Affinage

CD109

CD109 antigen · UniProt Q6YHK3

Length
1445 aa
Mass
161.7 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD109 is a GPI-anchored glycoprotein of the alpha2-macroglobulin/thioester-containing protein family that functions as a multifaceted regulator of TGF-β, STAT3, and EGFR signaling and as a protease inhibitor. As a membrane co-receptor, furin-processed CD109 (180/25 kDa fragments) associates with TGF-β type I receptor and directs it to caveolin-1-positive caveolae for SMAD7/Smurf2-mediated ubiquitin-dependent degradation, thereby suppressing canonical TGF-β/Smad2/3 signaling in keratinocytes, hematopoietic progenitors, and fibrotic tissues (PMID:16754747, PMID:20101215, PMID:21295082, PMID:21898545, PMID:23436317); soluble shed CD109 directly sequesters TGF-β ligand with high affinity (PMID:26621871). Simultaneously, membrane-anchored CD109 physically interacts with EGFR, GP130 (IL-6Rα), and GRP78 to promote AKT/mTOR, JAK-STAT3/NRF2, and YAP signaling, sustaining cancer cell stemness, metastasis, and chemoresistance (PMID:25724945, PMID:33986188, PMID:28191885, PMID:29654145, PMID:40317079). Structurally, cryo-EM reveals that bait-region proteolysis triggers a conformational change that activates the CD109 thioester for covalent conjugation and inhibition of proteases, while releasing CD109 from the cell surface — a mechanism analogous to A2ML1 (PMID:38587194, PMID:40482031).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 High

    Establishing CD109 as a thioester-containing member of the alpha2-macroglobulin superfamily resolved the molecular identity of this GPI-anchored surface glycoprotein and predicted a proteolysis-activated covalent-binding mechanism.

    Evidence cDNA cloning, sequence analysis, and biochemical demonstration of intact thioester bond in native CD109 from platelets and cell lines

    PMID:11861284

    Open questions at the time
    • No direct demonstration of protease inhibition at this stage
    • Physiological ligands/targets of the thioester unknown
    • Three-dimensional structure unavailable
  2. 2002 High

    Mapping the Gov/HPA-15 platelet alloantigen to a single Tyr703Ser polymorphism in CD109 resolved a clinically significant platelet antigen system at the molecular level.

    Evidence RT-PCR genotyping and CHO cell transfection with each CD109 variant confirmed allele-specific recognition by Gov antisera

    PMID:11861285

    Open questions at the time
    • Functional consequences of Y703S on CD109 biochemistry unknown
    • No structural explanation for why this site is immunogenic
  3. 2006 High

    Identifying CD109 as the 150 kDa GPI-anchored TGF-β1 binding protein in keratinocytes established its role as a co-receptor that negatively modulates TGF-β signaling, independent of simple ligand sequestration.

    Evidence Affinity purification and microsequencing from keratinocytes, plus loss-of-function (GPI-anchor deficient) and gain-of-function studies

    PMID:16754747

    Open questions at the time
    • Mechanism of TGF-β receptor modulation unresolved
    • Whether CD109 directly contacts the receptor versus ligand unclear
  4. 2010 High

    Demonstrating that furin cleaves CD109 into 180/25 kDa fragments and that this processing is required for TGF-β receptor association and signaling inhibition provided the first mechanistic step linking CD109 maturation to its co-receptor function.

    Evidence Site-directed mutagenesis of the tetra-arginine furin site (R1273S), co-IP with TGFBR1, and cell growth assays

    PMID:20101215

    Open questions at the time
    • Structural basis for how processed CD109 engages TGFBR1 unknown
    • Whether furin cleavage also activates the thioester not tested
  5. 2011 High

    Showing that CD109 associates with caveolin-1 and routes TGF-β receptors to caveolae for degradation revealed the trafficking mechanism underlying CD109-mediated TGF-β signal suppression, and subsequent work demonstrated this requires SMAD7/Smurf2 ubiquitin ligase activity.

    Evidence Co-IP of CD109 with caveolin-1, receptor internalization/degradation assays (2011); siRNA knockdown of SMAD7 and dominant-negative Smurf2 epistasis (2012)

    PMID:21295082 PMID:21898545

    Open questions at the time
    • Direct versus indirect nature of the CD109–caveolin-1 interaction not resolved
    • Stoichiometry of the CD109/caveolin-1/receptor complex unknown
  6. 2012 High

    CD109-deficient mice displaying epidermal hyperplasia with elevated STAT3 (but not Smad2) phosphorylation established that CD109 regulates skin homeostasis in vivo and revealed an unexpected STAT3-regulatory axis beyond TGF-β.

    Evidence CD109 knockout mouse phenotyping with immunohistochemistry for pSTAT3 and pSmad2

    PMID:22846721

    Open questions at the time
    • Whether CD109 directly regulates STAT3 or acts through an intermediate receptor unknown at this stage
    • Relationship between STAT3 hyperactivation and TGF-β suppression in vivo unclear
  7. 2013 High

    Transgenic CD109 overexpression in murine epidermis protected against wound-healing inflammation and bleomycin-induced skin fibrosis by suppressing Smad2/3 phosphorylation and ECM production, validating CD109 as an in vivo antifibrotic factor.

    Evidence CD109 transgenic mice in excisional wound and bleomycin scleroderma models with pSmad2/3, collagen, and cytokine readouts

    PMID:23436317 PMID:23438099

    Open questions at the time
    • Therapeutic potential of exogenous sCD109 in fibrosis not tested
    • Whether CD109 modulates non-Smad TGF-β pathways in fibrosis not assessed
  8. 2015 High

    Biophysical demonstration that soluble CD109 binds TGF-β with high affinity and blocks receptor binding established a second, ligand-sequestration mechanism of TGF-β inhibition complementary to the membrane co-receptor function.

    Evidence Surface plasmon resonance, radioligand competition, and Smad2/3 phosphorylation assays

    PMID:26621871

    Open questions at the time
    • Relative contribution of ligand sequestration versus receptor routing in vivo not quantified
    • Binding site on TGF-β not mapped
  9. 2015 Medium

    Discovery of a cell-surface CD109–EGFR interaction that enhances EGF signaling in glioblastoma cells expanded CD109's receptor repertoire beyond TGF-β, later confirmed in lung and squamous cell carcinoma where CD109 stabilizes EGFR and activates AKT/mTOR signaling.

    Evidence Co-IP of CD109 with EGFR, migration/invasion assays in glioblastoma (2015); co-IP and EGFR phosphorylation/AKT/mTOR assays in lung adenocarcinoma (2020) and SCC (2022)

    PMID:25724945 PMID:32133706 PMID:35954339

    Open questions at the time
    • Structural basis of CD109–EGFR interaction not determined
    • Whether the GPI anchor directly mediates the interaction or lipid raft co-localization is responsible remains unresolved
  10. 2017 High

    An in vivo barcoded tumor screen identified CD109 as a driver of lung cancer metastasis through JAK-STAT3, establishing CD109's oncogenic signaling role in an unbiased genetic framework and showing pharmacological JAK inhibition blocks CD109-driven metastasis.

    Evidence In vivo tumor barcoding in mouse lung adenocarcinoma model with JAK inhibitor validation

    PMID:28191885

    Open questions at the time
    • Direct physical link between CD109 and JAK-STAT3 components not identified at this point
    • Whether CD109's STAT3 role is ligand-dependent or constitutive unclear
  11. 2018 High

    Identification of cell-surface GRP78 as a CD109-binding partner under ER stress showed that the GRP78–CD109 complex promotes caveolar routing of TGF-β receptors, linking the unfolded protein response to TGF-β signal suppression in cancer.

    Evidence Cell-surface co-IP of GRP78 with CD109, Smad2 phosphorylation and receptor trafficking assays

    PMID:29654145

    Open questions at the time
    • Whether GRP78 interaction requires furin-processed CD109 not tested
    • Generalizability beyond the cell line used unclear
  12. 2019 High

    CD109-deficient mice develop spontaneous psoriasiform skin inflammation via barrier disruption and γδ T17 cell activation, indicating that CD109 maintains skin barrier integrity and restrains IL-23-dependent innate immune responses in a cell-extrinsic manner.

    Evidence CD109 KO mice with allergen challenge, microbiota depletion, IL-23 blockade, and adoptive transfer

    PMID:31597099

    Open questions at the time
    • Molecular mechanism by which CD109 fortifies the skin barrier not elucidated
    • Relative contributions of TGF-β versus STAT3 deregulation to barrier defect unknown
  13. 2021 High

    Demonstrating that CD109 physically interacts with GP130 to activate IL-6/STAT3 in glioblastoma stem cells resolved the receptor-level mechanism linking CD109 to STAT3 activation and explained how CD109 sustains cancer stemness and chemoresistance.

    Evidence Reciprocal co-IP of CD109 with GP130, STAT3 phosphorylation, sphere formation, and in vivo tumor growth assays

    PMID:33986188

    Open questions at the time
    • Whether CD109–GP130 interaction is direct or scaffolded by IL-6Rα not resolved
    • Whether GP130 interaction applies outside glioblastoma not tested
  14. 2024 High

    Biochemical reconstitution showed that bait-region proteolysis by diverse proteases activates the CD109 thioester for covalent protease conjugation and inhibition, and that GPI-anchor dissociation accompanies this conformational change — establishing CD109 as a functional protease inhibitor.

    Evidence In vitro protease cleavage, thioester activation, and protease conjugation/activity assays with multiple proteases

    PMID:38587194

    Open questions at the time
    • Physiological protease substrates for CD109 inhibition not identified in vivo
    • Whether protease-inhibitor function operates independently of TGF-β co-receptor function unclear
  15. 2025 High

    Cryo-EM structures of native, protease-activated, and methylamine-activated CD109 revealed atomic-resolution conformational states analogous to A2ML1, showing how glycans limit substrate access and how thioester exposure enables covalent protease capture.

    Evidence Cryo-EM structure determination in multiple states, deglycosylation and chymotrypsin conjugation assays

    PMID:40482031

    Open questions at the time
    • No structure of CD109 in complex with TGF-β receptor or EGFR
    • How thioester-mediated protease inhibition relates to signaling co-receptor functions is mechanistically unresolved
  16. 2025 Medium

    CD109 was shown to stabilize IL-6Rα at the SCC cell surface and promote IL-6/STAT3/NRF2 antioxidant signaling, and separately, tumor-derived sCD109 was found to expand immunosuppressive CD73+ macrophages via FcγRI/SYK/NF-κB and TRIM21-mediated prevention of CD73 degradation, broadening CD109's roles into immune evasion.

    Evidence Co-IP of CD109 with IL-6Rα and signaling readouts in SCC (2025); proteomic/scRNA-seq, co-IP of sCD109 with TRIM21, and dual CD109/PD-L1 blockade in vivo in hepatocellular carcinoma (2025)

    PMID:40220905 PMID:40317079

    Open questions at the time
    • Whether sCD109-TRIM21 interaction occurs in other tumor types not tested
    • Structural basis of sCD109 engagement with FcγRI unknown
    • Single-lab findings for both; independent replication needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CD109's three biochemically distinct activities — thioester-mediated protease inhibition, membrane co-receptor function for TGF-β/EGFR/GP130, and soluble ligand sequestration/immune modulation — are coordinated in vivo remains the central unresolved question.
  • No structure of CD109 in complex with any signaling receptor
  • Relative in vivo contributions of protease-inhibitor versus co-receptor functions unknown
  • No genetic disease clearly mapped to CD109 mutations in humans

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8 GO:0060090 molecular adaptor activity 5 GO:0016787 hydrolase activity 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 8 GO:0005576 extracellular region 5 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 19 R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 3
Partners
CAV1EGFRHSPA5IL6RIL6STLTBP1TGFBR1TRIM21
Complex memberships
CD109/EGFR complexCD109/GP130 complexTGF-β receptor/CD109/caveolin-1 complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 CD109 is a GPI-anchored glycoprotein and novel member of the alpha2-macroglobulin/C3,C4,C5 family of thioester-containing proteins; native CD109 contains an intact thioester bond, is predicted to be activated by proteolytic cleavage, and can then mediate covalent binding to adjacent molecules or cells via its thioester with complement-like chemical reactivity. cDNA cloning, sequence analysis, biochemical demonstration of intact thioester in native CD109 Blood High 11861284
2002 The Gov platelet alloantigen system (HPA-15) is defined by a single nucleotide polymorphism (A2108C) in CD109 resulting in a Tyr703Ser amino acid substitution; transfection of CHO cells with each variant confirmed allele-specific recognition by Gov antisera. RT-PCR, allele-specific PCR, real-time PCR, CHO cell transfection with CD109 cDNA variants and recognition by allele-specific antisera Blood High 11861285
2006 CD109 is the molecular identity of the 150 kDa GPI-anchored TGF-β1 binding protein (r150) in keratinocytes; loss- and gain-of-function studies establish CD109 as a component of the TGF-β receptor system and a negative modulator of TGF-β responses, acting independently of ligand sequestration, possibly by direct modulation of receptor activity. Affinity purification, microsequencing, biochemical thioester assay, loss-of-function (GPI-anchor-deficient keratinocytes) and gain-of-function studies FASEB journal High 16754747
2010 CD109 is processed by the Golgi protease furin at a tetra-arginine cleavage motif (RRRR at aa 1270–1273), converting the 205 kDa precursor into 180 kDa and 25 kDa fragments. The processed 180/25 kDa complex associates with the type I TGF-β receptor and is required for negative regulation of TGF-β signaling and cell growth suppression; an R1273S mutant that cannot be cleaved fails to associate with TGFBR1 or inhibit TGF-β signaling. Site-directed mutagenesis of furin cleavage site (R1273S), co-immunoprecipitation with TGFBR1, western blotting, cell growth assays Oncogene High 20101215
2011 CD109 associates with caveolin-1 and promotes localization of TGF-β receptors into the caveolar compartment in the presence of ligand, enhancing TGF-β receptor internalization via the caveolae pathway and facilitating TGF-β receptor degradation, thereby inhibiting TGF-β signaling. Co-immunoprecipitation of CD109 with caveolin-1, receptor internalization assays, caveolae fractionation, TGF-β receptor degradation assays Biochimica et biophysica acta High 21295082
2012 CD109 promotes SMAD7/Smurf2-mediated ubiquitin-dependent degradation of TGFBR1 in a ligand-dependent manner; CD109 regulates the localization and association of SMAD7/Smurf2 with TGFBR1, and CD109's inhibitory effect on TGF-β signaling requires SMAD7 expression and Smurf2 ubiquitin ligase activity. siRNA knockdown of SMAD7, dominant-negative Smurf2 (ubiquitin ligase-dead mutant), co-immunoprecipitation, western blotting, TGF-β response assays Journal of cellular biochemistry High 21898545
2011 Release of CD109 from the keratinocyte cell surface (soluble/shed CD109) downregulates TGF-β signaling and TGF-β receptor expression and increases phospho-STAT3 levels, total STAT3, Bcl-2, and cell growth/survival, indicating that soluble CD109 can activate STAT3 signaling while inhibiting TGF-β signaling. Addition of recombinant CD109 protein to keratinocytes, phospho-STAT3 western blotting, TGF-β receptor quantification, cell proliferation/survival assays Experimental dermatology Medium 21539622
2012 CD109-deficient mice develop epidermal hyperplasia, kinked hair shafts, ectatic hair follicles, and increased sebaceous gland hyperplasia; this is associated with elevated STAT3 phosphorylation (not altered Smad2 phosphorylation) in the epidermis, indicating that CD109 regulates keratinocyte differentiation in vivo primarily via STAT3 rather than TGF-β/Smad signaling. CD109 knockout mouse generation, histology, immunohistochemistry for phospho-Smad2 and phospho-STAT3 The American journal of pathology High 22846721
2013 Transgenic mice overexpressing CD109 in the epidermis show decreased macrophage/neutrophil recruitment, reduced granulation tissue, decreased Smad2/3 phosphorylation, reduced pro-inflammatory cytokines (IL-1α, MCP-1), and decreased ECM components during wound healing, and improved dermal architecture in incisional wounds, establishing CD109 as an in vivo inhibitor of TGF-β/Smad-mediated wound inflammation and fibrosis. CD109 transgenic mice, excisional and incisional wound models, immunohistochemistry, western blotting for phospho-Smad2/3, cytokine quantification Wound repair and regeneration High 23438099
2013 CD109 overexpression in the epidermis of transgenic mice protects against bleomycin-induced skin fibrosis, evidenced by decreased dermal thickness, collagen crosslinking, fibronectin content, and phospho-Smad2/3 levels, demonstrating that CD109 inhibits TGF-β/Smad-mediated fibrotic responses in vivo. CD109 transgenic mice, bleomycin-induced scleroderma model, Masson's trichrome/picrosirius red staining, western blotting for phospho-Smad2/3 Arthritis and rheumatism High 23436317
2013 CD109 plays a role in osteoclastogenesis: CD109 is upregulated >17-fold during RANKL-induced osteoclast differentiation from RAW264.7 macrophages and from primary murine monocytes; stable knockdown of CD109 reduces the formation of large multinucleated osteoclasts. Microarray analysis, RT-qPCR, western blotting, stable CD109 knockdown cell lines, osteoclast fusion assays PloS one Medium 23593435
2015 Soluble CD109 (sCD109) binds TGF-β with high affinity (slow dissociation kinetics by surface plasmon resonance), inhibits TGF-β binding to its receptors, and antagonizes TGF-β-induced Smad2/3 phosphorylation, transcription, and cell migration. Surface plasmon resonance, radioligand binding competition assays, affinity labelling, Smad2/3 phosphorylation assays, cell migration assays The Biochemical journal High 26621871
2015 Cell surface CD109 interacts with EGFR in glioblastoma cells (SK-MG-1), and this interaction enhances EGF signaling, cell migration, and invasion, while secreted N-terminal CD109 fragment selectively inhibits TGF-β1 signaling but not EGF signaling. Co-immunoprecipitation of CD109 with EGFR, conditioned medium transfer experiments, cell migration/invasion assays, western blotting for EGF and TGF-β1 signaling Biochemical and biophysical research communications Medium 25724945
2015 CD109 is a component of exosomes secreted from HEK293 cells; the C-terminal region of CD109 is required for its sorting into exosomes, as a truncated CD109 lacking the C-terminal region is not found in the exosomal fraction. Immunoprecipitation with anti-FLAG affinity gel, mass spectrometry, western blotting, immuno-electron microscopy of exosome fractions Biochemical and biophysical research communications Medium 26707640
2016 In transgenic mice overexpressing CD109 in the epidermis, CD109 differentially regulates TGF-β signaling: it enhances ALK1-Smad1/5 signaling while decreasing ALK5-Smad2/3 signaling, and reduces TGF-β expression and ECM production; CD109 and ALK1 co-localize in mouse keratinocytes. CD109 transgenic mouse model, immunohistochemistry, co-localization of CD109 and ALK1, western blotting for phospho-Smad1/5 and phospho-Smad2/3, fibroblast conditioned medium experiments The Journal of investigative dermatology Medium 27866969
2017 CD109 drives lung cancer metastasis through activation of JAK-STAT3 signaling; pharmacological targeting of JAK-STAT3 blocks CD109-driven metastasis in a mouse model of lung adenocarcinoma. In vivo tumor barcoding mouse model, in vivo screening, JAK inhibitor pharmacological blockade, genomic analysis Nature medicine High 28191885
2018 Upon ER stress, GRP78 translocates to the cell surface where it binds to CD109, and the GRP78-CD109 complex promotes routing of TGF-β receptor to caveolae, disrupting TGF-β receptor binding to and activation of Smad2, thereby blocking TGF-β tumor-suppressor signaling. Cell surface co-immunoprecipitation of GRP78 with CD109, receptor trafficking assays, Smad2 phosphorylation assays, IRE1α-SRC-ASAP1 pathway analysis Proceedings of the National Academy of Sciences of the United States of America High 29654145
2019 CD109 regulates skin homeostasis and restrains IL-17-producing γδ T (γδ17) cell activation in a cell-extrinsic manner by fortifying skin barrier integrity; CD109-deficient mice show spontaneous epidermal hyperplasia, accumulation of dermal γδ17 cells, and enhanced susceptibility to psoriasiform inflammation dependent on IL-23 and skin microbiota. CD109 knockout mice, transient skin microbiota depletion, IL-23 blockade, γδ T cell flow cytometry, skin barrier assays Cell reports High 31597099
2019 CD109 CRISPR/Cas9 knockout in SCC cells represses epithelial traits and promotes EMT (elevated mesenchymal markers), which can be reversed by recombinant CD109 protein treatment; CD109 levels inversely correlate with TGF-β signaling activation in SCC tumor samples. CRISPR/Cas9 KO, recombinant CD109 protein rescue, microarray gene expression, KEGG pathway analysis, immunohistochemistry of 52 tumor samples Scientific reports Medium 31695056
2020 CD109 associates with EGFR at the cell surface in lung adenocarcinoma cells; CD109 overexpression activates AKT/mTOR signaling via EGFR association, and CD109 inhibition decreases EGFR phosphorylation and sensitizes tumor cells to EGFR inhibitors. Co-immunoprecipitation of CD109 with EGFR, EGFR phosphorylation assays, AKT/mTOR western blotting, pharmacological EGFR inhibitor sensitivity assays Cancer science Medium 32133706
2020 CD109 promotes lung adenocarcinoma EMT and stemness via activation of the Hippo-YAP signaling pathway; YAP activation participates in CD109-elicited EMT gene expression and tumor invasiveness. siRNA knockdown of CD109, YAP inhibition, gene expression analysis, invasion assays, correlation with patient YAP signature Cells Medium 33375719
2020 CD109 interacts with latent TGF-β binding protein-1 (LTBP1), identified by mass spectrometry and confirmed by co-immunoprecipitation; increased CD109 expression enhances stromal TGF-β activation in the presence of LTBP1, promoting lung adenocarcinoma stromal invasion. Mass spectrometry of CD109 interactors, co-immunoprecipitation, CD109-deficient lung adenocarcinoma mouse model, TGF-β activation assays Cancer science Medium 33007133
2021 CD109 physically interacts with glycoprotein 130 (GP130) in glioblastoma stem cells (GSCs) to promote activation of the IL-6/STAT3 pathway; genetic depletion of CD109 abolishes GSC stemness and self-renewal and induces phenotypic shift to astrocytic-like cells; CD109/STAT3 axis mediates chemoresistance. Co-immunoprecipitation of CD109 with GP130, STAT3 phosphorylation assays, CD109 genetic depletion, sphere formation/stemness assays, in vivo tumor growth, pharmacological STAT3 inhibition JCI insight High 33986188
2021 CD109 (GPI-anchored) suppresses TGF-β-induced erythroid differentiation in hematopoietic stem/progenitor cells (HSPCs); CD109 knockout/knockdown in TF-1 cells and cord blood MEPs leads to enhanced TGF-β-driven erythroid commitment. CD109 KO/KD in TF-1 leukemia cells and primary cord blood MEPs, TGF-β stimulation, flow cytometry for erythroid markers (CD36), PNH patient cell analysis Leukemia Medium 34743190
2021 Meprin β, a membrane-bound metalloproteinase, cleaves CD109 within its bait region at the cell surface, releasing soluble fragments; this proteolytic shedding reduces the amount of CD109 sorted to extracellular vesicles. Homology modeling and single-particle analysis provided a structural model localizing the meprin β and BMP-1 cleavage sites. Protease cleavage assays with meprin β, identification of cleavage sites, homology modeling/single-particle analysis structural model, EV isolation and CD109 quantification Frontiers in cell and developmental biology Medium 33738281
2022 CD109 forms a heteromeric complex with EGFR at the cell surface in SCC cells, stabilizing EGFR protein and mRNA levels and promoting EGFR/AKT signaling; CD109 cell-surface localization is required for maintenance of epithelial morphology and stemness in vulvar and hypopharyngeal SCC cells. Co-immunoprecipitation and co-localization of CD109 and EGFR, EGFR mRNA/protein quantification, immunofluorescence, spheroid formation assays, xenograft tumor models Cancers Medium 35954339
2024 Proteolytic cleavage of the CD109 bait region by diverse proteases induces a conformational change that activates the CD109 thioester, enabling covalent conjugation of proteases (protease inhibition); the GPI-anchored MG8 domain dissociates during this conformational change, releasing CD109 from the cell surface. In vitro protease cleavage assays, thioester activation assay, protease conjugation and activity assays, conformational change analysis The FEBS journal High 38587194
2025 Cryo-EM structures of CD109 in native, protease-activated, and methylamine-activated conformations reveal that bait-region proteolysis triggers a conformational change analogous to that of the protease inhibitor A2ML1, exposing a reactive thioester that conjugates and inhibits proteases; CD109 glycans contribute to protease inhibition by limiting substrate access. Cryo-electron microscopy structure determination, deglycosylation experiments, chymotrypsin conjugation assays, comparison with A2ML1 structure Cell reports High 40482031
2025 CD109 interacts with and stabilizes IL-6 receptor alpha (IL6Rα) expression at the cell surface in SCC cells; CD109 promotes IL-6/STAT3/NRF2 pathway activation and maintains cancer cell stemness and antioxidant state (SOD1, HO-1); loss of CD109 attenuates this pathway. Co-immunoprecipitation of CD109 with IL6Rα, immunofluorescence, FACS, western blotting for STAT3/NRF2/SOD1/HO1, spheroid formation assays, multi-omic tumor analysis Experimental hematology & oncology Medium 40317079
2025 Tumor-derived soluble CD109 (sCD109) upregulates CD73 on macrophages by activating the FcγRI/SYK/NF-κB signaling pathway; additionally, internalized sCD109 in macrophages binds E3 ligase TRIM21 at the same site as CD73, preventing CD73 protein degradation, thereby expanding CD73+ immunosuppressive tumor-associated macrophages and inhibiting T-cell responses. Proteomic/single-cell transcriptomic analysis, mass spectrometry, co-immunoprecipitation of sCD109 with TRIM21, CD73 ubiquitination assays, FcγRI/SYK/NF-κB pathway analysis, dual CD109/PD-L1 blockade in vivo Journal of hepatology Medium 40220905
2009 Mesotrypsin (PRSS3), upregulated in malignant breast cancer T4-2 cells, cleaves/sheds CD109 from the cell surface; CD109 is identified as a functional proteolytic target of mesotrypsin mediating the malignant growth phenotype. Proteomic identification of mesotrypsin substrate, PRSS3 knockdown, recombinant mesotrypsin treatment, 3D organotypic culture assays Breast cancer research and treatment Medium 20035377
2018 CD109 deficiency in mice leads to osteopenia/osteoporosis-like phenotype with reduced bone volume and increased bone turnover (elevated N-terminal telopeptide of collagen I and alkaline phosphatase), indicating that CD109 plays a role in bone metabolism in vivo. CD109 knockout mice, micro-CT analysis of femur, bone histomorphometry, serum bone turnover markers Genes to cells Medium 29767469
2023 In osteosarcoma cells, CD109 knockdown enhances SMAD1/5/9 phosphorylation under BMP-2 stimulation and reduces cell migration in the presence of BMP, indicating that CD109 negatively regulates BMP signaling and BMP-dependent migration in sarcoma (distinct from its TGF-β regulatory role). CD109 knockdown in osteosarcoma cell lines, BMP-2 stimulation, western blotting for phospho-SMAD1/5/9, in vitro wound healing migration assay, immunohistochemistry of human tumor tissue Pathology, research and practice Medium 37030166
2023 CD109 on conventional DC2s (cDC2s) is required for airway hyperreactivity and eosinophilic inflammation; CD109-deficient cDC2s have high RUNX3 expression and poor ability to drive Th2 differentiation; adoptive transfer of CD109-deficient DCs fails to induce AHR and eosinophilic inflammation. CD109 KO mice, allergen sensitization models (house dust mite, OVA), ex vivo DC-T cell co-cultures, adoptive transfer of bone marrow-derived DCs, anti-CD109 antibody administration American journal of respiratory cell and molecular biology High 36215676
2024 Mechanical force induces CD109 expression on periodontal ligament stem cells (PDLSCs) via repression of miR-340-5p; CD109 suppresses osteogenesis of PDLSCs via the JAK/STAT3 signaling pathway, while promoting osteoclast formation and M1 macrophage polarization through paracrine signaling; CD109 lentiviral knockdown in vivo increases osteogenic activity and decreases osteoclast numbers during tooth movement. In vitro mechanical force stimulation, miR-340-5p manipulation, JAK/STAT3 inhibition, lentiviral shRNA knockdown in rat periodontal tissues in vivo, flow cytometry, osteogenic/osteoclast differentiation assays Stem cells translational medicine Medium 38885217

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Cell surface antigen CD109 is a novel member of the alpha(2) macroglobulin/C3, C4, C5 family of thioester-containing proteins. Blood 154 11861284
2017 Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nature medicine 132 28191885
2006 Identification of CD109 as part of the TGF-beta receptor system in human keratinocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 121 16754747
2011 The TGF-β co-receptor, CD109, promotes internalization and degradation of TGF-β receptors. Biochimica et biophysica acta 119 21295082
2018 Endoplasmic reticulum stress activates SRC, relocating chaperones to the cell surface where GRP78/CD109 blocks TGF-β signaling. Proceedings of the National Academy of Sciences of the United States of America 110 29654145
2012 CD109-mediated degradation of TGF-β receptors and inhibition of TGF-β responses involve regulation of SMAD7 and Smurf2 localization and function. Journal of cellular biochemistry 78 21898545
2004 Expression of CD109 in human cancer. Oncogene 71 15116102
2002 A tyrosine703serine polymorphism of CD109 defines the Gov platelet alloantigens. Blood 69 11861285
2010 Processing of CD109 by furin and its role in the regulation of TGF-beta signaling. Oncogene 67 20101215
1999 CD109 is expressed on a subpopulation of CD34+ cells enriched in hematopoietic stem and progenitor cells. Experimental hematology 65 10428505
2021 Single-cell analysis pinpoints distinct populations of cytotoxic CD4+ T cells and an IL-10+CD109+ TH2 cell population in nasal polyps. Science immunology 61 34389612
2011 CD109 release from the cell surface in human keratinocytes regulates TGF-β receptor expression, TGF-β signalling and STAT3 activation: relevance to psoriasis. Experimental dermatology 60 21539622
2008 Up-regulation of CD109 expression is associated with carcinogenesis of the squamous epithelium of the oral cavity. Cancer science 60 19016750
2009 Mesotrypsin promotes malignant growth of breast cancer cells through shedding of CD109. Breast cancer research and treatment 59 20035377
2020 Elevation of CD109 promotes metastasis and drug resistance in lung cancer via activation of EGFR-AKT-mTOR signaling. Cancer science 49 32133706
2007 High-level expression of CD109 is frequently detected in lung squamous cell carcinomas. Pathology international 49 17922683
2005 CD109 expression in squamous cell carcinoma of the uterine cervix. Pathology international 49 15826242
2016 CD109 is identified as a potential nasopharyngeal carcinoma biomarker using aptamer selected by cell-SELEX. Oncotarget 48 27419372
2005 Relevance of the HPA-15 (Gov) polymorphism on CD109 in alloimmune thrombocytopenic syndromes. Transfusion 47 15752154
2021 CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity. JCI insight 46 33986188
2017 Significance of perivascular tumour cells defined by CD109 expression in progression of glioma. The Journal of pathology 46 28888050
2008 CD109 expression in basal-like breast carcinoma. Pathology international 45 18429827
2015 CD109 attenuates TGF-β1 signaling and enhances EGF signaling in SK-MG-1 human glioblastoma cells. Biochemical and biophysical research communications 42 25724945
2007 CD109, a new marker for myoepithelial cells of mammary, salivary, and lacrimal glands and prostate basal cells. Pathology international 42 17493171
2019 CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis. Annals of the rheumatic diseases 41 31455659
2014 SWATH™- and iTRAQ-based quantitative proteomic analyses reveal an overexpression and biological relevance of CD109 in advanced NSCLC. Journal of proteomics 38 24667143
2010 Correlation of pathological grade and tumor stage of urothelial carcinomas with CD109 expression. Pathology international 38 20946523
2020 CD109 mediates tumorigenicity and cancer aggressiveness via regulation of EGFR and STAT3 signalling in cervical squamous cell carcinoma. British journal of cancer 36 32507856
2014 CD109 is a potential target for triple-negative breast cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 36 25149155
2020 Upregulation of CD109 Promotes the Epithelial-to-Mesenchymal Transition and Stemness Properties of Lung Adenocarcinomas via Activation of the Hippo-YAP Signaling. Cells 35 33375719
2012 CD109, a TGF-β co-receptor, attenuates extracellular matrix production in scleroderma skin fibroblasts. Arthritis research & therapy 35 22694813
2015 Soluble CD109 binds TGF-β and antagonizes TGF-β signalling and responses. The Biochemical journal 34 26621871
2012 Epidermal hyperplasia and appendage abnormalities in mice lacking CD109. The American journal of pathology 33 22846721
2004 CD109 represents a novel branch of the alpha2-macroglobulin/complement gene family. Gene 33 14980714
2019 CD109: a multifunctional GPI-anchored protein with key roles in tumor progression and physiological homeostasis. Pathology international 32 31219232
2013 Human hepatic progenitor cells express hematopoietic cell markers CD45 and CD109. International journal of medical sciences 30 24396288
2013 Transgenic mice overexpressing CD109 in the epidermis display decreased inflammation and granulation tissue and improved collagen architecture during wound healing. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 28 23438099
2003 Antibody W7C5 defines a CD109 epitope expressed on CD34+ and CD34- hematopoietic and mesenchymal stem cell subsets. Annals of the New York Academy of Sciences 28 12799300
2015 CD109 is a component of exosome secreted from cultured cells. Biochemical and biophysical research communications 27 26707640
2019 CD109 Restrains Activation of Cutaneous IL-17-Producing γδ T Cells by Commensal Microbiota. Cell reports 26 31597099
1998 ABH antigens on human platelets: expression on the glycosyl phosphatidylinositol-anchored protein CD109. The Journal of laboratory and clinical medicine 26 9708575
2019 CD109 acts as a gatekeeper of the epithelial trait by suppressing epithelial to mesenchymal transition in squamous cell carcinoma cells in vitro. Scientific reports 24 31695056
2015 CD109 is a novel marker for squamous cell/adenosquamous carcinomas of the gallbladder. Diagnostic pathology 24 26249215
2013 CD109 overexpression ameliorates skin fibrosis in a mouse model of bleomycin-induced scleroderma. Arthritis and rheumatism 24 23436317
2016 CD109, a negative regulator of TGF-β signaling, is a putative risk marker in diffuse large B-cell lymphoma. International journal of hematology 22 28032275
2013 CD109 plays a role in osteoclastogenesis. PloS one 22 23593435
2020 CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling. Cancer science 21 33007133
2018 CD109 deficiency induces osteopenia with an osteoporosis-like phenotype in vivo. Genes to cells : devoted to molecular & cellular mechanisms 21 29767469
2016 Overexpression of CD109 in the Epidermis Differentially Regulates ALK1 Versus ALK5 Signaling and Modulates Extracellular Matrix Synthesis in the Skin. The Journal of investigative dermatology 21 27866969
2016 Suppression of skin tumorigenesis in CD109-deficient mice. Oncotarget 18 27756876
2014 CD109 Overexpression in Pancreatic Cancer Identified by Cell-Surface Glycoprotein Capture. Journal of proteomics & bioinformatics 18 25635161
2021 Cell Surface Processing of CD109 by Meprin β Leads to the Release of Soluble Fragments and Reduced Expression on Extracellular Vesicles. Frontiers in cell and developmental biology 17 33738281
2016 Reduced expression of CD109 in tumor-associated endothelial cells promotes tumor progression by paracrine interleukin-8 in hepatocellular carcinoma. Oncotarget 17 27121053
2014 A subpopulation of circulating endothelial cells express CD109 and is enriched in the blood of cancer patients. PloS one 17 25506915
2021 The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β. Leukemia 16 34743190
2020 Tumor edge-to-core transition promotes malignancy in primary-to-recurrent glioblastoma progression in a PLAGL1/CD109-mediated mechanism. Neuro-oncology advances 16 33392508
2018 CD109 and squamous cell carcinoma. Journal of translational medicine 16 29625613
2023 CD109 on Dendritic Cells Regulates Airway Hyperreactivity and Eosinophilic Airway Inflammation. American journal of respiratory cell and molecular biology 15 36215676
2004 Gene frequencies of the HPA-15 (Gov) platelet alloantigen system in Brazilians. Transfusion medicine (Oxford, England) 15 15569238
2023 CD109 Promotes Drug Resistance in A2780 Ovarian Cancer Cells by Regulating the STAT3-NOTCH1 Signaling Axis. International journal of molecular sciences 14 37373457
2014 CD109, a novel TGF-β antagonist, decreases fibrotic responses in a hypoxic wound model. Experimental dermatology 14 24815824
2020 CD109 promotes the tumorigenic ability and metastatic motility of pancreatic ductal adenocarcinoma cells. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 13 32007357
2013 Human platelet antigen genotyping and expression of CD109 (human platelet antigen 15) mRNA in various human cell types. BioMed research international 12 23509816
2011 The relevance of HPA-15 antigen expression for anti-HPA-15 antibody detection. International journal of laboratory hematology 12 21752233
2017 CD109 released from human bone marrow mesenchymal stem cells attenuates TGF-β-induced epithelial to mesenchymal transition and stemness of squamous cell carcinoma. Oncotarget 11 29221155
2022 Mining of transcriptome identifies CD109 and LRP12 as possible biomarkers and deregulation mechanism of T cell receptor pathway in Acute Myeloid Leukemia. Heliyon 10 36299526
2018 Development of novel monoclonal antibodies against CD109 overexpressed in human pancreatic cancer. Oncotarget 10 29731998
2014 Detection of a soluble form of CD109 in serum of CD109 transgenic and tumor xenografted mice. PloS one 10 24400073
2023 Epicardial deletion of Sox9 leads to myxomatous valve degeneration and identifies Cd109 as a novel gene associated with valve development. Journal of molecular and cellular cardiology 9 37935281
2022 CD109 Is a Critical Determinant of EGFR Expression and Signaling, and Tumorigenicity in Squamous Cell Carcinoma Cells. Cancers 9 35954339
2016 Association of down-regulation of CD109 expression with up-expression of Smad7 in pathogenesis of psoriasis. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 9 26838754
2024 CD109 Attenuates Bleomycin-induced Pulmonary Fibrosis by Inhibiting TGF-β Signaling. Journal of immunology (Baltimore, Md. : 1950) 8 38334455
2020 CD109 antigen-like gene is induced by ecdysone signaling and involved in the cellular immunity of Helicoverpa armigera. Bioscience, biotechnology, and biochemistry 8 32141410
2020 Caveolae, CD109, and endothelial cells as targets for treating Alzheimer's disease. Alzheimer's & dementia (New York, N. Y.) 8 32995471
2017 CD109 expression is upregulated in penile squamous cell carcinoma. Oncology letters 8 29113239
2014 Comparison of a simple-probe real-time PCR and multiplex PCR techniques for HPA-1 to HPA-6 and HPA-15 genotyping. Journal of clinical laboratory analysis 8 24687514
2024 Mechanical force-activated CD109 on periodontal ligament stem cells governs osteogenesis and osteoclast to promote alveolar bone remodeling. Stem cells translational medicine 7 38885217
2016 CD109 Mediates Cell Survival in Hepatocellular Carcinoma Cells. Digestive diseases and sciences 7 27074923
2025 CD109, a master regulator of inflammatory responses. Frontiers in immunology 6 39990858
2024 Endosomal Trafficking Bypassed by the RAB5B-CD109 Interplay Promotes Axonogenesis in KRAS-Mutant Pancreatic Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 39488792
2023 Significance of expression of CD109 in osteosarcoma and its involvement in tumor progression via BMP signaling. Pathology, research and practice 6 37030166
2023 FLOT2 promotes nasopharyngeal carcinoma progression through suppression of TGF-β pathway via facilitating CD109 expression. iScience 6 38161417
2019 Curcumin mitigates the epithelial-to-mesenchymal transition in biliary epithelial cells through upregulating CD109 expression. Drug development research 6 31403228
2024 CD109 identified in circulating proteomics mitigates postoperative recurrence in chronic rhinosinusitis with nasal polyps by suppressing TGF-β1-induced epithelial-mesenchymal transition. International immunopharmacology 5 38442581
2023 Smooth muscle αv integrins regulate vascular fibrosis via CD109 downregulation of TGF-β signalling. European heart journal open 5 36909248
2021 Serum CD109 levels reflect the node metastasis status in head and neck squamous cell carcinoma. Cancer medicine 5 33565282
2025 Tumor-derived CD109 orchestrates reprogramming of tumor-associated macrophages to dampen immune response. Journal of hepatology 4 40220905
2023 H3K27 acetylation activated-CD109 evokes 5-fluorouracil resistance in gastric cancer via the JNK/MAPK signaling pathway. Environmental toxicology 4 37661780
2019 A novel simple assay system for the detection of human platelet antigen 15 (HPA-15) alloantibodies based on three techniques: an HPA-15 expressing cell line, a monoclonal antibody-specific antigen-capture method and mixed-passive haemagglutination. Vox sanguinis 4 31777077
2024 Proteolytic cleavage of the TGFβ co-receptor CD109 changes its conformation, resulting in protease inhibition via activation of its thiol ester, and dissociation from the cell membrane. The FEBS journal 3 38587194
2024 Identification of CD109 in the extracellular vesicles derived from ovarian cancer stem-like cells. BMB reports 3 39567205
2024 Microglial upregulation of CD109 expression in spinal cord of amyotrophic lateral sclerosis mouse model and its role in modulating inflammation and TGFβ/SMAD pathway. Neuroscience 3 39577687
2025 IL-6-mediated tumorigenicity and antioxidant state in squamous cell carcinoma cells are driven by CD109 via stabilization of IL-6 receptor-alpha and activation of STAT3/NRF2 pathway. Experimental hematology & oncology 2 40317079
2024 HPV16 E7 modulates the cell surface expression of MET and CD109 via the AP2 complex. Tumour virus research 2 38485055
2022 The Significance of CD109 Expression in Oropharyngeal Squamous Cell Carcinoma. Anticancer research 2 35347029
2008 [Establishment of genotyping method for human platelet antigens of HPA-15 system by PCR-SSP]. Zhongguo shi yan xue ye xue za zhi 2 18315927
2025 Three cryo-EM structures of CD109 reveal its mechanism of protease inhibition. Cell reports 1 40482031
2024 Asporin and CD109, expressed in the injured neonatal spinal cord, attenuate axonal re-growth in vitro. Neuroscience letters 1 38796094
2023 CD109-regulated mechanical properties of endothelial cells. Cytoskeleton (Hoboken, N.J.) 1 36929132
2022 Relationship between donor-specific HPA-15 antibodies and poor graft function in HPA-15 mismatched cord blood transplantation. International journal of hematology 1 35028883