental defects involving cranial neural crest cells.","method":"Patient mutation identification (sequencing), functional expression studies of mutant proteins (expression/secretion assays), immunohistochemistry of murine embryo tissue, genetic mapping","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (patient genetics, mutant protein functional assays, embryo IHC), replicated across multiple patient families and consistent with other genes in the same pathway","pmids":["28301481"],"is_preprint":false},{"year":2018,"finding":"CL-L1 (COLEC10) and CL-K1 (COLEC11) have widespread and almost identical tissue distribution, with high expression in epithelial cells of endo-/exocrine secretory tissues and mucosa. mRNA localization corresponds to protein detection, indicating local synthesis underlies peripheral localization and likely drives formation of CL-LK heteromeric complexes in those tissues.","method":"Immunohistochemistry with monoclonal antibodies across major human tissues, mRNA localization","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic IHC with monoclonal antibodies across tissues with mRNA-protein concordance, single study","pmids":["30108587"],"is_preprint":false},{"year":2021,"finding":"A COLEC10 frameshift variant (c.807_810delCTGT; p.Cys270Serfs*33) causing loss of a conserved cysteine residue does not alter CL-L1 plasma levels but abolishes the chemoattractive function of CL-L1: HeLa cells migrate significantly less in response to the mutant protein compared to wild-type CL-L1.","method":"Sanger sequencing, plasma CL-L1 level measurement, cell migration assay (wound healing/chemotaxis with wild-type vs. mutant protein)","journal":"European journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay comparing wild-type vs. mutant protein in cell migration, single lab","pmids":["34740859"],"is_preprint":false},{"year":2023,"finding":"COLEC10 is predominantly produced by hepatic stellate cells (not hepatocytes) in both mouse and human liver, especially quiescent stellate cells. In CCl4-induced fibrosis, COLEC10 expression is decreased. In vitro overexpression of COLEC10 in LX-2 cells promotes mRNA expression of extracellular matrix components (COL1A1, COL1A2, COL3A1) and MMP2, implicating COLEC10 in ECM regulation during fibrosis.","method":"Single-cell RNA sequencing re-analysis, pseudotime trajectory inference, CCl4 mouse model, lentivirus-mediated overexpression in LX-2 cells, bulk RNA sequencing, ELISA for serum levels","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, in vitro OE with transcriptomic readout, mouse model, human serum), single lab","pmids":["38036508"],"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 increases GRP78 occupancy and releases/activates ER stress transducers PERK and IRE1α, triggering the unfolded protein response. COLEC10 overexpression leads to elevated phospho-PERK, phospho-IRE1α, ATF4, DDIT3, and XBP1s, and a dilated/fragmented ER morphology, suppressing HCC cell growth and migration.","method":"Co-immunoprecipitation (COLEC10-GRP78 interaction), domain mapping (CRD required for binding), Western blot for UPR markers, ER morphology imaging, in vitro and in vivo overexpression studies, ROS measurement","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, multiple UPR marker readouts, in vitro and in vivo validation, single lab","pmids":["36925047"],"is_preprint":false},{"year":2024,"finding":"COLEC10 overexpression suppresses Wnt/β-catenin signaling in HCC cells by upregulating the Wnt inhibitory factor WIF1 and reducing cytoplasmic β-catenin levels. COLEC10 promotes the interaction of β-catenin with the destruction complex component CK1α (shown by immunoprecipitation). Additionally, KLHL22 (an E3 ligase adaptor) was found to interact with CK1α and facilitates COLEC10 monoubiquitination and degradation.","method":"Wnt/β-catenin reporter assay, immunoprecipitation (β-catenin/CK1α interaction), colony/sphere formation assay, side population assay, in vivo tumor initiation assay, KLHL22 interaction studies","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (reporter, Co-IP, in vivo), single lab; mechanistic pathway placement via epistasis and direct binding","pmids":["39080215"],"is_preprint":false}],"current_model":"COLEC10 (CL-L1) is a C-type lectin collectin that acts as a pattern recognition molecule via its C-terminal carbohydrate recognition domain, binding mannose and related sugars; it circulates in heteromeric complexes with CL-K1 (COLEC11) to activate the lectin complement pathway via MASPs, serves as a chemoattractant for neural crest cell migration during embryonic development (with loss-of-function mutations causing 3MC syndrome craniofacial defects), directly binds GRP78 in the ER to induce the unfolded protein response, and suppresses Wnt/β-catenin signaling by promoting β-catenin interaction with the CK1α destruction complex while itself being subject to KLHL22-mediated monoubiquitination."},"narrative":{"mechanistic_narrative":"COLEC10 (CL-L1) is a collectin pattern-recognition molecule built from an N-terminal cysteine-rich domain, a collagen-like domain, a neck region, and a C-terminal carbohydrate recognition domain (CRD) that confers preferential binding to d-mannose and related sugars [PMID:10224141]. It is locally synthesized across endo-/exocrine secretory epithelia and, in liver, is produced predominantly by quiescent hepatic stellate cells [PMID:30108587, PMID:38036508]. Through its CRD and collagenous regions, CL-L1 assembles into heteromeric complexes with CL-K1 (COLEC11), and the two proteins display tightly co-regulated tissue and serum profiles consistent with extensive heterooligomerization [PMID:28301481, PMID:30108587]. Loss-of-function mutations in COLEC10 that impair CL-L1 expression or secretion cause 3MC syndrome, a developmental disorder of craniofacial morphogenesis, with murine expression in the palatal basement membrane and a CRD-dependent chemoattractive activity supporting a role in cell migration during development [PMID:28301481, PMID:34740859]. Beyond development, COLEC10 acts as a tumor suppressor in hepatocellular carcinoma: it binds the ER chaperone GRP78 via its CRD to trigger PERK/IRE1α-mediated unfolded protein response and ER stress [PMID:36925047], and it suppresses Wnt/β-catenin signaling by upregulating WIF1 and promoting β-catenin association with the CK1α destruction complex, while COLEC10 is itself subject to KLHL22-dependent monoubiquitination and degradation [PMID:39080215]. In fibrotic liver, COLEC10 is downregulated and its overexpression drives extracellular matrix gene expression in stellate cells [PMID:38036508].","teleology":[{"year":1999,"claim":"Established the existence and domain architecture of COLEC10 as a liver-expressed collectin, defining the modular structure (cysteine-rich, collagen-like, neck, CRD) that underlies all later functional work.","evidence":"cDNA cloning, blotting, and recombinant CRD carbohydrate-binding assays in E. coli","pmids":["10224141"],"confidence":"Medium","gaps":["Weak mannose binding and failure to bind mannan columns left the physiological ligand undefined","Cytosolic/hepatic assignment did not address secreted or complexed forms"]},{"year":2015,"claim":"Showed that circulating CL-L1 and CL-K1 levels are strongly correlated, providing population-level evidence that the two collectins co-exist as heterooligomers or are co-regulated.","evidence":"COLEC10/COLEC11 sequencing with ELISA serum quantification and correlation analysis","pmids":["25710878"],"confidence":"Low","gaps":["Association-based; no direct biochemical reconstitution of the heterooligomer","Functional consequence of the Arg125Trp variant on serum level not mechanistically explained"]},{"year":2017,"claim":"Connected COLEC10 loss of function to a defined human disease, demonstrating that COLEC10 mutations cause 3MC syndrome and implicating CL-L1 in craniofacial neural crest development.","evidence":"Patient mutation identification, mutant expression/secretion assays, and murine embryo immunohistochemistry","pmids":["28301481"],"confidence":"High","gaps":["Molecular ligand/receptor mediating the developmental signal not identified","Relationship between complement role and developmental role unresolved"]},{"year":2018,"claim":"Mapped where COLEC10 is made and acts, showing local epithelial/mucosal synthesis concordant at mRNA and protein levels and overlapping with CL-K1, supporting in situ formation of CL-LK complexes.","evidence":"Systematic monoclonal-antibody immunohistochemistry and mRNA localization across human tissues","pmids":["30108587"],"confidence":"Medium","gaps":["Does not establish the functional output of CL-LK at each tissue site","Single study, no functional perturbation"]},{"year":2021,"claim":"Separated CL-L1's chemoattractive function from its abundance, showing a conserved-cysteine frameshift variant abolishes migration-promoting activity without changing plasma levels.","evidence":"Sanger sequencing, plasma level measurement, and wild-type versus mutant cell migration assays","pmids":["34740859"],"confidence":"Medium","gaps":["Receptor or signaling pathway mediating chemoattraction not identified","Cell type used (HeLa) is not the developmentally relevant neural crest cell"]},{"year":2023,"claim":"Identified an intracellular role linking COLEC10 to ER proteostasis, showing CRD-dependent binding to GRP78 that triggers the unfolded protein response and suppresses HCC growth.","evidence":"Reciprocal Co-IP with domain mapping, UPR-marker Western blots, ER imaging, and in vitro/in vivo overexpression","pmids":["36925047"],"confidence":"Medium","gaps":["How a secretory collectin engages GRP78 in the ER lumen versus cytosol not resolved","Single lab; no loss-of-function (knockdown) confirmation of the UPR effect"]},{"year":2023,"claim":"Re-assigned the hepatic cellular source of COLEC10 to quiescent stellate cells and tied its downregulation to fibrosis and ECM gene induction.","evidence":"scRNA-seq re-analysis, pseudotime, CCl4 mouse model, and lentiviral overexpression in LX-2 cells with transcriptomic readout","pmids":["38036508"],"confidence":"Medium","gaps":["Mechanism by which COLEC10 regulates ECM/MMP2 transcription not defined","Causality between COLEC10 loss and fibrosis progression not tested by knockout"]},{"year":2024,"claim":"Placed COLEC10 as a suppressor of Wnt/β-catenin signaling and defined its own regulation, showing it promotes β-catenin/CK1α destruction-complex interaction and is degraded via KLHL22-mediated monoubiquitination.","evidence":"Wnt reporter assays, β-catenin/CK1α and KLHL22 immunoprecipitation, colony/sphere/side-population assays, and in vivo tumor initiation","pmids":["39080215"],"confidence":"Medium","gaps":["Direct molecular link between COLEC10 and WIF1 upregulation not established","Whether KLHL22-dependent degradation is regulated physiologically unknown"]},{"year":null,"claim":"How COLEC10's complement/pattern-recognition role, its developmental chemoattractant function, and its intracellular tumor-suppressive ER/Wnt activities are mechanistically unified within one protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified cell-surface receptor for the chemoattractant/developmental signal","Reconciliation of secreted-collectin versus intracellular ER/cytosolic functions is open","No structural model of the CL-LK heterocomplex or of CRD-GRP78 binding"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[8]}],"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":[4]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9]}],"complexes":["CL-LK (COLEC10–COLEC11 heterocomplex)"],"partners":["COLEC11","GRP78/HSPA5","CTNNB1","CSNK1A1","KLHL22"],"other_free_text":[]}},"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":71,"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":18,"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":10,"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. 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Expression studies of recombinant fusion proteins lacking the collagen and N-terminal domains showed that CL-L1 binds mannose weakly but does not bind to mannan columns. CL-L1 was identified as a cytosolic protein predominantly expressed in liver.\",\n      \"method\": \"cDNA cloning, Northern blot, Western blot, RT-PCR, recombinant fusion protein expression in E. coli with carbohydrate-binding assay, chromosomal localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (molecular cloning, recombinant protein functional assay, blotting), single lab\",\n      \"pmids\": [\"10224141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CL-L1 (COLEC10) shows preference for d-mannose, d-fucose, N-acetylglucosamine, and d-galactose via its carbohydrate recognition domain, whereas CL-L1 appears restricted to the cytosol of hepatocytes rather than being a serum protein like CL-K1 (CL-11).\",\n      \"method\": \"Specificity analyses of CRDs, cellular localization studies (review synthesizing primary experimental data)\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper synthesizing prior experimental findings; no new primary experiments described in this abstract\",\n      \"pmids\": [\"22475410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CL-L1 (COLEC10) and CL-K1 (COLEC11) form heteromeric complexes in circulation (known as CL-LK), which activate the lectin complement pathway via MASPs, implicating COLEC10 in complement-mediated innate immunity.\",\n      \"method\": \"Biochemical characterization of circulating complexes, complement activation assays (review synthesizing primary experimental data)\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper summarizing experimental findings from other groups; no new primary experiments described in this abstract\",\n      \"pmids\": [\"27377710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CL-L1 serum levels strongly correlate with CL-K1 serum levels (ρ=0.74, P<0.0001), suggesting a large proportion exists as heterooligomers or are co-regulated. The COLEC10 Arg125Trp variant was associated with increased CL-L1 serum levels.\",\n      \"method\": \"Gene sequencing of COLEC10 and COLEC11, serum concentration measurement by ELISA, statistical correlation analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, association-based, no direct biochemical reconstitution of heterooligomer formation\",\n      \"pmids\": [\"25710878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COLEC10 is mutated in 3MC syndrome patients (mutations c.25C>T; p.Arg9Ter, c.226delA; p.Gly77Glufs*66, and c.528C>G; p.Cys176Trp), and these mutations impair the expression and/or secretion of CL-L1. COLEC10 is expressed in the basement membrane of the palate during murine embryo development, and CL-L1 and CL-K1 form heteromeric complexes. Loss of COLEC10 function is linked to craniofacial developmental defects involving cranial neural crest cells.\",\n      \"method\": \"Patient mutation identification (sequencing), functional expression studies of mutant proteins (expression/secretion assays), immunohistochemistry of murine embryo tissue, genetic mapping\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (patient genetics, mutant protein functional assays, embryo IHC), replicated across multiple patient families and consistent with other genes in the same pathway\",\n      \"pmids\": [\"28301481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CL-L1 (COLEC10) and CL-K1 (COLEC11) have widespread and almost identical tissue distribution, with high expression in epithelial cells of endo-/exocrine secretory tissues and mucosa. mRNA localization corresponds to protein detection, indicating local synthesis underlies peripheral localization and likely drives formation of CL-LK heteromeric complexes in those tissues.\",\n      \"method\": \"Immunohistochemistry with monoclonal antibodies across major human tissues, mRNA localization\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic IHC with monoclonal antibodies across tissues with mRNA-protein concordance, single study\",\n      \"pmids\": [\"30108587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A COLEC10 frameshift variant (c.807_810delCTGT; p.Cys270Serfs*33) causing loss of a conserved cysteine residue does not alter CL-L1 plasma levels but abolishes the chemoattractive function of CL-L1: HeLa cells migrate significantly less in response to the mutant protein compared to wild-type CL-L1.\",\n      \"method\": \"Sanger sequencing, plasma CL-L1 level measurement, cell migration assay (wound healing/chemotaxis with wild-type vs. mutant protein)\",\n      \"journal\": \"European journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay comparing wild-type vs. mutant protein in cell migration, single lab\",\n      \"pmids\": [\"34740859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COLEC10 is predominantly produced by hepatic stellate cells (not hepatocytes) in both mouse and human liver, especially quiescent stellate cells. In CCl4-induced fibrosis, COLEC10 expression is decreased. In vitro overexpression of COLEC10 in LX-2 cells promotes mRNA expression of extracellular matrix components (COL1A1, COL1A2, COL3A1) and MMP2, implicating COLEC10 in ECM regulation during fibrosis.\",\n      \"method\": \"Single-cell RNA sequencing re-analysis, pseudotime trajectory inference, CCl4 mouse model, lentivirus-mediated overexpression in LX-2 cells, bulk RNA sequencing, ELISA for serum levels\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (scRNA-seq, in vitro OE with transcriptomic readout, mouse model, human serum), single lab\",\n      \"pmids\": [\"38036508\"],\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 increases GRP78 occupancy and releases/activates ER stress transducers PERK and IRE1α, triggering the unfolded protein response. COLEC10 overexpression leads to elevated phospho-PERK, phospho-IRE1α, ATF4, DDIT3, and XBP1s, and a dilated/fragmented ER morphology, suppressing HCC cell growth and migration.\",\n      \"method\": \"Co-immunoprecipitation (COLEC10-GRP78 interaction), domain mapping (CRD required for binding), Western blot for UPR markers, ER morphology imaging, in vitro and in vivo overexpression studies, ROS measurement\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, multiple UPR marker readouts, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"36925047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COLEC10 overexpression suppresses Wnt/β-catenin signaling in HCC cells by upregulating the Wnt inhibitory factor WIF1 and reducing cytoplasmic β-catenin levels. COLEC10 promotes the interaction of β-catenin with the destruction complex component CK1α (shown by immunoprecipitation). Additionally, KLHL22 (an E3 ligase adaptor) was found to interact with CK1α and facilitates COLEC10 monoubiquitination and degradation.\",\n      \"method\": \"Wnt/β-catenin reporter assay, immunoprecipitation (β-catenin/CK1α interaction), colony/sphere formation assay, side population assay, in vivo tumor initiation assay, KLHL22 interaction studies\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (reporter, Co-IP, in vivo), single lab; mechanistic pathway placement via epistasis and direct binding\",\n      \"pmids\": [\"39080215\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COLEC10 (CL-L1) is a C-type lectin collectin that acts as a pattern recognition molecule via its C-terminal carbohydrate recognition domain, binding mannose and related sugars; it circulates in heteromeric complexes with CL-K1 (COLEC11) to activate the lectin complement pathway via MASPs, serves as a chemoattractant for neural crest cell migration during embryonic development (with loss-of-function mutations causing 3MC syndrome craniofacial defects), directly binds GRP78 in the ER to induce the unfolded protein response, and suppresses Wnt/β-catenin signaling by promoting β-catenin interaction with the CK1α destruction complex while itself being subject to KLHL22-mediated monoubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COLEC10 (CL-L1) is a collectin pattern-recognition molecule built from an N-terminal cysteine-rich domain, a collagen-like domain, a neck region, and a C-terminal carbohydrate recognition domain (CRD) that confers preferential binding to d-mannose and related sugars [#0]. It is locally synthesized across endo-/exocrine secretory epithelia and, in liver, is produced predominantly by quiescent hepatic stellate cells [#5, #7]. Through its CRD and collagenous regions, CL-L1 assembles into heteromeric complexes with CL-K1 (COLEC11), and the two proteins display tightly co-regulated tissue and serum profiles consistent with extensive heterooligomerization [#4, #5]. Loss-of-function mutations in COLEC10 that impair CL-L1 expression or secretion cause 3MC syndrome, a developmental disorder of craniofacial morphogenesis, with murine expression in the palatal basement membrane and a CRD-dependent chemoattractive activity supporting a role in cell migration during development [#4, #6]. Beyond development, COLEC10 acts as a tumor suppressor in hepatocellular carcinoma: it binds the ER chaperone GRP78 via its CRD to trigger PERK/IRE1\\u03b1-mediated unfolded protein response and ER stress [#8], and it suppresses Wnt/\\u03b2-catenin signaling by upregulating WIF1 and promoting \\u03b2-catenin association with the CK1\\u03b1 destruction complex, while COLEC10 is itself subject to KLHL22-dependent monoubiquitination and degradation [#9]. In fibrotic liver, COLEC10 is downregulated and its overexpression drives extracellular matrix gene expression in stellate cells [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the existence and domain architecture of COLEC10 as a liver-expressed collectin, defining the modular structure (cysteine-rich, collagen-like, neck, CRD) that underlies all later functional work.\",\n      \"evidence\": \"cDNA cloning, blotting, and recombinant CRD carbohydrate-binding assays in E. coli\",\n      \"pmids\": [\"10224141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Weak mannose binding and failure to bind mannan columns left the physiological ligand undefined\", \"Cytosolic/hepatic assignment did not address secreted or complexed forms\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that circulating CL-L1 and CL-K1 levels are strongly correlated, providing population-level evidence that the two collectins co-exist as heterooligomers or are co-regulated.\",\n      \"evidence\": \"COLEC10/COLEC11 sequencing with ELISA serum quantification and correlation analysis\",\n      \"pmids\": [\"25710878\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Association-based; no direct biochemical reconstitution of the heterooligomer\", \"Functional consequence of the Arg125Trp variant on serum level not mechanistically explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected COLEC10 loss of function to a defined human disease, demonstrating that COLEC10 mutations cause 3MC syndrome and implicating CL-L1 in craniofacial neural crest development.\",\n      \"evidence\": \"Patient mutation identification, mutant expression/secretion assays, and murine embryo immunohistochemistry\",\n      \"pmids\": [\"28301481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular ligand/receptor mediating the developmental signal not identified\", \"Relationship between complement role and developmental role unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped where COLEC10 is made and acts, showing local epithelial/mucosal synthesis concordant at mRNA and protein levels and overlapping with CL-K1, supporting in situ formation of CL-LK complexes.\",\n      \"evidence\": \"Systematic monoclonal-antibody immunohistochemistry and mRNA localization across human tissues\",\n      \"pmids\": [\"30108587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish the functional output of CL-LK at each tissue site\", \"Single study, no functional perturbation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Separated CL-L1's chemoattractive function from its abundance, showing a conserved-cysteine frameshift variant abolishes migration-promoting activity without changing plasma levels.\",\n      \"evidence\": \"Sanger sequencing, plasma level measurement, and wild-type versus mutant cell migration assays\",\n      \"pmids\": [\"34740859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor or signaling pathway mediating chemoattraction not identified\", \"Cell type used (HeLa) is not the developmentally relevant neural crest cell\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an intracellular role linking COLEC10 to ER proteostasis, showing CRD-dependent binding to GRP78 that triggers the unfolded protein response and suppresses HCC growth.\",\n      \"evidence\": \"Reciprocal Co-IP with domain mapping, UPR-marker Western blots, ER imaging, and in vitro/in vivo overexpression\",\n      \"pmids\": [\"36925047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a secretory collectin engages GRP78 in the ER lumen versus cytosol not resolved\", \"Single lab; no loss-of-function (knockdown) confirmation of the UPR effect\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Re-assigned the hepatic cellular source of COLEC10 to quiescent stellate cells and tied its downregulation to fibrosis and ECM gene induction.\",\n      \"evidence\": \"scRNA-seq re-analysis, pseudotime, CCl4 mouse model, and lentiviral overexpression in LX-2 cells with transcriptomic readout\",\n      \"pmids\": [\"38036508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which COLEC10 regulates ECM/MMP2 transcription not defined\", \"Causality between COLEC10 loss and fibrosis progression not tested by knockout\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed COLEC10 as a suppressor of Wnt/\\u03b2-catenin signaling and defined its own regulation, showing it promotes \\u03b2-catenin/CK1\\u03b1 destruction-complex interaction and is degraded via KLHL22-mediated monoubiquitination.\",\n      \"evidence\": \"Wnt reporter assays, \\u03b2-catenin/CK1\\u03b1 and KLHL22 immunoprecipitation, colony/sphere/side-population assays, and in vivo tumor initiation\",\n      \"pmids\": [\"39080215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between COLEC10 and WIF1 upregulation not established\", \"Whether KLHL22-dependent degradation is regulated physiologically unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How COLEC10's complement/pattern-recognition role, its developmental chemoattractant function, and its intracellular tumor-suppressive ER/Wnt activities are mechanistically unified within one protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified cell-surface receptor for the chemoattractant/developmental signal\", \"Reconciliation of secreted-collectin versus intracellular ER/cytosolic functions is open\", \"No structural model of the CL-LK heterocomplex or of CRD-GRP78 binding\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"CL-LK (COLEC10–COLEC11 heterocomplex)\"],\n    \"partners\": [\"COLEC11\", \"GRP78/HSPA5\", \"CTNNB1\", \"CSNK1A1\", \"KLHL22\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}