{"gene":"CD109","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2002,"finding":"CD109 is a GPI-anchored glycoprotein and a novel member of the alpha2-macroglobulin/C3, C4, C5 family of thioester-containing proteins; native CD109 contains an intact thioester bond capable of covalent binding to adjacent molecules upon proteolytic activation, with complement-like reactivity (short t½, spatially restricted action).","method":"cDNA cloning, sequence analysis, biochemical demonstration of intact thioester in native CD109","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical demonstration of thioester, sequence-based mechanistic inference confirmed experimentally, replicated conceptually across multiple subsequent papers","pmids":["11861284"],"is_preprint":false},{"year":2002,"finding":"The Gov (HPA-15) platelet alloantigens are defined by a single A-to-C SNP at position 2108 of the CD109 coding region, resulting in a Tyr703Ser substitution; CHO cells transfected with the respective cDNA variants are specifically recognized by allele-specific antisera, confirming this polymorphism as the alloantigen determinant.","method":"RT-PCR, allele-specific PCR-SSP, PCR-RFLP, real-time PCR genotyping, CHO cell transfection with variant cDNA + serological testing","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional confirmation by transfection + serology, multiple orthogonal genotyping methods, independently replicated in subsequent population studies","pmids":["11861285"],"is_preprint":false},{"year":2006,"finding":"CD109 (identified as the 150 kDa GPI-anchored TGF-β1-binding protein r150 in keratinocytes) is a component of the TGF-β receptor system and a negative modulator of TGF-β responses; loss-of-function and gain-of-function studies show CD109 inhibits TGF-β signaling independently of ligand sequestration, likely by direct modulation of receptor activity; CD109 contains an internal thioester bond.","method":"Affinity purification and microsequencing of r150, biochemical thioester demonstration, siRNA knockdown (loss-of-function) and CD109 overexpression (gain-of-function) with TGF-β signaling readouts","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical identification plus both loss- and gain-of-function in the same study; replicated across multiple labs","pmids":["16754747"],"is_preprint":false},{"year":2010,"finding":"CD109 is processed in the Golgi by furin (furinase) from a 205 kDa precursor into 180 kDa and 25 kDa fragments; the 180 kDa form associates with GPI-anchored 25 kDa CD109 on the cell surface and is secreted. Furin cleavage (at RRRR motif, Arg1273) is required for CD109 to associate with TβRI and to inhibit TGF-β signaling; the furin-cleavage-deficient mutant (R1273S) neither impairs TGF-β signaling nor associates with TβRI.","method":"Western blotting of CD109 processing products, site-directed mutagenesis of furin cleavage site (R1273S), co-immunoprecipitation of CD109 with TβRI, TGF-β signaling assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis + co-IP + functional signaling assay in a single study; mechanism confirmed by negative control mutant","pmids":["20101215"],"is_preprint":false},{"year":2011,"finding":"CD109 associates with caveolin-1 and promotes internalization and degradation of TGF-β receptors via the caveolae pathway; CD109 increases TGF-β binding to its receptors, enhances their internalization via caveolae, localizes TGF-β receptors to the caveolar compartment in a ligand-dependent manner, and facilitates receptor degradation, thereby inhibiting TGF-β signaling.","method":"Co-immunoprecipitation of CD109 with caveolin-1, immunofluorescence localization, receptor degradation assays, TGF-β binding assays, caveolae pathway inhibitors","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with caveolin-1, multiple orthogonal methods (Co-IP, localization, degradation assay), replicated in subsequent papers","pmids":["21295082"],"is_preprint":false},{"year":2012,"finding":"CD109 enhances SMAD7/Smurf2-mediated degradation of TGFBR1 in a ligand-dependent manner; CD109 regulates the subcellular localization and association of SMAD7/Smurf2 with TGFBR1; CD109's inhibitory effect on TGF-β signaling requires SMAD7 expression and Smurf2 ubiquitin ligase activity.","method":"Co-immunoprecipitation, immunofluorescence localization, SMAD7 siRNA knockdown, Smurf2 ubiquitin ligase activity assays, TGF-β receptor degradation assays","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, localization, genetic rescue with siRNA, enzymatic activity requirement), single lab","pmids":["21898545"],"is_preprint":false},{"year":2011,"finding":"CD109 released from the keratinocyte cell surface (soluble CD109) downregulates TGF-β signaling and TGF-β receptor expression, and increases STAT3 phosphorylation, total STAT3, Bcl-2 expression, and cell growth/survival; decreased CD109 protein in psoriatic epidermis (with unchanged mRNA) suggests enhanced CD109 release as a disease mechanism.","method":"CD109 shedding experiments, addition of recombinant CD109 protein to keratinocytes, western blotting, immunohistochemistry of psoriatic vs. normal skin","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based experiments with recombinant protein and shedding models, single lab, two orthogonal functional readouts","pmids":["21539622"],"is_preprint":false},{"year":2009,"finding":"Mesotrypsin (PRSS3) proteolytically sheds CD109 from the cell surface of breast cancer cells; CD109 is identified as the functional proteolytic target of mesotrypsin using proteomic methods; mesotrypsin knockdown attenuates and recombinant mesotrypsin enhances the malignant growth phenotype.","method":"Proteomic identification of CD109 as mesotrypsin substrate, PRSS3 knockdown, recombinant mesotrypsin treatment, 3D organotypic culture morphological assays","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic substrate identification plus gain/loss-of-function, single lab","pmids":["20035377"],"is_preprint":false},{"year":2012,"finding":"CD109-deficient mice develop epidermal hyperplasia, kinked hair shafts, ectatic hair follicles, sebum accumulation, and persistent thickening of basal/suprabasal epidermal layers; this is accompanied by elevated STAT3 phosphorylation (not elevated Smad2 phosphorylation) in the epidermis, indicating CD109 regulates keratinocyte differentiation via a STAT3-dependent pathway in vivo.","method":"CD109 knockout mouse generation, histological analysis, immunohistochemistry for pSmad2 and pSTAT3","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined molecular readout (pSTAT3 elevation, not pSmad2), replicated in multiple CD109 KO studies","pmids":["22846721"],"is_preprint":false},{"year":2013,"finding":"Transgenic mice overexpressing CD109 in the epidermis display reduced macrophage and neutrophil recruitment, reduced granulation tissue, decreased Smad2/3 phosphorylation, decreased proinflammatory cytokines (IL-1α, MCP-1), and decreased ECM components in excisional wounds, with improved dermal collagen architecture in incisional wounds; wound closure rates are unaffected.","method":"CD109 transgenic mouse wound healing model, immunohistochemistry, western blotting for pSmad2/3, cytokine expression, collagen organization","journal":"Wound repair and regeneration","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic overexpression with multiple defined molecular readouts, confirmed in two wound models","pmids":["23438099"],"is_preprint":false},{"year":2013,"finding":"CD109 transgenic mice overexpressing CD109 in the epidermis show resistance to bleomycin-induced skin fibrosis, with significant decreases in dermal thickness, collagen crosslinking, collagen and fibronectin content, and phospho-Smad2/3 levels compared to wild-type mice.","method":"Bleomycin-induced scleroderma mouse model, CD109 transgenic mice, histological staining, western blotting and immunohistochemistry for pSmad2/3","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic overexpression in a disease model with multiple molecular endpoints, consistent with other CD109 overexpression studies","pmids":["23436317"],"is_preprint":false},{"year":2013,"finding":"CD109 plays a role in osteoclastogenesis; CD109 mRNA and protein are significantly upregulated during RANKL-induced osteoclast differentiation in RAW264.7 cells, primary murine monocytes, and pre-osteoclast lines; stable CD109 knockdown reduces the formation of large multinucleated osteoclasts.","method":"Microarray, RT-qPCR, western blot during osteoclastogenesis, stable shRNA knockdown cell lines, osteoclast fusion assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple expression methods plus functional knockdown, single lab","pmids":["23593435"],"is_preprint":false},{"year":2015,"finding":"Soluble CD109 (sCD109) directly binds TGF-β with high affinity (slow dissociation by surface plasmon resonance); sCD109 inhibits TGF-β binding to its receptors (radioligand competition assay), antagonizes Smad2/3 phosphorylation, and decreases TGF-β-induced transcription and cell migration.","method":"Surface plasmon resonance (SPR) binding kinetics, radioligand binding and affinity labelling competition assays, Smad2/3 phosphorylation assays, transcriptional reporter assays, cell migration assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro SPR binding with kinetics plus cell-based competition assays plus functional signaling readouts; multiple orthogonal methods","pmids":["26621871"],"is_preprint":false},{"year":2015,"finding":"Cell surface CD109 interacts with EGFR in glioblastoma SK-MG-1 cells overexpressing CD109; CD109 overexpression attenuates TGF-β1 signaling and enhances EGF signaling and cell migration/invasion in SK-MG-1 but not in U251MG or MG178 cells; the secreted N-terminal CD109 fragment (hyperglycosylated in SK-MG-1) inhibits TGF-β1 signaling via paracrine effect but does not affect EGF signaling.","method":"Co-immunoprecipitation of CD109 with EGFR, conditioned medium experiments, TGF-β and EGF signaling assays, migration/invasion assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of CD109-EGFR plus functional signaling and migration assays, single lab, cell-line-specific effects","pmids":["25724945"],"is_preprint":false},{"year":2016,"finding":"CD109 overexpression in mouse epidermis differentially regulates TGF-β receptor signaling: it enhances ALK1-Smad1/5 signaling while decreasing ALK5-Smad2/3 signaling; ALK1 co-localizes with CD109 in keratinocytes; CD109-overexpressing epidermal cells reduce ECM production in adjacent skin fibroblasts via a paracrine mechanism.","method":"CD109 transgenic mice, immunofluorescence co-localization of ALK1 and CD109, western blotting for pSmad1/5 and pSmad2/3, conditioned medium from isolated keratinocytes/epidermal explants applied to fibroblasts","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic overexpression model plus co-localization and paracrine experiment, single lab","pmids":["27866969"],"is_preprint":false},{"year":2017,"finding":"CD109 drives lung cancer metastasis through activation of JAK-STAT3 signaling; CD109 promotes a metastatic transcriptional state in lung adenocarcinoma cells, and pharmacological targeting of the JAK-STAT3 pathway blocks CD109-driven metastasis.","method":"Tumor barcoding in mouse lung adenocarcinoma model, in vivo small-scale screening, genomic approaches, JAK inhibitor treatment","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic screen plus pharmacological validation in mouse model with human validation; multiple orthogonal approaches","pmids":["28191885"],"is_preprint":false},{"year":2018,"finding":"Upon ER stress, GRP78 translocates to the cell surface where it binds CD109 and acts in concert with CD109 to block TGF-β signaling by routing TGF-β receptor to the caveolae, thereby disrupting Smad2 activation; the upstream mechanism involves IRE1α-triggered SRC activation, ASAP1 phosphorylation, and suppression of retrograde transport.","method":"Co-immunoprecipitation of GRP78 with CD109, immunofluorescence localization, Smad2 activation assays, ER stress induction, SRC inhibition, dominant-negative and knockdown experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus multiple orthogonal mechanistic experiments, published in high-tier journal","pmids":["29654145"],"is_preprint":false},{"year":2018,"finding":"CD109 deficiency in mice induces a high-turnover osteoporosis-like phenotype in vivo, with reduced bone volume, increased bone turnover markers (NTX collagen, alkaline phosphatase), demonstrating a role for CD109 in bone metabolism.","method":"CD109 knockout mice, micro-computed tomography, bone histomorphometry, serum bone turnover marker measurements","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with quantitative bone phenotype, single lab","pmids":["29767469"],"is_preprint":false},{"year":2019,"finding":"CD109 regulates the NF-κB signaling pathway in rheumatoid arthritis fibroblast-like synoviocytes; CD109 silencing or neutralizing antibody reduces proinflammatory factor production, cell migration, invasion, chemoattraction, and osteoclast differentiation in RA FLSs; CD109-deficient mice are protected against collagen-induced arthritis.","method":"CD109 siRNA knockdown, neutralizing anti-CD109 antibody in RA FLS in vitro, CD109 knockout mice in CIA model, cytokine assays, migration/invasion assays","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 2 / Strong — both in vitro (siRNA + antibody) and in vivo (KO mice) genetic evidence with multiple functional readouts","pmids":["31455659"],"is_preprint":false},{"year":2019,"finding":"CD109 genetic deletion in mice leads to spontaneous epidermal hyperplasia, aberrant accumulation of dermal γδ17 T cells, and enhanced susceptibility to psoriasiform inflammation; CD109 restrains γδ17 cell activation in a cell-extrinsic manner by maintaining skin barrier integrity; γδ17 activation requires IL-23 signals and is reversed by microbiota depletion.","method":"CD109 knockout mice, flow cytometry, IL-23 blockade, antibiotic-mediated microbiota depletion, skin inflammation models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple mechanistic interventions (IL-23 blockade, microbiota depletion) establishing cell-extrinsic mechanism","pmids":["31597099"],"is_preprint":false},{"year":2019,"finding":"CD109 CRISPR/Cas9 knockout in SCC cells represses epithelial traits and promotes EMT (elevated mesenchymal markers); recombinant CD109 protein rescues epithelial traits in KO cells; CD109 loss dysregulates 15 signaling pathways including TGF-β; CD109 levels inversely correlate with TGF-β activation in human oral SCC tumors.","method":"CRISPR/Cas9 CD109 knockout, recombinant CD109 protein rescue, microarray gene expression, KEGG pathway analysis, immunohistochemistry of 52 human oral SCC tumors","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO plus protein rescue plus clinical validation, single lab","pmids":["31695056"],"is_preprint":false},{"year":2020,"finding":"CD109 associates with EGFR and regulates AKT/mTOR signaling; CD109 inhibition decreases EGFR phosphorylation and diminishes EGF-elicited AKT/mTOR activation, sensitizing lung adenocarcinoma cells to EGFR inhibitors.","method":"Co-immunoprecipitation of CD109 with EGFR, CD109 knockdown, EGFR phosphorylation assays, AKT/mTOR signaling assays, EGFR inhibitor sensitivity assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional signaling and drug sensitivity assays, single lab","pmids":["32133706"],"is_preprint":false},{"year":2020,"finding":"CD109 promotes stromal invasion of lung adenocarcinoma in vivo; CD109-deficient lung adenocarcinoma mouse model shows significantly reduced stromal invasive lesions; CD109 interacts with LTBP1 (identified by mass spectrometry and confirmed by co-immunoprecipitation), and increased CD109 expression enhances stromal TGF-β activation in the presence of LTBP1.","method":"CD109-deficient genetically engineered lung adenocarcinoma mouse model, mass spectrometry identification of CD109-interacting proteins, co-immunoprecipitation of CD109 with LTBP1, TGF-β activation assays","journal":"Cancer science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model plus biochemical identification and co-IP validation of LTBP1 interaction plus functional TGF-β activation assay","pmids":["33007133"],"is_preprint":false},{"year":2020,"finding":"CD109 promotes EMT and stemness in lung adenocarcinoma via activation of YAP (Hippo pathway); CD109 elevation correlates with YAP signature; YAP activation participates in CD109-elicited EMT gene expression and tumor invasiveness.","method":"CD109 overexpression and knockdown in lung adenocarcinoma cells, YAP pathway activity assays, EMT marker analysis, invasion assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function plus YAP pathway analysis, single lab","pmids":["33375719"],"is_preprint":false},{"year":2020,"finding":"CD109 mediates cervical squamous cell carcinoma tumorigenicity and aggressiveness via EGFR-mediated STAT3 phosphorylation; CD109 knockdown (siRNA) or CRISPR/Cas9 knockout reverses in vitro and in vivo tumorigenic and aggressive properties.","method":"siRNA knockdown, CRISPR/Cas9 knockout, EGFR and STAT3 phosphorylation assays, xenograft models, sphere-forming and colony assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO/KD plus in vivo xenograft with signaling pathway analysis, single lab","pmids":["32507856"],"is_preprint":false},{"year":2021,"finding":"CD109 physically interacts with glycoprotein 130 (GP130) to promote IL-6/STAT3 pathway activation in glioblastoma stem cells; genetic depletion of CD109 abolishes stemness/self-renewal and impairs tumorigenicity, causing phenotypic shift to astrocytic-like differentiation; CD109/STAT3 axis mediates chemoresistance.","method":"Co-immunoprecipitation of CD109 with GP130, genetic CD109 depletion, STAT3 activation assays, sphere formation, xenograft tumorigenicity, pharmacological STAT3 inhibition","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP of CD109-GP130, genetic depletion with defined molecular phenotype, pharmacological validation, in vivo xenograft","pmids":["33986188"],"is_preprint":false},{"year":2021,"finding":"CD109 (GPI-anchored protein on hematopoietic stem/progenitor cells) suppresses TGF-β signaling in HSPCs; CD109 knockout/knockdown in TF-1 cells and primary cord blood MEPs leads to erythroid differentiation upon TGF-β stimulation; in PNH patients, CD109-negative (GPI-deficient) MEPs show greater CD36 expression (erythroid commitment marker) than CD109-positive MEPs.","method":"CD109 knockout and knockdown in TF-1 cells and primary HSPCs, erythroid differentiation assays, flow cytometry of PNH patient peripheral blood MEPs","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO/KD plus patient cell analysis, single lab, consistent with established CD109-TGF-β inhibitory function","pmids":["34743190"],"is_preprint":false},{"year":2021,"finding":"Meprin β cleaves CD109 at the cell surface within its bait region, releasing soluble CD109 fragments; proteolytic cleavage by meprin β reduces the amount of full-length CD109 sorted to extracellular vesicles; the C-terminal region of CD109 is required for its association with exosomes.","method":"Meprin β cleavage assay in vitro and in cells, western blotting of CD109 fragments, homology modeling of CD109 structure, single-particle analysis, extracellular vesicle isolation and quantification","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protease cleavage assay plus EV quantification plus structural modeling, single lab","pmids":["33738281"],"is_preprint":false},{"year":2015,"finding":"CD109 is a component of exosomes secreted from cultured cells; the C-terminal region of CD109 is required for its incorporation into exosomes (truncated CD109 lacking the C-terminal region is not associated with exosomes).","method":"FLAG-tagged CD109 immunoprecipitation from conditioned medium, mass spectrometry identification of co-precipitated exosomal proteins, immuno-electron microscopy, truncation mutant analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immuno-EM plus truncation mutant, Co-IP with exosomal markers, single lab","pmids":["26707640"],"is_preprint":false},{"year":2022,"finding":"CD109 forms a heteromeric complex with EGFR at the cell surface, stabilizing EGFR protein levels and promoting EGFR/AKT signaling in vulvar and hypopharyngeal SCC cells; CD109 is required for in vivo tumorigenicity and for maintaining epithelial morphology and stemness; cell-surface localization of CD109 is required for its pro-tumorigenic effects.","method":"Co-immunoprecipitation and immunofluorescence co-localization of CD109-EGFR, CD109 knockdown/knockout, mRNA and protein level analysis of EGFR, AKT phosphorylation, xenograft tumor models, spheroid formation","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus co-localization plus in vivo xenograft, single lab","pmids":["35954339"],"is_preprint":false},{"year":2024,"finding":"Proteolytic cleavage of CD109 bait region by diverse proteases induces a conformational change that activates the CD109 thioester; activated CD109 conjugates proteases via its thioester and decreases their activity toward protein substrates, demonstrating CD109 is a protease inhibitor; the GPI-anchored MG8 domain dissociates during conformational change, enabling CD109 release from the cell surface by proteases rather than unspecific shedding.","method":"In vitro protease cleavage assays with diverse proteases, thioester activation assays, protease conjugation assays, activity inhibition assays, protease-induced membrane release experiments","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted biochemical assays demonstrating protease inhibition mechanism, thioester activation, and domain dissociation; multiple orthogonal in vitro methods","pmids":["38587194"],"is_preprint":false},{"year":2025,"finding":"Three cryo-EM structures of CD109 in native, protease-activated, and methylamine-activated conformations reveal the structural mechanism of protease inhibition: protease cleavage of the bait region triggers a conformational change similar to A2ML1 (suggesting shared mechanism); CD109 glycans contribute to protease inhibition; deglycosylation enhances substrate access but does not affect chymotrypsin conjugation.","method":"Cryo-electron microscopy structure determination of three CD109 conformations, deglycosylation experiments, chymotrypsin conjugation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple cryo-EM structures at distinct conformational states with functional validation by conjugation assays","pmids":["40482031"],"is_preprint":false},{"year":2025,"finding":"Tumor-derived soluble CD109 (sCD109) upregulates CD73 mRNA transcription in macrophages by activating the FcγRI/SYK/NF-κB signaling pathway; sCD109 is internalized into macrophage cytoplasm and inhibits CD73 protein degradation by binding E3 ligase TRIM21, competing with CD73 for its binding site; this promotes enrichment of CD73+ tumor-associated macrophages that inhibit T-cell responses.","method":"Proteomic analysis, single-cell transcriptomics, mass spectrometry, NF-κB pathway activation assays, Co-IP of sCD109 with TRIM21 and CD73, CD73 protein stability assays, T-cell functional assays","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with TRIM21 plus NF-κB pathway assays, single lab, multiomics supported","pmids":["40220905"],"is_preprint":false},{"year":2023,"finding":"CD109 expression is required on conventional dendritic cells (cDC2s) for airway hyperreactivity and eosinophilic inflammation; CD109 is induced in lung cDC2s upon allergic challenge; CD109-deficient cDC2s have elevated RUNX3 expression and impaired ability to drive Th2 cytokine production and Th2 differentiation; adoptive transfer of CD109-deficient DCs fails to reconstitute AHR and eosinophilic inflammation.","method":"CD109 knockout mice, allergen sensitization models (HDM, OVA), ex vivo DC-T cell co-cultures, adoptive transfer of bone marrow-derived DCs, anti-CD109 monoclonal antibody treatment","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus adoptive transfer reconstitution plus pharmacological blockade; multiple models confirm cDC2-specific mechanism","pmids":["36215676"],"is_preprint":false},{"year":2023,"finding":"CD109 inhibits BMP signaling in osteosarcoma: CD109 knockdown enhances SMAD1/5/9 phosphorylation under BMP-2 stimulation and attenuates osteosarcoma cell migration; CD109 expression inversely correlates with pSMAD1/5/9 in human osteosarcoma tissue; no association found between CD109 and TGF-β signaling in osteosarcoma cells.","method":"CD109 siRNA knockdown, BMP-2 stimulation with pSMAD1/5/9 western blotting, in vitro wound healing assay, immunohistochemistry of human osteosarcoma tissue","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined BMP-signaling readout plus clinical tissue correlation, single lab","pmids":["37030166"],"is_preprint":false},{"year":2024,"finding":"Under mechanical force, CD109 expression on PDLSCs is upregulated (via miR-340-5p repression); CD109 suppresses osteogenesis of PDLSCs through the JAK/STAT3 signaling pathway and promotes osteoclast formation and M1 macrophage polarization through paracrine mechanisms; CD109 knockdown in vivo increases osteogenic activity and decreases osteoclast numbers and tooth movement.","method":"Mechanical force stimulation in vitro and rat tooth movement model in vivo, JAK/STAT3 pathway analysis, lentiviral shRNA injection, miR-340-5p functional studies, co-culture paracrine assays","journal":"Stem cells translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo genetic knockdown plus JAK/STAT3 pathway analysis plus miRNA mechanism, single lab","pmids":["38885217"],"is_preprint":false},{"year":2025,"finding":"CD109 interacts with and stabilizes IL-6 receptor alpha (IL6Rα) expression; CD109 promotes IL-6/STAT3/NRF2/SOD1/HO1 pathway activation in oral and vulvar SCC cells; CD109 loss attenuates this pathway, reducing cancer stemness and antioxidant protein expression.","method":"Co-immunoprecipitation of CD109 with IL6Rα, immunofluorescence and FACS co-localization, IL6Rα protein stability assays, STAT3/NRF2 pathway assays, CD109 knockdown/knockout, spheroid formation, multi-omic clinical validation","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional signaling assays plus clinical multi-omics validation, single lab","pmids":["40317079"],"is_preprint":false},{"year":1998,"finding":"CD109 (a GPI-anchored protein on platelets) carries ABH blood group antigens; anti-A monoclonal antibodies react with CD109 on immunoprecipitation/immunoblotting; phosphatidylinositol-specific phospholipase C treatment releases a 175 kDa GPI-anchored protein (CD109) expressing blood group determinants.","method":"Immunoprecipitation/immunoblotting with monoclonal antibodies against glycoproteins and blood group antigens, PI-PLC cleavage and Western blot","journal":"The Journal of laboratory and clinical medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical identification by Co-IP/WB and PI-PLC cleavage, single lab","pmids":["9708575"],"is_preprint":false},{"year":2016,"finding":"Reduced CD109 expression in hepatocellular carcinoma tumor-associated endothelial cells promotes tumor progression through paracrine IL-8; CD109 knockdown in HUVEC activates TGF-β/Akt/NF-κB pathway, upregulating IL-8 secretion, which in turn promotes hepatoma cell proliferation, migration, and invasion; co-implantation with CD109 knockdown HUVEC accelerates tumor growth and metastasis in mice.","method":"CD109 knockdown in HUVEC, cytokine antibody array screening, IL-8 validation, TGF-β/Akt/NF-κB pathway analysis, co-culture assays, xenograft co-implantation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus cytokine identification plus in vivo co-implantation, single lab","pmids":["27121053"],"is_preprint":false},{"year":2023,"finding":"αv integrins in vascular smooth muscle cells act in concert with CD109 to regulate TGF-β signaling; αv SMKO mice show prolonged CD109 expression; CD109 overexpression in cultured VSMCs phenocopies αv integrin knockdown (attenuating collagen expression, TGF-β activation, and Smad2/3 signaling); CD109 and TGF-β receptor are co-internalized in early endosomes.","method":"αv integrin conditional knockout mice, transcriptomic analysis, CD109 overexpression in mouse and human VSMCs, Smad2/3 signaling assays, collagen expression assays, endosomal co-localization","journal":"European heart journal open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model plus in vitro gain-of-function phenocopy plus localization, single lab","pmids":["36909248"],"is_preprint":false},{"year":2024,"finding":"CD109 attenuates bleomycin-induced pulmonary fibrosis by inhibiting TGF-β signaling; CD109 transgenic mice show attenuated fibrosis; recombinant CD109 protein inhibits TGF-β signaling and decreases ACTA2 expression in lung fibroblasts in vitro and reduces pulmonary fibrosis in vivo upon administration.","method":"CD109 transgenic and CD109-/- mice in bleomycin model, recombinant CD109 protein in vitro signaling assays, in vivo recombinant protein administration, ACTA2 and TGF-β signaling readouts","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — both genetic overexpression and recombinant protein administration with in vitro and in vivo concordant results","pmids":["38334455"],"is_preprint":false}],"current_model":"CD109 is a GPI-anchored, thioester-containing glycoprotein of the alpha2-macroglobulin/complement family that functions as a multifunctional co-receptor and negative regulator of TGF-β signaling: at the cell surface it binds TGF-β receptors (requiring furin-mediated processing into 180/25 kDa fragments), recruits SMAD7/Smurf2 to promote TGFBR1 ubiquitin-mediated degradation, and directs TGF-β receptors into caveolae (via caveolin-1 association) for degradation; the soluble released form directly binds TGF-β with high affinity to sequester the ligand; CD109 also interacts with EGFR and IL-6 receptor alpha to promote EGFR/AKT and IL-6/STAT3/NRF2 signaling in cancer cells, interacts with GP130 to activate IL-6/STAT3 in glioblastoma stem cells, and with LTBP1 to modulate stromal TGF-β activation; structurally, protease cleavage of a bait region triggers a conformational change that activates its thioester, enabling covalent protease conjugation and inhibition, and releases the major fragment from the membrane, a mechanism now resolved by cryo-EM."},"narrative":{"mechanistic_narrative":"CD109 is a GPI-anchored, thioester-containing glycoprotein of the alpha2-macroglobulin/complement family that operates as a cell-surface co-receptor and dominant negative regulator of TGF-β signaling while doubling as a thioester-dependent protease inhibitor [PMID:11861284, PMID:16754747, PMID:38587194]. It is synthesized as a precursor that furin cleaves in the Golgi into associating 180/25 kDa fragments, and this processing is required for CD109 to bind TβRI and to inhibit TGF-β responses [PMID:20101215]. Membrane-bound CD109 suppresses TGF-β signaling by multiple convergent routes: it recruits SMAD7/Smurf2 to drive ligand-dependent ubiquitin-mediated TGFBR1 degradation [PMID:21898545], associates with caveolin-1 to route TGF-β receptors into caveolae for internalization and degradation [PMID:21295082], and acts together with cell-surface GRP78 to redirect receptor trafficking and block Smad2 activation under ER stress [PMID:29654145]. A soluble, shed form binds TGF-β directly with high affinity and competes with receptor binding, thereby sequestering ligand [PMID:26621871]. Across genetic models this TGF-β-restraining activity controls keratinocyte differentiation, wound healing, and fibrosis, with CD109 loss producing epidermal hyperplasia via elevated STAT3 rather than Smad2 signaling and CD109 overexpression conferring resistance to skin and pulmonary fibrosis [PMID:22846721, PMID:23436317, PMID:38334455]. Independent of TGF-β inhibition, CD109 forms surface complexes with EGFR, GP130, and IL-6Rα to stabilize these receptors and amplify EGFR/AKT and IL-6/JAK-STAT3 signaling, driving tumor growth, metastasis, stemness, and chemoresistance in lung, glioblastoma, and squamous-cell cancers [PMID:28191885, PMID:32133706, PMID:33986188, PMID:35954339, PMID:40317079]. Structurally, protease cleavage of a bait region triggers a conformational change that activates the internal thioester, enabling covalent conjugation and inhibition of the attacking protease and dissociation of the GPI-anchored MG8 domain to release CD109 from the membrane — a mechanism resolved across native and activated cryo-EM conformations [PMID:38587194, PMID:40482031].","teleology":[{"year":1998,"claim":"Before molecular cloning, CD109 was characterized as a GPI-anchored platelet glycoprotein, establishing its membrane attachment mode and antigenic properties.","evidence":"Immunoprecipitation/immunoblotting and PI-PLC release of a 175 kDa GPI-anchored protein carrying ABH blood group determinants","pmids":["9708575"],"confidence":"Medium","gaps":["No protein sequence or function defined","Did not establish thioester or signaling roles"]},{"year":2002,"claim":"Cloning placed CD109 in the alpha2-macroglobulin/complement thioester-containing protein family and demonstrated a reactive internal thioester, defining its biochemical class; in parallel, a single SNP was shown to determine the Gov/HPA-15 platelet alloantigens.","evidence":"cDNA cloning with biochemical thioester demonstration in native CD109; allele-specific genotyping plus CHO transfection and serology","pmids":["11861284","11861285"],"confidence":"High","gaps":["Cellular function of the thioester not yet defined","No receptor or signaling partners identified"]},{"year":2006,"claim":"Identification of CD109 as the keratinocyte TGF-β-binding protein r150 established it as a negative modulator of TGF-β signaling acting on receptor activity rather than only by ligand sequestration.","evidence":"Affinity purification/microsequencing plus reciprocal siRNA loss- and overexpression gain-of-function with TGF-β signaling readouts","pmids":["16754747"],"confidence":"High","gaps":["Mechanism of receptor modulation unresolved","Processing requirements unknown"]},{"year":2010,"claim":"Furin processing into 180/25 kDa fragments was shown to be obligatory for CD109 to bind TβRI and inhibit TGF-β signaling, linking maturation to function.","evidence":"Site-directed mutagenesis of the furin site (R1273S), Co-IP with TβRI, and signaling assays","pmids":["20101215"],"confidence":"High","gaps":["Did not resolve downstream degradation route","Stoichiometry of receptor binding unknown"]},{"year":2011,"claim":"CD109 was shown to inhibit TGF-β signaling by recruiting receptors into caveolae for degradation, and a soluble shed form was implicated in disease via enhanced release.","evidence":"Reciprocal Co-IP with caveolin-1, localization and receptor degradation assays; shedding and recombinant-protein experiments in keratinocytes with psoriatic skin histology","pmids":["21295082","21539622"],"confidence":"High","gaps":["Trigger for caveolar routing not defined","Mechanism of STAT3 elevation by soluble CD109 unclear"]},{"year":2012,"claim":"The receptor-degradation mechanism was refined to a SMAD7/Smurf2-dependent ubiquitin pathway, and a knockout demonstrated CD109 controls keratinocyte differentiation in vivo via STAT3 rather than Smad2.","evidence":"Co-IP, SMAD7 siRNA and Smurf2 ligase-activity requirement assays; CD109 knockout mouse histology with pSTAT3/pSmad2 immunohistochemistry","pmids":["21898545","22846721"],"confidence":"High","gaps":["How CD109 loss elevates STAT3 mechanistically not defined","Connection between TGF-β inhibition and STAT3 readout unresolved"]},{"year":2013,"claim":"Epidermal CD109 overexpression dampened TGF-β/Smad signaling, inflammation, and fibrosis in vivo, establishing CD109 as an anti-fibrotic regulator.","evidence":"CD109 transgenic mice in wound-healing and bleomycin scleroderma models with pSmad2/3 and ECM readouts; knockdown in RANKL-driven osteoclastogenesis","pmids":["23438099","23436317","23593435"],"confidence":"High","gaps":["Cell-type-specific contributions not dissected","Osteoclast mechanism only correlative"]},{"year":2015,"claim":"Quantitative binding studies established that soluble CD109 directly sequesters TGF-β, and surface CD109 was first linked to EGFR, broadening its receptor repertoire.","evidence":"SPR binding kinetics and radioligand competition with signaling readouts; Co-IP of CD109 with EGFR and exosome incorporation via truncation mutants","pmids":["26621871","25724945","26707640"],"confidence":"High","gaps":["EGFR effects were cell-line-specific","Exosomal cargo function unknown"]},{"year":2017,"claim":"CD109 was established as a driver of cancer metastasis through JAK-STAT3 activation, defining an oncogenic role distinct from its TGF-β suppression.","evidence":"In vivo tumor barcoding screen in mouse lung adenocarcinoma plus JAK inhibitor validation; differential ALK1/ALK5 regulation in transgenic epidermis","pmids":["28191885","27866969"],"confidence":"High","gaps":["Receptor mediating STAT3 activation not yet defined","Reconciliation of pro- and anti-tumor roles unresolved"]},{"year":2018,"claim":"An ER-stress-responsive mechanism was added wherein surface GRP78 partners with CD109 to reroute TGF-β receptors to caveolae, and a knockout revealed CD109 maintains bone homeostasis.","evidence":"Reciprocal Co-IP of GRP78 with CD109 plus IRE1α/SRC/ASAP1 dissection; CD109 knockout micro-CT and bone histomorphometry","pmids":["29654145","29767469"],"confidence":"High","gaps":["Generality of GRP78 mechanism beyond ER stress unclear","Cellular target driving bone turnover not identified"]},{"year":2019,"claim":"Genetic and antibody studies expanded CD109 into inflammatory and EMT contexts, showing it restrains gamma-delta-17 cells, NF-κB-driven synovial inflammation, and maintains epithelial identity.","evidence":"CD109 knockout mice in psoriasis/CIA models with IL-23 blockade and microbiota depletion; siRNA/antibody in RA FLSs; CRISPR knockout with recombinant rescue and SCC tumor IHC","pmids":["31597099","31455659","31695056"],"confidence":"High","gaps":["Receptor mediating NF-κB regulation undefined","Cell-extrinsic vs intrinsic contributions across tissues not fully separated"]},{"year":2020,"claim":"Multiple studies converged on CD109 stabilizing receptor signaling (EGFR/AKT/mTOR, YAP, EGFR/STAT3) and engaging LTBP1 to activate stromal TGF-β, defining context-dependent oncogenic outputs.","evidence":"Co-IP with EGFR plus drug-sensitivity assays; mass-spec identification and Co-IP of LTBP1 with TGF-β activation assays in CD109-deficient lung adenocarcinoma model; YAP pathway and EGFR-STAT3 analyses with xenografts","pmids":["32133706","33007133","33375719","32507856"],"confidence":"High","gaps":["How a TGF-β inhibitor activates stromal TGF-β via LTBP1 mechanistically unclear","Direct vs indirect receptor stabilization not distinguished"]},{"year":2021,"claim":"CD109 was shown to partner with GP130 to sustain IL-6/STAT3 stemness in glioblastoma and to suppress TGF-β-driven erythroid commitment in hematopoietic progenitors, linking its co-receptor activity to cell fate.","evidence":"Reciprocal Co-IP of CD109 with GP130, genetic depletion with STAT3/xenograft readouts; CD109 KO/KD in TF-1 and primary HSPCs with PNH patient analysis; meprin β cleavage and EV studies","pmids":["33986188","34743190","33738281"],"confidence":"High","gaps":["Determinants selecting GP130 vs TGF-β receptor engagement unknown","Physiological proteases releasing CD109 in vivo not defined"]},{"year":2023,"claim":"CD109 was extended to BMP signaling, dendritic-cell-driven allergic inflammation, and integrin-coupled vascular TGF-β control, demonstrating regulation of multiple TGF-β-superfamily receptor systems.","evidence":"siRNA knockdown with pSMAD1/5/9 readouts and osteosarcoma IHC; CD109 KO mice with adoptive DC transfer and anti-CD109 antibody; αv integrin conditional KO with CD109 gain-of-function phenocopy and endosomal co-localization","pmids":["37030166","36215676","36909248"],"confidence":"Medium","gaps":["Whether BMP inhibition uses the same machinery as TGF-β inhibition unclear","Mechanistic link between CD109 and RUNX3 in cDC2s undefined"]},{"year":2024,"claim":"Reconstituted biochemistry established CD109's long-predicted thioester function: protease cleavage of the bait region activates the thioester to conjugate and inhibit proteases and to release the protein from the membrane, and recombinant CD109 was confirmed anti-fibrotic in lung.","evidence":"In vitro protease cleavage, thioester activation, conjugation and inhibition assays with membrane-release experiments; CD109 transgenic/KO bleomycin lung models plus recombinant protein administration","pmids":["38587194","38334455","38885217"],"confidence":"High","gaps":["Physiological protease targets of the thioester in vivo unknown","Relationship between protease-inhibitor and receptor-regulator activities unresolved"]},{"year":2025,"claim":"Cryo-EM resolved the conformational basis of protease inhibition, and new partners (IL-6Rα, the sCD109/FcγRI/TRIM21/CD73 macrophage axis) extended CD109's reach into antioxidant signaling and tumor immune evasion.","evidence":"Cryo-EM of native and activated CD109 conformations with deglycosylation/conjugation assays; Co-IP of CD109 with IL6Rα and of sCD109 with TRIM21/CD73 with NF-κB and T-cell functional assays","pmids":["40482031","40317079","40220905"],"confidence":"Medium","gaps":["Structural basis of receptor engagement (vs protease inhibition) not resolved","In vivo relevance of CD73/TAM axis to therapy untested"]},{"year":null,"claim":"It remains unclear how CD109's single thioester/conformational machinery is mechanistically partitioned between protease inhibition, TGF-β receptor degradation, and the stabilization of growth-factor receptors that yields its opposite pro-tumorigenic outputs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of CD109 bound to a TGF-β or growth-factor receptor","Determinants of context-dependent signaling switching unknown","Direct vs indirect nature of EGFR/GP130/IL6Rα stabilization undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,4,5,12,30]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[30,31]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,12,25]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[12,30]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,4,29,37]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,6,12,13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[27,28]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,39]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4,5,12,25,36]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,22,25,32]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,19,33,32]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,5,27]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4,16]}],"complexes":["CD109–EGFR receptor complex","TGF-β receptor system"],"partners":["TGFBR1","CAV1","SMAD7","SMURF2","EGFR","IL6ST","IL6R","LTBP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6YHK3","full_name":"CD109 antigen","aliases":["150 kDa TGF-beta-1-binding protein","C3 and PZP-like alpha-2-macroglobulin domain-containing protein 7","Platelet-specific Gov antigen","p180","r150"],"length_aa":1445,"mass_kda":161.7,"function":"Modulates negatively TGFB1 signaling in keratinocytes","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q6YHK3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD109","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CD109","total_profiled":1310},"omim":[{"mim_id":"621264","title":"FETOMATERNAL ALLOIMMUNE THROMBOCYTOPENIA 1; FMAIT1","url":"https://www.omim.org/entry/621264"},{"mim_id":"617810","title":"GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 15; GPIBD15","url":"https://www.omim.org/entry/617810"},{"mim_id":"608859","title":"CD109 ANTIGEN; CD109","url":"https://www.omim.org/entry/608859"},{"mim_id":"605754","title":"PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS Q PROTEIN; PIGQ","url":"https://www.omim.org/entry/605754"},{"mim_id":"603048","title":"GLYCOSYLPHOSPHATIDYLINOSITOL ANCHOR ATTACHMENT PROTEIN 1; GPAA1","url":"https://www.omim.org/entry/603048"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":310.7}],"url":"https://www.proteinatlas.org/search/CD109"},"hgnc":{"alias_symbol":["HPA-15","FLJ38569","DKFZp762L1111","CPAMD7"],"prev_symbol":[]},"alphafold":{"accession":"Q6YHK3","domains":[{"cath_id":"2.60.40.2950","chopping":"29-125","consensus_level":"high","plddt":86.7523,"start":29,"end":125},{"cath_id":"2.60.40.1930","chopping":"130-225_556-616_685-745","consensus_level":"medium","plddt":88.75,"start":130,"end":745},{"cath_id":"2.60.40.1940","chopping":"230-306_318-346","consensus_level":"medium","plddt":83.1458,"start":230,"end":346},{"cath_id":"2.60.40.1930","chopping":"468-553","consensus_level":"medium","plddt":89.299,"start":468,"end":553},{"cath_id":"2.60.40.10","chopping":"749-852","consensus_level":"high","plddt":82.8598,"start":749,"end":852},{"cath_id":"1.50.10.20","chopping":"904-1128_1135-1200","consensus_level":"medium","plddt":87.5034,"start":904,"end":1200},{"cath_id":"2.60.40.690","chopping":"1279-1396","consensus_level":"medium","plddt":84.8549,"start":1279,"end":1396}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6YHK3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6YHK3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6YHK3-F1-predicted_aligned_error_v6.png","plddt_mean":81.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD109","jax_strain_url":"https://www.jax.org/strain/search?query=CD109"},"sequence":{"accession":"Q6YHK3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6YHK3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6YHK3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6YHK3"}},"corpus_meta":[{"pmid":"11861284","id":"PMC_11861284","title":"Cell 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Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. 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immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38442581","citation_count":5,"is_preprint":false},{"pmid":"36909248","id":"PMC_36909248","title":"Smooth muscle αv integrins regulate vascular fibrosis via CD109 downregulation of TGF-β signalling.","date":"2023","source":"European heart journal open","url":"https://pubmed.ncbi.nlm.nih.gov/36909248","citation_count":5,"is_preprint":false},{"pmid":"37661780","id":"PMC_37661780","title":"H3K27 acetylation activated-CD109 evokes 5-fluorouracil resistance in gastric cancer via the JNK/MAPK signaling pathway.","date":"2023","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/37661780","citation_count":4,"is_preprint":false},{"pmid":"39577687","id":"PMC_39577687","title":"Microglial upregulation of CD109 expression in spinal cord of amyotrophic lateral sclerosis mouse model and its role in modulating inflammation and TGFβ/SMAD 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activation of its thiol ester, and dissociation from the cell membrane.","date":"2024","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/38587194","citation_count":3,"is_preprint":false},{"pmid":"35347029","id":"PMC_35347029","title":"The Significance of CD109 Expression in Oropharyngeal Squamous Cell Carcinoma.","date":"2022","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35347029","citation_count":2,"is_preprint":false},{"pmid":"38485055","id":"PMC_38485055","title":"HPV16 E7 modulates the cell surface expression of MET and CD109 via the AP2 complex.","date":"2024","source":"Tumour virus research","url":"https://pubmed.ncbi.nlm.nih.gov/38485055","citation_count":2,"is_preprint":false},{"pmid":"40317079","id":"PMC_40317079","title":"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 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hematology","url":"https://pubmed.ncbi.nlm.nih.gov/35028883","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51043,"output_tokens":10698,"usd":0.1568,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21586,"output_tokens":6084,"usd":0.130015,"stage2_stop_reason":"end_turn"},"total_usd":0.286815,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"CD109 is a GPI-anchored glycoprotein and a novel member of the alpha2-macroglobulin/C3, C4, C5 family of thioester-containing proteins; native CD109 contains an intact thioester bond capable of covalent binding to adjacent molecules upon proteolytic activation, with complement-like reactivity (short t½, spatially restricted action).\",\n      \"method\": \"cDNA cloning, sequence analysis, biochemical demonstration of intact thioester in native CD109\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical demonstration of thioester, sequence-based mechanistic inference confirmed experimentally, replicated conceptually across multiple subsequent papers\",\n      \"pmids\": [\"11861284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The Gov (HPA-15) platelet alloantigens are defined by a single A-to-C SNP at position 2108 of the CD109 coding region, resulting in a Tyr703Ser substitution; CHO cells transfected with the respective cDNA variants are specifically recognized by allele-specific antisera, confirming this polymorphism as the alloantigen determinant.\",\n      \"method\": \"RT-PCR, allele-specific PCR-SSP, PCR-RFLP, real-time PCR genotyping, CHO cell transfection with variant cDNA + serological testing\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional confirmation by transfection + serology, multiple orthogonal genotyping methods, independently replicated in subsequent population studies\",\n      \"pmids\": [\"11861285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD109 (identified as the 150 kDa GPI-anchored TGF-β1-binding protein r150 in keratinocytes) is a component of the TGF-β receptor system and a negative modulator of TGF-β responses; loss-of-function and gain-of-function studies show CD109 inhibits TGF-β signaling independently of ligand sequestration, likely by direct modulation of receptor activity; CD109 contains an internal thioester bond.\",\n      \"method\": \"Affinity purification and microsequencing of r150, biochemical thioester demonstration, siRNA knockdown (loss-of-function) and CD109 overexpression (gain-of-function) with TGF-β signaling readouts\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical identification plus both loss- and gain-of-function in the same study; replicated across multiple labs\",\n      \"pmids\": [\"16754747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD109 is processed in the Golgi by furin (furinase) from a 205 kDa precursor into 180 kDa and 25 kDa fragments; the 180 kDa form associates with GPI-anchored 25 kDa CD109 on the cell surface and is secreted. Furin cleavage (at RRRR motif, Arg1273) is required for CD109 to associate with TβRI and to inhibit TGF-β signaling; the furin-cleavage-deficient mutant (R1273S) neither impairs TGF-β signaling nor associates with TβRI.\",\n      \"method\": \"Western blotting of CD109 processing products, site-directed mutagenesis of furin cleavage site (R1273S), co-immunoprecipitation of CD109 with TβRI, TGF-β signaling assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis + co-IP + functional signaling assay in a single study; mechanism confirmed by negative control mutant\",\n      \"pmids\": [\"20101215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD109 associates with caveolin-1 and promotes internalization and degradation of TGF-β receptors via the caveolae pathway; CD109 increases TGF-β binding to its receptors, enhances their internalization via caveolae, localizes TGF-β receptors to the caveolar compartment in a ligand-dependent manner, and facilitates receptor degradation, thereby inhibiting TGF-β signaling.\",\n      \"method\": \"Co-immunoprecipitation of CD109 with caveolin-1, immunofluorescence localization, receptor degradation assays, TGF-β binding assays, caveolae pathway inhibitors\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with caveolin-1, multiple orthogonal methods (Co-IP, localization, degradation assay), replicated in subsequent papers\",\n      \"pmids\": [\"21295082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD109 enhances SMAD7/Smurf2-mediated degradation of TGFBR1 in a ligand-dependent manner; CD109 regulates the subcellular localization and association of SMAD7/Smurf2 with TGFBR1; CD109's inhibitory effect on TGF-β signaling requires SMAD7 expression and Smurf2 ubiquitin ligase activity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, SMAD7 siRNA knockdown, Smurf2 ubiquitin ligase activity assays, TGF-β receptor degradation assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, localization, genetic rescue with siRNA, enzymatic activity requirement), single lab\",\n      \"pmids\": [\"21898545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD109 released from the keratinocyte cell surface (soluble CD109) downregulates TGF-β signaling and TGF-β receptor expression, and increases STAT3 phosphorylation, total STAT3, Bcl-2 expression, and cell growth/survival; decreased CD109 protein in psoriatic epidermis (with unchanged mRNA) suggests enhanced CD109 release as a disease mechanism.\",\n      \"method\": \"CD109 shedding experiments, addition of recombinant CD109 protein to keratinocytes, western blotting, immunohistochemistry of psoriatic vs. normal skin\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based experiments with recombinant protein and shedding models, single lab, two orthogonal functional readouts\",\n      \"pmids\": [\"21539622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mesotrypsin (PRSS3) proteolytically sheds CD109 from the cell surface of breast cancer cells; CD109 is identified as the functional proteolytic target of mesotrypsin using proteomic methods; mesotrypsin knockdown attenuates and recombinant mesotrypsin enhances the malignant growth phenotype.\",\n      \"method\": \"Proteomic identification of CD109 as mesotrypsin substrate, PRSS3 knockdown, recombinant mesotrypsin treatment, 3D organotypic culture morphological assays\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic substrate identification plus gain/loss-of-function, single lab\",\n      \"pmids\": [\"20035377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD109-deficient mice develop epidermal hyperplasia, kinked hair shafts, ectatic hair follicles, sebum accumulation, and persistent thickening of basal/suprabasal epidermal layers; this is accompanied by elevated STAT3 phosphorylation (not elevated Smad2 phosphorylation) in the epidermis, indicating CD109 regulates keratinocyte differentiation via a STAT3-dependent pathway in vivo.\",\n      \"method\": \"CD109 knockout mouse generation, histological analysis, immunohistochemistry for pSmad2 and pSTAT3\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined molecular readout (pSTAT3 elevation, not pSmad2), replicated in multiple CD109 KO studies\",\n      \"pmids\": [\"22846721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Transgenic mice overexpressing CD109 in the epidermis display reduced macrophage and neutrophil recruitment, reduced granulation tissue, decreased Smad2/3 phosphorylation, decreased proinflammatory cytokines (IL-1α, MCP-1), and decreased ECM components in excisional wounds, with improved dermal collagen architecture in incisional wounds; wound closure rates are unaffected.\",\n      \"method\": \"CD109 transgenic mouse wound healing model, immunohistochemistry, western blotting for pSmad2/3, cytokine expression, collagen organization\",\n      \"journal\": \"Wound repair and regeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic overexpression with multiple defined molecular readouts, confirmed in two wound models\",\n      \"pmids\": [\"23438099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD109 transgenic mice overexpressing CD109 in the epidermis show resistance to bleomycin-induced skin fibrosis, with significant decreases in dermal thickness, collagen crosslinking, collagen and fibronectin content, and phospho-Smad2/3 levels compared to wild-type mice.\",\n      \"method\": \"Bleomycin-induced scleroderma mouse model, CD109 transgenic mice, histological staining, western blotting and immunohistochemistry for pSmad2/3\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic overexpression in a disease model with multiple molecular endpoints, consistent with other CD109 overexpression studies\",\n      \"pmids\": [\"23436317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD109 plays a role in osteoclastogenesis; CD109 mRNA and protein are significantly upregulated during RANKL-induced osteoclast differentiation in RAW264.7 cells, primary murine monocytes, and pre-osteoclast lines; stable CD109 knockdown reduces the formation of large multinucleated osteoclasts.\",\n      \"method\": \"Microarray, RT-qPCR, western blot during osteoclastogenesis, stable shRNA knockdown cell lines, osteoclast fusion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple expression methods plus functional knockdown, single lab\",\n      \"pmids\": [\"23593435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Soluble CD109 (sCD109) directly binds TGF-β with high affinity (slow dissociation by surface plasmon resonance); sCD109 inhibits TGF-β binding to its receptors (radioligand competition assay), antagonizes Smad2/3 phosphorylation, and decreases TGF-β-induced transcription and cell migration.\",\n      \"method\": \"Surface plasmon resonance (SPR) binding kinetics, radioligand binding and affinity labelling competition assays, Smad2/3 phosphorylation assays, transcriptional reporter assays, cell migration assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro SPR binding with kinetics plus cell-based competition assays plus functional signaling readouts; multiple orthogonal methods\",\n      \"pmids\": [\"26621871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cell surface CD109 interacts with EGFR in glioblastoma SK-MG-1 cells overexpressing CD109; CD109 overexpression attenuates TGF-β1 signaling and enhances EGF signaling and cell migration/invasion in SK-MG-1 but not in U251MG or MG178 cells; the secreted N-terminal CD109 fragment (hyperglycosylated in SK-MG-1) inhibits TGF-β1 signaling via paracrine effect but does not affect EGF signaling.\",\n      \"method\": \"Co-immunoprecipitation of CD109 with EGFR, conditioned medium experiments, TGF-β and EGF signaling assays, migration/invasion assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of CD109-EGFR plus functional signaling and migration assays, single lab, cell-line-specific effects\",\n      \"pmids\": [\"25724945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD109 overexpression in mouse epidermis differentially regulates TGF-β receptor signaling: it enhances ALK1-Smad1/5 signaling while decreasing ALK5-Smad2/3 signaling; ALK1 co-localizes with CD109 in keratinocytes; CD109-overexpressing epidermal cells reduce ECM production in adjacent skin fibroblasts via a paracrine mechanism.\",\n      \"method\": \"CD109 transgenic mice, immunofluorescence co-localization of ALK1 and CD109, western blotting for pSmad1/5 and pSmad2/3, conditioned medium from isolated keratinocytes/epidermal explants applied to fibroblasts\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic overexpression model plus co-localization and paracrine experiment, single lab\",\n      \"pmids\": [\"27866969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD109 drives lung cancer metastasis through activation of JAK-STAT3 signaling; CD109 promotes a metastatic transcriptional state in lung adenocarcinoma cells, and pharmacological targeting of the JAK-STAT3 pathway blocks CD109-driven metastasis.\",\n      \"method\": \"Tumor barcoding in mouse lung adenocarcinoma model, in vivo small-scale screening, genomic approaches, JAK inhibitor treatment\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic screen plus pharmacological validation in mouse model with human validation; multiple orthogonal approaches\",\n      \"pmids\": [\"28191885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Upon ER stress, GRP78 translocates to the cell surface where it binds CD109 and acts in concert with CD109 to block TGF-β signaling by routing TGF-β receptor to the caveolae, thereby disrupting Smad2 activation; the upstream mechanism involves IRE1α-triggered SRC activation, ASAP1 phosphorylation, and suppression of retrograde transport.\",\n      \"method\": \"Co-immunoprecipitation of GRP78 with CD109, immunofluorescence localization, Smad2 activation assays, ER stress induction, SRC inhibition, dominant-negative and knockdown experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus multiple orthogonal mechanistic experiments, published in high-tier journal\",\n      \"pmids\": [\"29654145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD109 deficiency in mice induces a high-turnover osteoporosis-like phenotype in vivo, with reduced bone volume, increased bone turnover markers (NTX collagen, alkaline phosphatase), demonstrating a role for CD109 in bone metabolism.\",\n      \"method\": \"CD109 knockout mice, micro-computed tomography, bone histomorphometry, serum bone turnover marker measurements\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with quantitative bone phenotype, single lab\",\n      \"pmids\": [\"29767469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD109 regulates the NF-κB signaling pathway in rheumatoid arthritis fibroblast-like synoviocytes; CD109 silencing or neutralizing antibody reduces proinflammatory factor production, cell migration, invasion, chemoattraction, and osteoclast differentiation in RA FLSs; CD109-deficient mice are protected against collagen-induced arthritis.\",\n      \"method\": \"CD109 siRNA knockdown, neutralizing anti-CD109 antibody in RA FLS in vitro, CD109 knockout mice in CIA model, cytokine assays, migration/invasion assays\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both in vitro (siRNA + antibody) and in vivo (KO mice) genetic evidence with multiple functional readouts\",\n      \"pmids\": [\"31455659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD109 genetic deletion in mice leads to spontaneous epidermal hyperplasia, aberrant accumulation of dermal γδ17 T cells, and enhanced susceptibility to psoriasiform inflammation; CD109 restrains γδ17 cell activation in a cell-extrinsic manner by maintaining skin barrier integrity; γδ17 activation requires IL-23 signals and is reversed by microbiota depletion.\",\n      \"method\": \"CD109 knockout mice, flow cytometry, IL-23 blockade, antibiotic-mediated microbiota depletion, skin inflammation models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple mechanistic interventions (IL-23 blockade, microbiota depletion) establishing cell-extrinsic mechanism\",\n      \"pmids\": [\"31597099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD109 CRISPR/Cas9 knockout in SCC cells represses epithelial traits and promotes EMT (elevated mesenchymal markers); recombinant CD109 protein rescues epithelial traits in KO cells; CD109 loss dysregulates 15 signaling pathways including TGF-β; CD109 levels inversely correlate with TGF-β activation in human oral SCC tumors.\",\n      \"method\": \"CRISPR/Cas9 CD109 knockout, recombinant CD109 protein rescue, microarray gene expression, KEGG pathway analysis, immunohistochemistry of 52 human oral SCC tumors\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO plus protein rescue plus clinical validation, single lab\",\n      \"pmids\": [\"31695056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD109 associates with EGFR and regulates AKT/mTOR signaling; CD109 inhibition decreases EGFR phosphorylation and diminishes EGF-elicited AKT/mTOR activation, sensitizing lung adenocarcinoma cells to EGFR inhibitors.\",\n      \"method\": \"Co-immunoprecipitation of CD109 with EGFR, CD109 knockdown, EGFR phosphorylation assays, AKT/mTOR signaling assays, EGFR inhibitor sensitivity assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional signaling and drug sensitivity assays, single lab\",\n      \"pmids\": [\"32133706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD109 promotes stromal invasion of lung adenocarcinoma in vivo; CD109-deficient lung adenocarcinoma mouse model shows significantly reduced stromal invasive lesions; CD109 interacts with LTBP1 (identified by mass spectrometry and confirmed by co-immunoprecipitation), and increased CD109 expression enhances stromal TGF-β activation in the presence of LTBP1.\",\n      \"method\": \"CD109-deficient genetically engineered lung adenocarcinoma mouse model, mass spectrometry identification of CD109-interacting proteins, co-immunoprecipitation of CD109 with LTBP1, TGF-β activation assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model plus biochemical identification and co-IP validation of LTBP1 interaction plus functional TGF-β activation assay\",\n      \"pmids\": [\"33007133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD109 promotes EMT and stemness in lung adenocarcinoma via activation of YAP (Hippo pathway); CD109 elevation correlates with YAP signature; YAP activation participates in CD109-elicited EMT gene expression and tumor invasiveness.\",\n      \"method\": \"CD109 overexpression and knockdown in lung adenocarcinoma cells, YAP pathway activity assays, EMT marker analysis, invasion assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function plus YAP pathway analysis, single lab\",\n      \"pmids\": [\"33375719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD109 mediates cervical squamous cell carcinoma tumorigenicity and aggressiveness via EGFR-mediated STAT3 phosphorylation; CD109 knockdown (siRNA) or CRISPR/Cas9 knockout reverses in vitro and in vivo tumorigenic and aggressive properties.\",\n      \"method\": \"siRNA knockdown, CRISPR/Cas9 knockout, EGFR and STAT3 phosphorylation assays, xenograft models, sphere-forming and colony assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO/KD plus in vivo xenograft with signaling pathway analysis, single lab\",\n      \"pmids\": [\"32507856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD109 physically interacts with glycoprotein 130 (GP130) to promote IL-6/STAT3 pathway activation in glioblastoma stem cells; genetic depletion of CD109 abolishes stemness/self-renewal and impairs tumorigenicity, causing phenotypic shift to astrocytic-like differentiation; CD109/STAT3 axis mediates chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation of CD109 with GP130, genetic CD109 depletion, STAT3 activation assays, sphere formation, xenograft tumorigenicity, pharmacological STAT3 inhibition\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP of CD109-GP130, genetic depletion with defined molecular phenotype, pharmacological validation, in vivo xenograft\",\n      \"pmids\": [\"33986188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD109 (GPI-anchored protein on hematopoietic stem/progenitor cells) suppresses TGF-β signaling in HSPCs; CD109 knockout/knockdown in TF-1 cells and primary cord blood MEPs leads to erythroid differentiation upon TGF-β stimulation; in PNH patients, CD109-negative (GPI-deficient) MEPs show greater CD36 expression (erythroid commitment marker) than CD109-positive MEPs.\",\n      \"method\": \"CD109 knockout and knockdown in TF-1 cells and primary HSPCs, erythroid differentiation assays, flow cytometry of PNH patient peripheral blood MEPs\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO/KD plus patient cell analysis, single lab, consistent with established CD109-TGF-β inhibitory function\",\n      \"pmids\": [\"34743190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Meprin β cleaves CD109 at the cell surface within its bait region, releasing soluble CD109 fragments; proteolytic cleavage by meprin β reduces the amount of full-length CD109 sorted to extracellular vesicles; the C-terminal region of CD109 is required for its association with exosomes.\",\n      \"method\": \"Meprin β cleavage assay in vitro and in cells, western blotting of CD109 fragments, homology modeling of CD109 structure, single-particle analysis, extracellular vesicle isolation and quantification\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protease cleavage assay plus EV quantification plus structural modeling, single lab\",\n      \"pmids\": [\"33738281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD109 is a component of exosomes secreted from cultured cells; the C-terminal region of CD109 is required for its incorporation into exosomes (truncated CD109 lacking the C-terminal region is not associated with exosomes).\",\n      \"method\": \"FLAG-tagged CD109 immunoprecipitation from conditioned medium, mass spectrometry identification of co-precipitated exosomal proteins, immuno-electron microscopy, truncation mutant analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immuno-EM plus truncation mutant, Co-IP with exosomal markers, single lab\",\n      \"pmids\": [\"26707640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD109 forms a heteromeric complex with EGFR at the cell surface, stabilizing EGFR protein levels and promoting EGFR/AKT signaling in vulvar and hypopharyngeal SCC cells; CD109 is required for in vivo tumorigenicity and for maintaining epithelial morphology and stemness; cell-surface localization of CD109 is required for its pro-tumorigenic effects.\",\n      \"method\": \"Co-immunoprecipitation and immunofluorescence co-localization of CD109-EGFR, CD109 knockdown/knockout, mRNA and protein level analysis of EGFR, AKT phosphorylation, xenograft tumor models, spheroid formation\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus co-localization plus in vivo xenograft, single lab\",\n      \"pmids\": [\"35954339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Proteolytic cleavage of CD109 bait region by diverse proteases induces a conformational change that activates the CD109 thioester; activated CD109 conjugates proteases via its thioester and decreases their activity toward protein substrates, demonstrating CD109 is a protease inhibitor; the GPI-anchored MG8 domain dissociates during conformational change, enabling CD109 release from the cell surface by proteases rather than unspecific shedding.\",\n      \"method\": \"In vitro protease cleavage assays with diverse proteases, thioester activation assays, protease conjugation assays, activity inhibition assays, protease-induced membrane release experiments\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted biochemical assays demonstrating protease inhibition mechanism, thioester activation, and domain dissociation; multiple orthogonal in vitro methods\",\n      \"pmids\": [\"38587194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Three cryo-EM structures of CD109 in native, protease-activated, and methylamine-activated conformations reveal the structural mechanism of protease inhibition: protease cleavage of the bait region triggers a conformational change similar to A2ML1 (suggesting shared mechanism); CD109 glycans contribute to protease inhibition; deglycosylation enhances substrate access but does not affect chymotrypsin conjugation.\",\n      \"method\": \"Cryo-electron microscopy structure determination of three CD109 conformations, deglycosylation experiments, chymotrypsin conjugation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple cryo-EM structures at distinct conformational states with functional validation by conjugation assays\",\n      \"pmids\": [\"40482031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tumor-derived soluble CD109 (sCD109) upregulates CD73 mRNA transcription in macrophages by activating the FcγRI/SYK/NF-κB signaling pathway; sCD109 is internalized into macrophage cytoplasm and inhibits CD73 protein degradation by binding E3 ligase TRIM21, competing with CD73 for its binding site; this promotes enrichment of CD73+ tumor-associated macrophages that inhibit T-cell responses.\",\n      \"method\": \"Proteomic analysis, single-cell transcriptomics, mass spectrometry, NF-κB pathway activation assays, Co-IP of sCD109 with TRIM21 and CD73, CD73 protein stability assays, T-cell functional assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with TRIM21 plus NF-κB pathway assays, single lab, multiomics supported\",\n      \"pmids\": [\"40220905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD109 expression is required on conventional dendritic cells (cDC2s) for airway hyperreactivity and eosinophilic inflammation; CD109 is induced in lung cDC2s upon allergic challenge; CD109-deficient cDC2s have elevated RUNX3 expression and impaired ability to drive Th2 cytokine production and Th2 differentiation; adoptive transfer of CD109-deficient DCs fails to reconstitute AHR and eosinophilic inflammation.\",\n      \"method\": \"CD109 knockout mice, allergen sensitization models (HDM, OVA), ex vivo DC-T cell co-cultures, adoptive transfer of bone marrow-derived DCs, anti-CD109 monoclonal antibody treatment\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus adoptive transfer reconstitution plus pharmacological blockade; multiple models confirm cDC2-specific mechanism\",\n      \"pmids\": [\"36215676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD109 inhibits BMP signaling in osteosarcoma: CD109 knockdown enhances SMAD1/5/9 phosphorylation under BMP-2 stimulation and attenuates osteosarcoma cell migration; CD109 expression inversely correlates with pSMAD1/5/9 in human osteosarcoma tissue; no association found between CD109 and TGF-β signaling in osteosarcoma cells.\",\n      \"method\": \"CD109 siRNA knockdown, BMP-2 stimulation with pSMAD1/5/9 western blotting, in vitro wound healing assay, immunohistochemistry of human osteosarcoma tissue\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined BMP-signaling readout plus clinical tissue correlation, single lab\",\n      \"pmids\": [\"37030166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under mechanical force, CD109 expression on PDLSCs is upregulated (via miR-340-5p repression); CD109 suppresses osteogenesis of PDLSCs through the JAK/STAT3 signaling pathway and promotes osteoclast formation and M1 macrophage polarization through paracrine mechanisms; CD109 knockdown in vivo increases osteogenic activity and decreases osteoclast numbers and tooth movement.\",\n      \"method\": \"Mechanical force stimulation in vitro and rat tooth movement model in vivo, JAK/STAT3 pathway analysis, lentiviral shRNA injection, miR-340-5p functional studies, co-culture paracrine assays\",\n      \"journal\": \"Stem cells translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo genetic knockdown plus JAK/STAT3 pathway analysis plus miRNA mechanism, single lab\",\n      \"pmids\": [\"38885217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD109 interacts with and stabilizes IL-6 receptor alpha (IL6Rα) expression; CD109 promotes IL-6/STAT3/NRF2/SOD1/HO1 pathway activation in oral and vulvar SCC cells; CD109 loss attenuates this pathway, reducing cancer stemness and antioxidant protein expression.\",\n      \"method\": \"Co-immunoprecipitation of CD109 with IL6Rα, immunofluorescence and FACS co-localization, IL6Rα protein stability assays, STAT3/NRF2 pathway assays, CD109 knockdown/knockout, spheroid formation, multi-omic clinical validation\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional signaling assays plus clinical multi-omics validation, single lab\",\n      \"pmids\": [\"40317079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CD109 (a GPI-anchored protein on platelets) carries ABH blood group antigens; anti-A monoclonal antibodies react with CD109 on immunoprecipitation/immunoblotting; phosphatidylinositol-specific phospholipase C treatment releases a 175 kDa GPI-anchored protein (CD109) expressing blood group determinants.\",\n      \"method\": \"Immunoprecipitation/immunoblotting with monoclonal antibodies against glycoproteins and blood group antigens, PI-PLC cleavage and Western blot\",\n      \"journal\": \"The Journal of laboratory and clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical identification by Co-IP/WB and PI-PLC cleavage, single lab\",\n      \"pmids\": [\"9708575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Reduced CD109 expression in hepatocellular carcinoma tumor-associated endothelial cells promotes tumor progression through paracrine IL-8; CD109 knockdown in HUVEC activates TGF-β/Akt/NF-κB pathway, upregulating IL-8 secretion, which in turn promotes hepatoma cell proliferation, migration, and invasion; co-implantation with CD109 knockdown HUVEC accelerates tumor growth and metastasis in mice.\",\n      \"method\": \"CD109 knockdown in HUVEC, cytokine antibody array screening, IL-8 validation, TGF-β/Akt/NF-κB pathway analysis, co-culture assays, xenograft co-implantation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus cytokine identification plus in vivo co-implantation, single lab\",\n      \"pmids\": [\"27121053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"αv integrins in vascular smooth muscle cells act in concert with CD109 to regulate TGF-β signaling; αv SMKO mice show prolonged CD109 expression; CD109 overexpression in cultured VSMCs phenocopies αv integrin knockdown (attenuating collagen expression, TGF-β activation, and Smad2/3 signaling); CD109 and TGF-β receptor are co-internalized in early endosomes.\",\n      \"method\": \"αv integrin conditional knockout mice, transcriptomic analysis, CD109 overexpression in mouse and human VSMCs, Smad2/3 signaling assays, collagen expression assays, endosomal co-localization\",\n      \"journal\": \"European heart journal open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model plus in vitro gain-of-function phenocopy plus localization, single lab\",\n      \"pmids\": [\"36909248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD109 attenuates bleomycin-induced pulmonary fibrosis by inhibiting TGF-β signaling; CD109 transgenic mice show attenuated fibrosis; recombinant CD109 protein inhibits TGF-β signaling and decreases ACTA2 expression in lung fibroblasts in vitro and reduces pulmonary fibrosis in vivo upon administration.\",\n      \"method\": \"CD109 transgenic and CD109-/- mice in bleomycin model, recombinant CD109 protein in vitro signaling assays, in vivo recombinant protein administration, ACTA2 and TGF-β signaling readouts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both genetic overexpression and recombinant protein administration with in vitro and in vivo concordant results\",\n      \"pmids\": [\"38334455\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD109 is a GPI-anchored, thioester-containing glycoprotein of the alpha2-macroglobulin/complement family that functions as a multifunctional co-receptor and negative regulator of TGF-β signaling: at the cell surface it binds TGF-β receptors (requiring furin-mediated processing into 180/25 kDa fragments), recruits SMAD7/Smurf2 to promote TGFBR1 ubiquitin-mediated degradation, and directs TGF-β receptors into caveolae (via caveolin-1 association) for degradation; the soluble released form directly binds TGF-β with high affinity to sequester the ligand; CD109 also interacts with EGFR and IL-6 receptor alpha to promote EGFR/AKT and IL-6/STAT3/NRF2 signaling in cancer cells, interacts with GP130 to activate IL-6/STAT3 in glioblastoma stem cells, and with LTBP1 to modulate stromal TGF-β activation; structurally, protease cleavage of a bait region triggers a conformational change that activates its thioester, enabling covalent protease conjugation and inhibition, and releases the major fragment from the membrane, a mechanism now resolved by cryo-EM.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD109 is a GPI-anchored, thioester-containing glycoprotein of the alpha2-macroglobulin/complement family that operates as a cell-surface co-receptor and dominant negative regulator of TGF-\\u03b2 signaling while doubling as a thioester-dependent protease inhibitor [#0, #2, #30]. It is synthesized as a precursor that furin cleaves in the Golgi into associating 180/25 kDa fragments, and this processing is required for CD109 to bind T\\u03b2RI and to inhibit TGF-\\u03b2 responses [#3]. Membrane-bound CD109 suppresses TGF-\\u03b2 signaling by multiple convergent routes: it recruits SMAD7/Smurf2 to drive ligand-dependent ubiquitin-mediated TGFBR1 degradation [#5], associates with caveolin-1 to route TGF-\\u03b2 receptors into caveolae for internalization and degradation [#4], and acts together with cell-surface GRP78 to redirect receptor trafficking and block Smad2 activation under ER stress [#16]. A soluble, shed form binds TGF-\\u03b2 directly with high affinity and competes with receptor binding, thereby sequestering ligand [#12]. Across genetic models this TGF-\\u03b2-restraining activity controls keratinocyte differentiation, wound healing, and fibrosis, with CD109 loss producing epidermal hyperplasia via elevated STAT3 rather than Smad2 signaling and CD109 overexpression conferring resistance to skin and pulmonary fibrosis [#8, #10, #40]. Independent of TGF-\\u03b2 inhibition, CD109 forms surface complexes with EGFR, GP130, and IL-6R\\u03b1 to stabilize these receptors and amplify EGFR/AKT and IL-6/JAK-STAT3 signaling, driving tumor growth, metastasis, stemness, and chemoresistance in lung, glioblastoma, and squamous-cell cancers [#15, #21, #25, #29, #36]. Structurally, protease cleavage of a bait region triggers a conformational change that activates the internal thioester, enabling covalent conjugation and inhibition of the attacking protease and dissociation of the GPI-anchored MG8 domain to release CD109 from the membrane \\u2014 a mechanism resolved across native and activated cryo-EM conformations [#30, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Before molecular cloning, CD109 was characterized as a GPI-anchored platelet glycoprotein, establishing its membrane attachment mode and antigenic properties.\",\n      \"evidence\": \"Immunoprecipitation/immunoblotting and PI-PLC release of a 175 kDa GPI-anchored protein carrying ABH blood group determinants\",\n      \"pmids\": [\"9708575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No protein sequence or function defined\", \"Did not establish thioester or signaling roles\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Cloning placed CD109 in the alpha2-macroglobulin/complement thioester-containing protein family and demonstrated a reactive internal thioester, defining its biochemical class; in parallel, a single SNP was shown to determine the Gov/HPA-15 platelet alloantigens.\",\n      \"evidence\": \"cDNA cloning with biochemical thioester demonstration in native CD109; allele-specific genotyping plus CHO transfection and serology\",\n      \"pmids\": [\"11861284\", \"11861285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular function of the thioester not yet defined\", \"No receptor or signaling partners identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of CD109 as the keratinocyte TGF-\\u03b2-binding protein r150 established it as a negative modulator of TGF-\\u03b2 signaling acting on receptor activity rather than only by ligand sequestration.\",\n      \"evidence\": \"Affinity purification/microsequencing plus reciprocal siRNA loss- and overexpression gain-of-function with TGF-\\u03b2 signaling readouts\",\n      \"pmids\": [\"16754747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of receptor modulation unresolved\", \"Processing requirements unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Furin processing into 180/25 kDa fragments was shown to be obligatory for CD109 to bind T\\u03b2RI and inhibit TGF-\\u03b2 signaling, linking maturation to function.\",\n      \"evidence\": \"Site-directed mutagenesis of the furin site (R1273S), Co-IP with T\\u03b2RI, and signaling assays\",\n      \"pmids\": [\"20101215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve downstream degradation route\", \"Stoichiometry of receptor binding unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"CD109 was shown to inhibit TGF-\\u03b2 signaling by recruiting receptors into caveolae for degradation, and a soluble shed form was implicated in disease via enhanced release.\",\n      \"evidence\": \"Reciprocal Co-IP with caveolin-1, localization and receptor degradation assays; shedding and recombinant-protein experiments in keratinocytes with psoriatic skin histology\",\n      \"pmids\": [\"21295082\", \"21539622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for caveolar routing not defined\", \"Mechanism of STAT3 elevation by soluble CD109 unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The receptor-degradation mechanism was refined to a SMAD7/Smurf2-dependent ubiquitin pathway, and a knockout demonstrated CD109 controls keratinocyte differentiation in vivo via STAT3 rather than Smad2.\",\n      \"evidence\": \"Co-IP, SMAD7 siRNA and Smurf2 ligase-activity requirement assays; CD109 knockout mouse histology with pSTAT3/pSmad2 immunohistochemistry\",\n      \"pmids\": [\"21898545\", \"22846721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD109 loss elevates STAT3 mechanistically not defined\", \"Connection between TGF-\\u03b2 inhibition and STAT3 readout unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Epidermal CD109 overexpression dampened TGF-\\u03b2/Smad signaling, inflammation, and fibrosis in vivo, establishing CD109 as an anti-fibrotic regulator.\",\n      \"evidence\": \"CD109 transgenic mice in wound-healing and bleomycin scleroderma models with pSmad2/3 and ECM readouts; knockdown in RANKL-driven osteoclastogenesis\",\n      \"pmids\": [\"23438099\", \"23436317\", \"23593435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions not dissected\", \"Osteoclast mechanism only correlative\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantitative binding studies established that soluble CD109 directly sequesters TGF-\\u03b2, and surface CD109 was first linked to EGFR, broadening its receptor repertoire.\",\n      \"evidence\": \"SPR binding kinetics and radioligand competition with signaling readouts; Co-IP of CD109 with EGFR and exosome incorporation via truncation mutants\",\n      \"pmids\": [\"26621871\", \"25724945\", \"26707640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EGFR effects were cell-line-specific\", \"Exosomal cargo function unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CD109 was established as a driver of cancer metastasis through JAK-STAT3 activation, defining an oncogenic role distinct from its TGF-\\u03b2 suppression.\",\n      \"evidence\": \"In vivo tumor barcoding screen in mouse lung adenocarcinoma plus JAK inhibitor validation; differential ALK1/ALK5 regulation in transgenic epidermis\",\n      \"pmids\": [\"28191885\", \"27866969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating STAT3 activation not yet defined\", \"Reconciliation of pro- and anti-tumor roles unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An ER-stress-responsive mechanism was added wherein surface GRP78 partners with CD109 to reroute TGF-\\u03b2 receptors to caveolae, and a knockout revealed CD109 maintains bone homeostasis.\",\n      \"evidence\": \"Reciprocal Co-IP of GRP78 with CD109 plus IRE1\\u03b1/SRC/ASAP1 dissection; CD109 knockout micro-CT and bone histomorphometry\",\n      \"pmids\": [\"29654145\", \"29767469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of GRP78 mechanism beyond ER stress unclear\", \"Cellular target driving bone turnover not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic and antibody studies expanded CD109 into inflammatory and EMT contexts, showing it restrains gamma-delta-17 cells, NF-\\u03baB-driven synovial inflammation, and maintains epithelial identity.\",\n      \"evidence\": \"CD109 knockout mice in psoriasis/CIA models with IL-23 blockade and microbiota depletion; siRNA/antibody in RA FLSs; CRISPR knockout with recombinant rescue and SCC tumor IHC\",\n      \"pmids\": [\"31597099\", \"31455659\", \"31695056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating NF-\\u03baB regulation undefined\", \"Cell-extrinsic vs intrinsic contributions across tissues not fully separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies converged on CD109 stabilizing receptor signaling (EGFR/AKT/mTOR, YAP, EGFR/STAT3) and engaging LTBP1 to activate stromal TGF-\\u03b2, defining context-dependent oncogenic outputs.\",\n      \"evidence\": \"Co-IP with EGFR plus drug-sensitivity assays; mass-spec identification and Co-IP of LTBP1 with TGF-\\u03b2 activation assays in CD109-deficient lung adenocarcinoma model; YAP pathway and EGFR-STAT3 analyses with xenografts\",\n      \"pmids\": [\"32133706\", \"33007133\", \"33375719\", \"32507856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a TGF-\\u03b2 inhibitor activates stromal TGF-\\u03b2 via LTBP1 mechanistically unclear\", \"Direct vs indirect receptor stabilization not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CD109 was shown to partner with GP130 to sustain IL-6/STAT3 stemness in glioblastoma and to suppress TGF-\\u03b2-driven erythroid commitment in hematopoietic progenitors, linking its co-receptor activity to cell fate.\",\n      \"evidence\": \"Reciprocal Co-IP of CD109 with GP130, genetic depletion with STAT3/xenograft readouts; CD109 KO/KD in TF-1 and primary HSPCs with PNH patient analysis; meprin \\u03b2 cleavage and EV studies\",\n      \"pmids\": [\"33986188\", \"34743190\", \"33738281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting GP130 vs TGF-\\u03b2 receptor engagement unknown\", \"Physiological proteases releasing CD109 in vivo not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CD109 was extended to BMP signaling, dendritic-cell-driven allergic inflammation, and integrin-coupled vascular TGF-\\u03b2 control, demonstrating regulation of multiple TGF-\\u03b2-superfamily receptor systems.\",\n      \"evidence\": \"siRNA knockdown with pSMAD1/5/9 readouts and osteosarcoma IHC; CD109 KO mice with adoptive DC transfer and anti-CD109 antibody; \\u03b1v integrin conditional KO with CD109 gain-of-function phenocopy and endosomal co-localization\",\n      \"pmids\": [\"37030166\", \"36215676\", \"36909248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BMP inhibition uses the same machinery as TGF-\\u03b2 inhibition unclear\", \"Mechanistic link between CD109 and RUNX3 in cDC2s undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reconstituted biochemistry established CD109's long-predicted thioester function: protease cleavage of the bait region activates the thioester to conjugate and inhibit proteases and to release the protein from the membrane, and recombinant CD109 was confirmed anti-fibrotic in lung.\",\n      \"evidence\": \"In vitro protease cleavage, thioester activation, conjugation and inhibition assays with membrane-release experiments; CD109 transgenic/KO bleomycin lung models plus recombinant protein administration\",\n      \"pmids\": [\"38587194\", \"38334455\", \"38885217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological protease targets of the thioester in vivo unknown\", \"Relationship between protease-inhibitor and receptor-regulator activities unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM resolved the conformational basis of protease inhibition, and new partners (IL-6R\\u03b1, the sCD109/Fc\\u03b3RI/TRIM21/CD73 macrophage axis) extended CD109's reach into antioxidant signaling and tumor immune evasion.\",\n      \"evidence\": \"Cryo-EM of native and activated CD109 conformations with deglycosylation/conjugation assays; Co-IP of CD109 with IL6R\\u03b1 and of sCD109 with TRIM21/CD73 with NF-\\u03baB and T-cell functional assays\",\n      \"pmids\": [\"40482031\", \"40317079\", \"40220905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of receptor engagement (vs protease inhibition) not resolved\", \"In vivo relevance of CD73/TAM axis to therapy untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unclear how CD109's single thioester/conformational machinery is mechanistically partitioned between protease inhibition, TGF-\\u03b2 receptor degradation, and the stabilization of growth-factor receptors that yields its opposite pro-tumorigenic outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of CD109 bound to a TGF-\\u03b2 or growth-factor receptor\", \"Determinants of context-dependent signaling switching unknown\", \"Direct vs indirect nature of EGFR/GP130/IL6R\\u03b1 stabilization undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 5, 12, 30]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [30, 31]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 12, 25]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [12, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 4, 29, 37]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 6, 12, 13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [27, 28]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 5, 12, 25, 36]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 22, 25, 32]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 19, 33, 32]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 5, 27]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4, 16]}\n    ],\n    \"complexes\": [\"CD109\\u2013EGFR receptor complex\", \"TGF-\\u03b2 receptor system\"],\n    \"partners\": [\"TGFBR1\", \"CAV1\", \"SMAD7\", \"SMURF2\", \"EGFR\", \"IL6ST\", \"IL6R\", \"LTBP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}