COLEC10

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).

1. 1999 Medium

   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

   PMID:10224141

   Open questions at the time

   • Weak mannose binding and failure to bind mannan columns left the physiological ligand undefined
   • Cytosolic/hepatic assignment did not address secreted or complexed forms
2. 2015 Low

   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

   PMID:25710878

   Open questions at the time

   • Association-based; no direct biochemical reconstitution of the heterooligomer
   • Functional consequence of the Arg125Trp variant on serum level not mechanistically explained
3. 2017 High

   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

   PMID:28301481

   Open questions at the time

   • Molecular ligand/receptor mediating the developmental signal not identified
   • Relationship between complement role and developmental role unresolved
4. 2018 Medium

   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

   PMID:30108587

   Open questions at the time

   • Does not establish the functional output of CL-LK at each tissue site
   • Single study, no functional perturbation
5. 2021 Medium

   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

   PMID:34740859

   Open questions at the time

   • Receptor or signaling pathway mediating chemoattraction not identified
   • Cell type used (HeLa) is not the developmentally relevant neural crest cell
6. 2023 Medium

   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

   PMID:36925047

   Open questions at the time

   • 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
7. 2023 Medium

   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

   PMID:38036508

   Open questions at the time

   • Mechanism by which COLEC10 regulates ECM/MMP2 transcription not defined
   • Causality between COLEC10 loss and fibrosis progression not tested by knockout
8. 2024 Medium

   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

   PMID:39080215

   Open questions at the time

   • Direct molecular link between COLEC10 and WIF1 upregulation not established
   • Whether KLHL22-dependent degradation is regulated physiologically unknown

• 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.
• 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