Affinage

CLEC14A

C-type lectin domain family 14 member A · UniProt Q86T13

Length
490 aa
Mass
51.6 kDa
Annotated
2026-06-09
25 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLEC14A is an endothelial cell-surface transmembrane glycoprotein that drives sprouting angiogenesis through its C-type lectin-like domain (CTLD), which mediates homotypic endothelial cell-cell contact required for migration, filopodial protrusion, and tube formation (PMID:21095181, PMID:23644659). Its principal extracellular ligand is the matrix protein MMRN2 (Multimerin-2), which it binds directly via a long-loop region of the CTLD to promote sprouting angiogenesis and tumor vascularization; CLEC14A and CD93 engage the same non-glycosylated coiled-coil region of MMRN2, while CD248 occupies a distinct site, allowing CLEC14A and CD248 to bridge the endothelial-pericyte interface simultaneously (PMID:25745997, PMID:28671670). CLEC14A forms a complex with VEGFR-3 and sets the balance between VEGFR-2 and VEGFR-3 signaling to maintain vascular homeostasis: its loss reduces VEGFR-3 and elevates VEGFR-2 signaling, increasing blood-brain barrier permeability and neuroinflammation after ischemia-reperfusion injury (PMID:27991863, PMID:32019570). The receptor sits within a defined transcriptional axis, being directly activated by FLI1 and in turn driving VEGFC expression (PMID:41548484), and it genetically interacts with Etv2 and VEGF signaling during vascular development (PMID:30953479). The CTLD additionally binds heparin and heparan/chondroitin sulfate E with nanomolar affinity (PMID:31964714) and engages HSP70-1A to support ERK-dependent tube formation (PMID:28878328). CLEC14A activity is negatively regulated by RHBDL2-mediated ectodomain shedding, which releases a soluble inhibitor of angiogenesis that binds tip cells (PMID:26939791). Beyond the vasculature, CLEC14A regulates type-H-vessel-dependent osteoblast maturation through its MMRN2 interaction (PMID:39394430), mediates MMRN2-independent firm adhesion of neutrophils to liver endothelium (PMID:42223241), binds HMGB1 in podocytes to suppress NF-κB/EGR1 inflammatory signaling (PMID:34107098), and modulates cAMP/PKA and ERK signaling in trophoblasts (PMID:42113307).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2010 Medium

    Established CLEC14A as an endothelial-restricted plasma membrane protein whose CTLD mediates cell-cell adhesion and is required for angiogenic behaviors, defining its baseline cellular role.

    Evidence Deletion mutant mapping, siRNA knockdown, adhesion/migration/tube formation assays in endothelial cells

    PMID:21095181

    Open questions at the time
    • No ligand identified for the CTLD at this stage
    • Adhesion mechanism (homotypic vs heterotypic) not yet resolved
  2. 2011 Medium

    Confirmed CLEC14A as a positive regulator of endothelial migration and tube formation in vitro and in vivo, and linked its expression to low shear stress.

    Evidence Overexpression, antibody inhibition, zebrafish vascular development assays

    PMID:21706054

    Open questions at the time
    • Molecular mechanism of shear-stress induction unknown
    • No downstream signaling pathway defined
  3. 2013 Medium

    Resolved the adhesion mechanism as a CTLD-CTLD homotypic interaction and showed CTLD-blocking antibodies suppress angiogenesis, validating the domain as a therapeutic target.

    Evidence Phage-display antibody selection, functional blocking, flow cytometry for surface expression

    PMID:23644659

    Open questions at the time
    • Whether homotypic contact is the sole adhesive mode unaddressed
    • No structural model of the CTLD-CTLD interface
  4. 2015 High

    Identified MMRN2 as the direct extracellular ligand whose engagement drives sprouting angiogenesis and tumor vascularization, defining the receptor-ligand axis.

    Evidence Reciprocal Co-IP/pull-down, monoclonal antibody C4 blocking, clec14a-/- mouse aortic ring/sponge and tumor models

    PMID:25745997

    Open questions at the time
    • Binding determinants within the CTLD not yet mapped
    • Downstream signaling from CLEC14A-MMRN2 engagement undefined
  5. 2016 High

    Defined RHBDL2-mediated ectodomain shedding as a negative-feedback mechanism producing a soluble anti-angiogenic CLEC14A fragment that targets tip cells.

    Evidence Site-directed mutagenesis of cleavage site, siRNA of CLEC14A/RHBDL2, in vitro sprouting and in vivo sponge assays, recombinant fragment addition

    PMID:26939791

    Open questions at the time
    • Regulation of RHBDL2 activity unknown
    • Receptor/target on tip cells for shed ectodomain not identified
  6. 2016 High

    Placed CLEC14A within VEGFR signaling by showing it complexes with VEGFR-3 and balances VEGFR-2/VEGFR-3 output to maintain vascular homeostasis.

    Evidence Co-IP, CLEC14A-KO mice, Western blot for VEGFR-2/3, in vivo angiogenesis/lymphangiogenesis phenotyping, VEGFR-2 blockade rescue

    PMID:27991863

    Open questions at the time
    • Mechanism by which CLEC14A stabilizes VEGFR-3 unknown
    • Direct vs indirect nature of the complex not fully resolved
  7. 2017 High

    Mapped the MMRN2-binding determinant to a CTLD long-loop region and showed CLEC14A, CD93, and CD248 share/partition MMRN2 sites, enabling combinatorial endothelial-pericyte bridging.

    Evidence Direct binding and competitive assays, long-loop mutagenesis, MMRN2 peptide blocking, HUVEC adhesion, tissue co-localization

    PMID:28671670

    Open questions at the time
    • Functional consequence of simultaneous CLEC14A/CD248 binding not dissected
    • Stoichiometry of the multi-receptor MMRN2 assembly unknown
  8. 2017 Medium

    Identified HSP70-1A as a CTLD ligand (residues 43-69) that drives ERK-dependent tube formation, broadening CLEC14A's ligand repertoire beyond MMRN2.

    Evidence Proteomic isolation, Co-IP, truncation binding mapping, competitive peptide, ERK phosphorylation and tube formation assays

    PMID:28878328

    Open questions at the time
    • Physiological source of HSP70-1A ligand unclear
    • Link between HSP70-1A engagement and downstream ERK not mechanistically resolved
  9. 2019 Medium

    Positioned CLEC14A genetically within the Etv2/VEGFA developmental angiogenesis program via epistasis.

    Evidence TALEN clec14a mutant zebrafish, morpholino knockdown, double-mutant epistasis, vascular marker analysis

    PMID:30953479

    Open questions at the time
    • Whether interaction is direct or pathway-level unresolved
    • No molecular link to Etv2 transcriptional targets
  10. 2020 Medium

    Extended the VEGFR-2 balance model to barrier function, showing CLEC14A loss elevates VEGFR-2 signaling, increases BBB permeability, and worsens neuroinflammation.

    Evidence Endothelial knockdown, CLEC14A-KO mice, permeability/TEER/Evans blue assays, MCAO model, Western blot

    PMID:32019570

    Open questions at the time
    • Direct effect on tight junction proteins vs secondary to VEGFR-2 unresolved
    • Therapeutic window for CLEC14A modulation in stroke undefined
  11. 2020 High

    Demonstrated direct nanomolar heparin/heparan sulfate binding by the CTLD, identifying a glycosaminoglycan-recognition function and its structural determinants.

    Evidence Heparin-affinity chromatography, LC-MS/MS, quantified binding assays, molecular modeling, site-directed mutagenesis

    PMID:31964714

    Open questions at the time
    • Physiological role of GAG binding in vivo unestablished
    • Relationship between heparin and MMRN2/HSP70 binding sites unresolved
  12. 2021 Medium

    Revealed a non-endothelial, anti-inflammatory role in podocytes via direct HMGB1 binding that suppresses HMGB1 release and NF-κB/EGR1 signaling.

    Evidence Co-IP, overexpression/knockdown in podocytes, CLEC14A-KO adriamycin nephropathy model, signaling Western blots, HMGB1 release assay

    PMID:34107098

    Open questions at the time
    • Whether HMGB1 binding occurs intracellularly or at the surface unclear
    • Generalizability beyond podocytes untested
  13. 2024 Medium

    Showed CLEC14A on type-H endothelium restrains osteoblast maturation and bone mineralization downstream of its MMRN2 interaction, linking vascular CLEC14A to skeletal development.

    Evidence Clec14a-/- mice bone phenotyping, antibody blocking of Clec14a-Mmrn2, histology, bone density measurement

    PMID:39394430

    Open questions at the time
    • Signal relaying vascular CLEC14A status to osteoblasts unknown
    • Cell-autonomous vs angiocrine contribution not separated
  14. 2024 Medium

    Defined a transcriptional axis in which FLI1 directly activates CLEC14A and CLEC14A drives VEGFC, embedding the receptor in a feed-forward angiogenic circuit.

    Evidence Dual-luciferase promoter reporter, siRNA epistasis, overexpression rescue, transcriptome sequencing, choroidal neovascularization model

    PMID:41548484

    Open questions at the time
    • Mechanism by which CLEC14A regulates VEGFC transcription unknown
    • Whether axis operates outside retinal endothelium untested
  15. 2026 Medium

    Identified an MMRN2-independent function in immune cell trafficking, with CLEC14A mediating firm neutrophil adhesion to liver endothelium.

    Evidence siRNA, blocking antibodies, flow-based liver endothelial neutrophil recruitment assay, Clec14a-/- ischemia-reperfusion model

    PMID:42223241

    Open questions at the time
    • Neutrophil counter-receptor for CLEC14A not identified
    • Whether this adhesion uses the CTLD or another domain unresolved
  16. 2026 Medium

    Showed CLEC14A modulates intracellular signaling balance (cAMP/PKA up, ERK down) to impair trophoblast migration, invasion, and tube formation.

    Evidence Lentiviral overexpression in HTR-8/SVneo cells, RNA-seq, cAMP ELISA, PKA/ERK Western blots, adenylate cyclase inhibitor rescue

    PMID:42113307

    Open questions at the time
    • Receptor-proximal events linking CLEC14A to adenylate cyclase unknown
    • Physiological relevance in placentation in vivo untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CLEC14A's distinct ligand-binding modes (MMRN2, heparin/HS, HSP70-1A, HMGB1) and the VEGFR-3 complex are integrated into context-specific signaling outputs across endothelial, immune, skeletal, renal, and trophoblast settings remains unresolved.
  • No structural model of the CTLD with any of its multiple ligands
  • Proximal intracellular signaling effectors of CLEC14A undefined
  • Counter-receptor mediating MMRN2-independent neutrophil adhesion unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 4 GO:0060089 molecular transducer activity 2 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
CD248CD93FLI1HMGB1HSP70-1AMMRN2RHBDL2VEGFR-3

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 CLEC14A is a plasma membrane protein specifically expressed in endothelial cells that mediates cell-cell adhesion through its C-type lectin-like domain (CTLD); deletion mutant analysis demonstrated the CTLD is required for this adhesion function, and knockdown suppressed cell migration, filopodial protrusion, and tube formation. Deletion mutant analysis, siRNA knockdown, cell adhesion and migration assays, tube formation assay Biochemical and biophysical research communications Medium 21095181
2011 CLEC14A overexpression induces filopodia and facilitates endothelial cell migration and tube formation; anti-CLEC14A antisera inhibited cell migration and tube formation, and expression is induced by low shear stress in endothelial cultures. Overexpression studies, antibody inhibition assays, tube formation and migration assays, zebrafish in vivo vascular development assay Oncogene Medium 21706054
2013 The C-type lectin-like domain (CTLD) of CLEC14A mediates homotypic cell-cell contact between endothelial cells (CTLD-CTLD interaction); antibodies blocking CTLD inhibit endothelial migration and tube formation and downregulate CLEC14A surface expression. Phage display antibody selection, functional blocking assays, cell migration and tube formation assays, flow cytometry for surface expression Oncogene Medium 23644659
2015 CLEC14A binds directly to MMRN2 (Multimerin-2) via its extracellular region; this interaction promotes sprouting angiogenesis and tumor vascularization, as blocking CLEC14A-MMRN2 binding with monoclonal antibody C4 phenocopies CLEC14A deficiency. Pull-down, co-immunoprecipitation, monoclonal antibody blocking, clec14a+/+ vs clec14a-/- mouse aortic ring and sponge assays, tumor growth models Oncogene High 25745997
2016 CLEC14A ectodomain is specifically cleaved (shed) by rhomboid-like protease RHBDL2 but not by RHBDL1 or RHBDL3; site-directed mutagenesis identified the precise cleavage site; shed CLEC14A ectodomain inhibits sprouting angiogenesis and binds to tip cells, acting as a negative feedback regulator. Site-directed mutagenesis, siRNA knockdown of CLEC14A and RHBDL2, in vitro sprouting assays, rodent subcutaneous sponge implant in vivo assay, recombinant protein addition experiments FASEB journal High 26939791
2016 CLEC14A forms a complex with VEGFR-3 in endothelial cells; CLEC14A KO results in markedly reduced VEGFR-3 expression and concomitant increase in VEGFR-2 expression and downstream signaling, demonstrating that CLEC14A regulates the balance between VEGFR-2 and VEGFR-3 signaling to maintain vascular homeostasis. Co-immunoprecipitation (CLEC14A-VEGFR-3 complex), CLEC14A knockout mice, Western blot for VEGFR-2/3 expression, in vivo angiogenesis and lymphangiogenesis phenotyping, VEGFR-2 blockade rescue experiment The Journal of clinical investigation High 27991863
2017 CLEC14A, CD93, and CD248 all directly bind MMRN2; binding requires a predicted long-loop region in the C-type lectin domain and is abrogated by mutation within this region. CLEC14A and CD93 bind to the same non-glycosylated coiled-coil region of MMRN2, while CD248 binds a distinct non-competing region. CLEC14A and CD248 can bind MMRN2 simultaneously at the endothelial-pericyte interface. Direct binding assays, mutagenesis of CLD long-loop region, competitive binding assays, recombinant MMRN2 peptide blocking of CLEC14A surface binding, HUVEC adhesion assays, pancreatic cancer tissue co-localization Oncogene High 28671670
2017 CLEC14A CTLD directly binds HSP70-1A; the binding site on CLEC14A-CTLD spans amino acids 43–69; this interaction mediates HSP70-1A-induced ERK phosphorylation and endothelial tube formation, and a peptide of this CTLD region competitively inhibits HSP70-1A-induced angiogenesis. Proteomic isolation, co-immunoprecipitation, in vitro binding assays with truncation mapping, competitive blocking peptide experiments, ERK phosphorylation assay, tube formation assay Scientific reports Medium 28878328
2018 The CTLD of CLEC14A mediates endothelial cell-cell contact required for VEGF-dependent angiogenesis; an anti-CLEC14A-CTLD humanized monoclonal antibody directly inhibits CTLD-mediated cell-cell contact, downregulates surface CLEC14A expression, and suppresses tumor angiogenesis in multiple xenograft models including bevacizumab-adapted tumors. Antibody engineering, in vitro cell-cell contact assays, VEGF-dependent angiogenesis assays, multiple mouse tumor xenograft models (SNU182, CFPAC-1, U87, HCT116, bevacizumab-adapted HCT116) Molecular oncology Medium 29316206
2019 In zebrafish, clec14a genetically interacts with Etv2 (ETS transcription factor) and Vegfa signaling during vasculogenesis and angiogenesis; partial knockdown of Etv2 or Vegfaa in clec14a mutant background produces synergistic inhibition of vascular development, placing CLEC14A in the same pathway as Etv2 and VEGF signaling. TALEN-generated clec14a mutant zebrafish, morpholino knockdown, genetic epistasis (double mutant/knockdown), vascular marker expression analysis BMC developmental biology Medium 30953479
2020 CLEC14A loss increases VEGFR-2 signaling in endothelial cells, leading to increased BBB permeability (increased FITC-dextran leakage, decreased TEER, reduced tight junction proteins) and exacerbated neuroinflammation after ischemia-reperfusion injury in mice. CLEC14A knockdown in endothelial cells, CLEC14A-KO mice, FITC-dextran permeability assay, TEER assay, Evans blue dye injection, MCAO surgery model, Western blot, immunofluorescence Journal of neuroinflammation Medium 32019570
2020 The C-type lectin domain of CLEC14A binds heparin with nanomolar (one-to-one stoichiometric) affinity; molecular modeling and mutagenesis mapped the heparin-binding site within the CTLD; CLEC14A also physically interacts with endothelial heparan sulfate and chondroitin sulfate E but not with neutral or sialylated oligosaccharides. Proteomics-based LPHAMS workflow, heparin-affinity chromatography, LC-MS/MS, in vitro binding assays (quantified affinity), molecular modeling, site-directed mutagenesis The Journal of biological chemistry High 31964714
2021 CLEC14A is expressed in podocytes and directly binds HMGB1; this interaction inhibits HMGB1 release and suppresses HMGB1-mediated NF-κB and EGR1 signaling, thereby protecting against podocyte injury and inflammation. Co-immunoprecipitation (CLEC14A-HMGB1 binding), CLEC14A overexpression and knockdown in podocytes, CLEC14A-KO mice (adriamycin nephropathy model), Western blot for NF-κB/EGR1 signaling, HMGB1 release assay FASEB journal Medium 34107098
2024 Clec14a expressed in type-H endothelial cells regulates osteoblast maturation and mineralisation during postnatal bone development; Clec14a-/- mice show premature type-H vessel condensation, expanded osteoblast distribution, increased bone density, and enhanced osteoblast maturation; antibody-mediated blockade of Clec14a-Mmrn2 interaction recapitulates the KO phenotype, placing this effect downstream of Clec14a-Mmrn2 binding. Clec14a-/- mice (bone phenotyping), antibody blocking of Clec14a-Mmrn2 interaction, histology, immunofluorescence, bone density measurements Communications biology Medium 39394430
2024 FLI1 is a direct transcriptional activator of CLEC14A; CLEC14A in turn positively regulates VEGFC expression in retinal endothelial cells, placing CLEC14A downstream of FLI1 and upstream of VEGFC in a regulatory angiogenic axis (FLI1-CLEC14A-VEGFC). Dual-luciferase reporter assay (FLI1 binding to CLEC14A promoter), siRNA knockdown of FLI1 and CLEC14A, CLEC14A overexpression rescue of VEGFC, transcriptome sequencing, in vivo choroidal neovascularization mouse model Biochemical and biophysical research communications Medium 41548484
2026 CLEC14A mediates firm adhesion of neutrophils to liver endothelium; siRNA knockdown of CLEC14A and CLEC14A-blocking antibodies reduced neutrophil firm adhesion in flow-based assays, and Clec14a-/- mice showed significantly reduced neutrophil recruitment across sinusoids in an ischemia-reperfusion liver injury model. This effect is independent of CLEC14A's interaction with MMRN2. siRNA knockdown, specific blocking antibodies, flow-based human liver endothelial neutrophil recruitment assay, in vivo Clec14a-/- mouse ischemia-reperfusion model The Journal of pathology Medium 42223241
2026 CLEC14A overexpression in trophoblast cells activates the cAMP/PKA signaling pathway (increased intracellular cAMP and PKA phosphorylation) while suppressing ERK phosphorylation, thereby impairing trophoblast migration, invasion, and tube formation; inhibition of adenylate cyclase (SQ22536) reverses these effects. Lentiviral CLEC14A overexpression in HTR-8/SVneo cells, RNA sequencing, ELISA (cAMP), Western blot (PKA/ERK phosphorylation), adenylate cyclase inhibitor rescue, migration/invasion/tube formation assays Journal of molecular histology Medium 42113307

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Identification and angiogenic role of the novel tumor endothelial marker CLEC14A. Oncogene 98 21706054
2017 Multimerin-2 is a ligand for group 14 family C-type lectins CLEC14A, CD93 and CD248 spanning the endothelial pericyte interface. Oncogene 68 28671670
2020 CLEC14A deficiency exacerbates neuronal loss by increasing blood-brain barrier permeability and inflammation. Journal of neuroinflammation 66 32019570
2010 Clec14a is specifically expressed in endothelial cells and mediates cell to cell adhesion. Biochemical and biophysical research communications 47 21095181
2015 Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth. Oncogene 46 25745997
2018 Activin receptor-like kinase 1 is associated with immune cell infiltration and regulates CLEC14A transcription in cancer. Angiogenesis 42 30132150
2018 Inhibition of VEGF-dependent angiogenesis and tumor angiogenesis by an optimized antibody targeting CLEC14a. Molecular oncology 35 29316206
2020 CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth. JCI insight 34 33004686
2019 Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7. Nature communications 34 31852888
2016 Sprouting angiogenesis is regulated by shedding of the C-type lectin family 14, member A (CLEC14A) ectodomain, catalyzed by rhomboid-like 2 protein (RHBDL2). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 26939791
2020 Proteomics-based screening of the endothelial heparan sulfate interactome reveals that C-type lectin 14a (CLEC14A) is a heparin-binding protein. The Journal of biological chemistry 31 31964714
2016 Carbohydrate-binding protein CLEC14A regulates VEGFR-2- and VEGFR-3-dependent signals during angiogenesis and lymphangiogenesis. The Journal of clinical investigation 30 27991863
2013 Human antibodies targeting the C-type lectin-like domain of the tumor endothelial cell marker clec14a regulate angiogenic properties in vitro. Oncogene 30 23644659
2017 CLEC14a-HSP70-1A interaction regulates HSP70-1A-induced angiogenesis. Scientific reports 26 28878328
2021 CLEC14A protects against podocyte injury in mice with adriamycin nephropathy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 34107098
2020 An evaluation of the tumour endothelial marker CLEC14A as a therapeutic target in solid tumours. The journal of pathology. Clinical research 15 32696621
2018 Methylation of CLEC14A is associated with its expression and lung adenocarcinoma progression. Journal of cellular physiology 12 30191970
2019 Clec14a genetically interacts with Etv2 and Vegf signaling during vasculogenesis and angiogenesis in zebrafish. BMC developmental biology 9 30953479
2024 CLEC14A facilitates angiogenesis and alleviates inflammation in diabetic wound healing. Life sciences 6 39454994
2024 Type-H endothelial cell protein Clec14a orchestrates osteoblast activity during trabecular bone formation and patterning. Communications biology 4 39394430
2022 CLEC14A was up-regulated in hepatocellular carcinoma and may function as a potential diagnostic biomarker. Clinics (Sao Paulo, Brazil) 3 35576868
2026 Alpha-difluoromethylornithine suppresses angiogenesis via the FLI1-CLEC14A-VEGFC pathway in retinal endothelial cells. Biochemical and biophysical research communications 0 41548484
2026 A novel methylation marker on the CLEC14A gene for cervical cancer screening. Frontiers in oncology 0 42057822
2026 CLEC14A mediates trophoblast dysfunction in unexplained miscarriage by disrupting the cAMP/ERK signaling pathway. Journal of molecular histology 0 42113307
2026 CLEC14A correlates with neutrophil infiltration in hepatocellular carcinoma and mediates neutrophil recruitment across liver endothelial cells. The Journal of pathology 0 42223241

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