{"gene":"ENG","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2017,"finding":"Crystal structures of the ectodomain of human endoglin (ENG) and its complex with BMP9 revealed that BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of ENG, which adopts a new duplicated fold generated by circular permutation. The interface involves residues mutated in HHT1 and overlaps with the epitope of anti-ENG monoclonal antibody TRC105. The C-terminal zona pellucida (ZP) module structure suggests how two copies of ENG embrace homodimeric BMP9, and BMP9 binding is compatible with type I but not type II receptor recognition.","method":"X-ray crystallography (crystal structures of ENG ectodomain alone and in complex with BMP9)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation, multiple structural entities resolved in a single rigorous study","pmids":["28564608"],"is_preprint":false},{"year":2004,"finding":"Overexpression of CD105/endoglin in rat myoblasts antagonized TGF-β1-mediated inhibition of cell proliferation and reduced TGF-β1-mediated Smad3/4-dependent transcriptional activity (CAGA-Luc reporter). CD105 reduced serine phosphorylation of Smad3 and inhibited subsequent nuclear translocation of Smad3. CD105 overexpression also led to high phosphorylation of JNK1, which activates c-Jun, a known inhibitor of Smad3 transcriptional activity, suggesting CD105 inhibits TGF-β1/Smad3 signaling partly through JNK1.","method":"CD105 transfection in rat myoblasts; luciferase reporter assays (p3TP-Lux, CAGA12-Luc); Western blot for phospho-Smad3; immunofluorescence for Smad3 nuclear translocation; Western blot for phospho-JNK1","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, phosphorylation, nuclear translocation), single lab","pmids":["15274293"],"is_preprint":false},{"year":2003,"finding":"CD105/endoglin attenuates apoptosis in hypoxic endothelial cells. Hypoxia upregulated CD105 mRNA and protein in human microvascular endothelial cells. Antisense-mediated suppression of CD105 increased apoptosis under hypoxic stress (in the absence of exogenous TGF-β1), and hypoxia plus TGF-β1 synergistically induced apoptosis in CD105-deficient but not control cells. The anti-apoptotic effect correlated with maintenance of Bcl-2/Bax ratio and Bcl-XL/Mcl-1 levels.","method":"Antisense oligonucleotide knockdown of CD105; TUNEL assay; Western blot for Bcl-2, Bax, Bcl-XL, Mcl-1, caspase-3/8; hypoxia chamber culture","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined apoptotic phenotype, multiple apoptosis markers measured, single lab","pmids":["12746487"],"is_preprint":false},{"year":2001,"finding":"CD105/endoglin is required for myelopoiesis and definitive erythropoiesis but not lymphopoiesis during early hematopoiesis from Flk1+ mesodermal precursors. CD105-deficient embryonic stem cells showed severely impaired myeloid and definitive erythroid differentiation in vitro, while lymphoid differentiation was only mildly affected.","method":"CD105-knockout murine embryonic stem cell differentiation in vitro; flow cytometry for hematopoietic lineage markers (CD45, Flk1); colony-forming assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined lineage-specific phenotypic readouts, multiple differentiation assays","pmids":["11739167"],"is_preprint":false},{"year":2015,"finding":"ENG/endoglin contains an RGD motif within its zona pellucida domain that mediates integrin-based interactions. Endothelial endoglin was shown to interact with leukocyte integrins and is involved in leukocyte trafficking and extravasation. Ectopic endoglin expression also represses the synthesis of several integrin family members and modulates integrin-mediated cell adhesion.","method":"Functional and gene/protein expression analysis; RGD motif identification; co-expression and cell adhesion assays (review summarizing experimental findings from multiple cited studies)","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple experimental lines cited but this paper is a review; confidence limited by abstract-level detail","pmids":["25709613"],"is_preprint":false},{"year":2017,"finding":"HCV core protein increases endoglin (CD105) cell-surface expression in hepatocytes, activates downstream ALK1-SMAD1/5 phosphorylation and upregulates ID1. Cancer stem-like cell (CSC) generation by HCV core protein was dependent on the endoglin-ALK1 signaling pathway, as shown by blockade with ALK1-Fc and endoglin siRNA knockdown, which abrogated HCV core-induced CSC properties and reduced antiapoptotic (Bcl2), proliferative (cyclin D1), and stemness (Hes1, Notch1, Nanog, Sox2) proteins.","method":"HCV core gene transfection in HepG2 and IHH cells; Western blot for phospho-SMAD1/5, ID1, Bcl2, cyclin D1, Nanog, Sox2, Hes1, Notch1; siRNA knockdown of endoglin; ALK1-Fc blocking; flow cytometry for CD105 surface expression","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (siRNA knockdown, pharmacological blockade, western blot, flow cytometry), single lab","pmids":["28794048"],"is_preprint":false},{"year":2018,"finding":"Radiation-induced CD105/endoglin signaling (downstream of BMP/TGF-β) was sufficient and necessary for upregulation of SIRT1, which in turn stabilized p53 and activated PGC-1α. This CD105-SIRT1 axis promoted DNA damage repair and metabolic (glycolytic and mitochondrial) recovery after irradiation, conferring radiation resistance in p53-functional prostate cancer cells. Blockade with anti-CD105 antibody TRC105 combined with irradiation depleted ATP stores, caused G2 arrest, delayed DNA damage repair, and reduced tumor growth in xenograft models.","method":"Anti-CD105 monoclonal antibody (TRC105) treatment; clonogenic survival assay; Western blot for SIRT1, p53, PGC-1α; DNA damage repair assays (γH2AX foci); xenograft tumor models; p53-null cell comparison","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods, single lab","pmids":["29717261"],"is_preprint":false},{"year":2018,"finding":"TGF-β1-induced formation of vascular-like networks by human cardiosphere-derived cells (hCDCs) in hyaluronic acid hydrogels was dependent on the co-activity of CD105/endoglin with TGF-βR2. Knockdown or blockade of CD105 abrogated TGF-β1-induced vascular network formation and associated nitric oxide and VEGF production.","method":"CD105 knockdown/blockade in hCDC; TGF-β1 stimulation in HA hydrogels; vascular network formation assay; nitric oxide and VEGF quantification","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined mechanistic pathway placement with loss-of-function, single lab, two orthogonal readouts","pmids":["29566045"],"is_preprint":false},{"year":2020,"finding":"Continuous endoglin/CD105 overexpression in endothelial cells disrupts normal angiogenesis by maintaining cells in an active phenotype that impairs endothelium stabilization and mural cell recruitment, resulting in vessels with incomplete mural coverage that permit extravasation and intravasation of tumor cells. In vitro and in vivo sprouting/vascularization models showed that endoglin overexpression does not stimulate sprouting but instead produces abnormal, leaky vessels.","method":"Stable endoglin overexpression in endothelial cells; in vitro sprouting assays; in vivo vascularization/tumor models; histological analysis of mural cell coverage and vessel integrity","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo models, single lab, clear gain-of-function phenotype","pmids":["31897911"],"is_preprint":false},{"year":2022,"finding":"IL-6-mediated AR splice variant (AR-V7) expression in prostate cancer cells and associated fibroblasts requires CD105/endoglin-dependent BMP signaling. Chromatin immunoprecipitation showed CD105-dependent ID1- and E2F-mediated expression of RBM38. RNA immunoprecipitation showed RBM38 binds the AR cryptic exon 3 to enable AR-V7 generation. Anti-CD105 antibody carotuximab downregulated AR-V7 expression in vitro and in cancer patients on combination treatment.","method":"ChIP for ID1/E2F occupancy; RNA immunoprecipitation (RIP) for RBM38-AR mRNA interaction; CD105 neutralizing antibody (carotuximab); AR-V7 expression by western blot; patient circulating tumor cell analysis","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal molecular methods (ChIP, RIP, antibody blockade) plus translational clinical correlation, single lab","pmids":["36045587"],"is_preprint":false},{"year":2024,"finding":"Certain HHT1-causing ENG missense variants (L32R, V105D, P165L, I271N, C363Y) are retained in the endoplasmic reticulum and form heterodimers with wild-type endoglin, reducing its maturation and plasma membrane localization through dominant negative effects, thereby exacerbating loss of endoglin function beyond simple haploinsufficiency.","method":"Co-immunoprecipitation of HA-tagged ER-retained mutants with Myc-tagged WT endoglin; surface biotinylation and western blot for plasma membrane localization; endoglycosidase H sensitivity (ER retention assay)","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP demonstrating heterodimer formation, biochemical trafficking assays with multiple variants, mechanistically rigorous single study","pmids":["38272447"],"is_preprint":false},{"year":2011,"finding":"5'UTR mutations in ENG (c.-127C>T and c.-9G>A) cause HHT by reducing endoglin protein levels. In vitro expression studies demonstrated that a construct bearing c.-127C>T alters translation initiation and decreases endoglin protein, and c.-9G>A acts as a hypomorphic mutation reducing protein levels.","method":"Sequencing of ENG 5'UTR in HHT patients; in vitro expression constructs with mutations; western blot for endoglin protein levels; linkage analysis","journal":"Orphanet journal of rare diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro expression assays with mutant constructs demonstrating reduced protein, supported by genetic evidence, single lab","pmids":["22192717"],"is_preprint":false}],"current_model":"Endoglin (ENG/CD105) is a homodimeric transmembrane co-receptor for TGF-β superfamily ligands (including TGF-β1, TGF-β3, and BMP9) that modulates signaling by interacting with TGF-β type I and II receptors; structurally, BMP9 binds the N-terminal orphan domain of ENG via a hydrophobic interface, and the C-terminal zona pellucida module enables homodimerization that embraces dimeric BMP9; functionally, ENG inhibits TGF-β1/Smad3 signaling (reducing Smad3 phosphorylation and nuclear translocation while activating JNK1/c-Jun), promotes endothelial cell survival under hypoxia through suppression of apoptotic pathways, is required for myeloid and definitive erythroid differentiation from Flk1+ progenitors, mediates leukocyte-endothelial interactions via its RGD motif and integrin binding, supports radiation resistance in prostate cancer through a CD105-BMP-SIRT1-PGC-1α axis, and drives AR-V7 splice variant generation via BMP/ID1/E2F/RBM38 signaling; HHT1-causing mutations can cause ER retention with dominant negative effects on wild-type endoglin trafficking, exacerbating haploinsufficiency."},"narrative":{"mechanistic_narrative":"Endoglin (ENG/CD105) is a homodimeric endothelial transmembrane co-receptor for TGF-β superfamily ligands that shapes angiogenesis, hematopoiesis, and endothelial homeostasis by modulating downstream Smad signaling [PMID:28564608, PMID:11739167]. Crystal structures of the ectodomain show that BMP9 docks onto a hydrophobic surface of ENG's N-terminal orphan domain, which adopts a circularly permuted duplicated fold, while the C-terminal zona pellucida (ZP) module mediates the homodimerization that lets two ENG copies embrace dimeric BMP9; this binding mode is compatible with type I but not type II receptor recognition, and the interface coincides with residues mutated in HHT1 [PMID:28564608]. ENG antagonizes TGF-β1/Smad3 signaling, reducing Smad3 phosphorylation and nuclear translocation while activating JNK1/c-Jun [PMID:15274293], and acts as a positive co-factor with TGF-βR2 in TGF-β1-driven vascular network formation [PMID:29566045]. Through its activity it promotes endothelial survival under hypoxic stress by preserving anti-apoptotic Bcl-2/Bcl-XL balance [PMID:12746487] and is required for myeloid and definitive erythroid differentiation from Flk1+ progenitors [PMID:11739167]; an RGD motif in the ZP domain mediates integrin engagement during leukocyte–endothelial interactions [PMID:25709613]. In disease and cancer contexts ENG feeds BMP/ALK1–SMAD1/5–ID1 signaling, supporting HCV-core-induced cancer stem-like cells [PMID:28794048], a radiation-resistance CD105–SIRT1–p53–PGC-1α axis in prostate cancer [PMID:29717261], and ID1/E2F/RBM38-dependent generation of the AR-V7 splice variant [PMID:36045587]. ENG haploinsufficiency causes hereditary hemorrhagic telangiectasia type 1 (HHT1), with certain missense variants retained in the ER where they heterodimerize with wild-type endoglin and block its maturation, exerting dominant-negative effects beyond simple haploinsufficiency [PMID:38272447, PMID:22192717].","teleology":[{"year":2001,"claim":"Established a developmental requirement for endoglin in blood cell formation, defining its earliest functional role beyond vascular biology.","evidence":"CD105-knockout murine embryonic stem cell differentiation with lineage flow cytometry and colony assays","pmids":["11739167"],"confidence":"High","gaps":["Does not identify the ligand/receptor partners driving the lineage defect","In vitro ES differentiation may not reflect in vivo fetal/adult hematopoiesis"]},{"year":2003,"claim":"Showed endoglin is a hypoxia-inducible survival factor for endothelial cells, linking it to apoptosis regulation independent of exogenous TGF-β1.","evidence":"Antisense knockdown in microvascular endothelial cells with TUNEL and Bcl-2/Bax/Bcl-XL/Mcl-1 westerns under hypoxia","pmids":["12746487"],"confidence":"Medium","gaps":["Antisense knockdown specificity not orthogonally confirmed","Signaling link between endoglin and Bcl-2 family regulation not mapped"]},{"year":2004,"claim":"Defined a mechanism by which endoglin restrains TGF-β1/Smad3 signaling, reframing it as a modulator rather than a simple ligand binder.","evidence":"CD105 transfection in rat myoblasts with CAGA/3TP luciferase reporters, phospho-Smad3 westerns, Smad3 nuclear translocation imaging, and phospho-JNK1 westerns","pmids":["15274293"],"confidence":"Medium","gaps":["Overexpression in myoblasts may not reflect endogenous endothelial stoichiometry","Causal link between JNK1/c-Jun activation and Smad3 inhibition is correlative"]},{"year":2011,"claim":"Demonstrated that non-coding 5'UTR mutations cause HHT by lowering endoglin protein, establishing dosage sensitivity at the translational level.","evidence":"Patient ENG 5'UTR sequencing plus in vitro mutant expression constructs with endoglin westerns and linkage analysis","pmids":["22192717"],"confidence":"Medium","gaps":["Quantitative threshold of endoglin loss required for disease not defined","Mechanism of altered translation initiation not resolved at nucleotide level"]},{"year":2015,"claim":"Identified an RGD-integrin functional module in the ZP domain, extending endoglin's role to leukocyte trafficking and adhesion.","evidence":"Review summarizing RGD motif identification, integrin co-expression, and cell adhesion assays from multiple cited studies","pmids":["25709613"],"confidence":"Medium","gaps":["Review-level synthesis without primary experimental detail in this entry","Specific integrin partners and binding affinities not delineated here"]},{"year":2017,"claim":"Resolved the structural basis of ligand recognition, explaining how BMP9 selects ENG and how HHT1 mutations and the TRC105 antibody epitope map onto the binding surface.","evidence":"X-ray crystal structures of the ENG ectodomain alone and bound to BMP9","pmids":["28564608"],"confidence":"High","gaps":["Does not capture the full ternary complex with type I/II receptors in membrane context","Does not address how ligand binding transduces to intracellular signaling"]},{"year":2017,"claim":"Placed endoglin within an oncogenic ALK1-SMAD1/5-ID1 axis driving cancer stem-like cell generation, expanding its role into BMP-arm signaling and tumorigenesis.","evidence":"HCV core transfection in HepG2/IHH cells with phospho-SMAD1/5 and ID1 westerns, endoglin siRNA, ALK1-Fc blockade, and CD105 flow cytometry","pmids":["28794048"],"confidence":"Medium","gaps":["Mechanism linking HCV core to increased endoglin surface expression unknown","Single cell-line system, single lab"]},{"year":2018,"claim":"Showed endoglin is a required co-activator with TGF-βR2 for TGF-β1-induced vascular network formation, distinguishing its positive role in vascularization.","evidence":"CD105 knockdown/blockade in cardiosphere-derived cells in HA hydrogels with network formation, NO and VEGF readouts","pmids":["29566045"],"confidence":"Medium","gaps":["Direct physical interaction with TGF-βR2 not demonstrated in this system","Findings in engineered hydrogel may not generalize to native vasculature"]},{"year":2018,"claim":"Defined a CD105-SIRT1-p53-PGC-1α axis conferring radiation resistance, connecting endoglin to DNA repair and metabolic recovery in cancer.","evidence":"TRC105 antibody blockade, clonogenic survival, SIRT1/p53/PGC-1α westerns, γH2AX foci, and prostate cancer xenografts with p53-null comparison","pmids":["29717261"],"confidence":"Medium","gaps":["How CD105 signaling upregulates SIRT1 mechanistically not resolved","Dependence restricted to p53-functional cells limits generalizability"]},{"year":2020,"claim":"Demonstrated that sustained endoglin overexpression produces abnormal leaky vessels with poor mural coverage, clarifying that endoglin levels must be tightly balanced for normal angiogenesis.","evidence":"Stable endoglin overexpression in endothelial cells with in vitro sprouting and in vivo vascularization/tumor models and histological mural coverage analysis","pmids":["31897911"],"confidence":"Medium","gaps":["Molecular effectors maintaining the 'active' endothelial phenotype not identified","Overexpression magnitude relative to pathological states not calibrated"]},{"year":2022,"claim":"Linked endoglin/BMP signaling to androgen receptor splice variant generation via an ID1/E2F/RBM38 cascade, identifying a therapeutic node for resistant prostate cancer.","evidence":"ChIP for ID1/E2F, RIP for RBM38-AR cryptic exon binding, carotuximab blockade, AR-V7 westerns, and patient circulating tumor cell analysis","pmids":["36045587"],"confidence":"Medium","gaps":["Direct chain from endoglin receptor activation to ID1 induction not fully mapped","Clinical correlation is observational"]},{"year":2024,"claim":"Showed that ER-retained HHT1 missense variants act as dominant negatives by heterodimerizing with wild-type endoglin, explaining disease severity beyond haploinsufficiency.","evidence":"Reciprocal co-IP of ER-retained mutants with WT endoglin, surface biotinylation, and endoglycosidase H ER-retention assays across multiple variants","pmids":["38272447"],"confidence":"High","gaps":["Quantitative contribution of dominant-negative effect versus haploinsufficiency in patients not measured","Whether all HHT1 missense variants behave this way not tested"]},{"year":null,"claim":"How endoglin's ligand-binding and co-receptor function is coupled to selective activation of the Smad2/3 versus Smad1/5 arms in different cell types and disease contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the full ENG–type I/type II receptor signaling complex","Context-dependent switching between TGF-β/Smad3 inhibition and BMP/Smad1/5 promotion not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,10]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11]}],"complexes":[],"partners":["BMP9","TGFBR2","ACVRL1","TGFB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17813","full_name":"Endoglin","aliases":[],"length_aa":658,"mass_kda":70.6,"function":"Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis (PubMed:21737454, PubMed:23300529). Required for normal structure and integrity of adult vasculature (PubMed:7894484). Regulates the migration of vascular endothelial cells (PubMed:17540773). Required for normal extraembryonic angiogenesis and for embryonic heart development (By similarity). May regulate endothelial cell shape changes in response to blood flow, which drive vascular remodeling and establishment of normal vascular morphology during angiogenesis (By similarity). May play a critical role in the binding of endothelial cells to integrins and/or other RGD receptors (PubMed:1692830). Acts as a TGF-beta coreceptor and is involved in the TGF-beta/BMP signaling cascade that ultimately leads to the activation of SMAD transcription factors (PubMed:21737454, PubMed:22347366, PubMed:23300529, PubMed:8370410). Required for GDF2/BMP9 signaling through SMAD1 in endothelial cells and modulates TGFB1 signaling through SMAD3 (PubMed:21737454, PubMed:22347366, PubMed:23300529)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P17813/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ENG","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ENG","total_profiled":1310},"omim":[{"mim_id":"619539","title":"NEUROOCULAR SYNDROME 1; NOC1","url":"https://www.omim.org/entry/619539"},{"mim_id":"619335","title":"GRANULE-ASSOCIATED RAC AND RHOG EFFECTOR 1; GARRE1","url":"https://www.omim.org/entry/619335"},{"mim_id":"618423","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 31; ANKRD31","url":"https://www.omim.org/entry/618423"},{"mim_id":"618421","title":"REC114 MEIOTIC RECOMBINATION PROTEIN; REC114","url":"https://www.omim.org/entry/618421"},{"mim_id":"617602","title":"CONGENITAL HEART DEFECTS AND SKELETAL MALFORMATIONS SYNDROME; CHDSKM","url":"https://www.omim.org/entry/617602"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":518.6}],"url":"https://www.proteinatlas.org/search/ENG"},"hgnc":{"alias_symbol":["END","HHT1","CD105"],"prev_symbol":["ORW1","ORW"]},"alphafold":{"accession":"P17813","domains":[{"cath_id":"-","chopping":"48-192","consensus_level":"high","plddt":87.9241,"start":48,"end":192},{"cath_id":"-","chopping":"204-327","consensus_level":"high","plddt":89.6394,"start":204,"end":327},{"cath_id":"2.60.40.3210","chopping":"351-445","consensus_level":"high","plddt":84.0946,"start":351,"end":445},{"cath_id":"2.60.40.4100","chopping":"448-573","consensus_level":"high","plddt":82.1324,"start":448,"end":573}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17813","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17813-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17813-F1-predicted_aligned_error_v6.png","plddt_mean":80.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ENG","jax_strain_url":"https://www.jax.org/strain/search?query=ENG"},"sequence":{"accession":"P17813","fasta_url":"https://rest.uniprot.org/uniprotkb/P17813.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17813/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17813"}},"corpus_meta":[{"pmid":"9476899","id":"PMC_9476899","title":"TRF2 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The interface involves residues mutated in HHT1 and overlaps with the epitope of anti-ENG monoclonal antibody TRC105. The C-terminal zona pellucida (ZP) module structure suggests how two copies of ENG embrace homodimeric BMP9, and BMP9 binding is compatible with type I but not type II receptor recognition.\",\n      \"method\": \"X-ray crystallography (crystal structures of ENG ectodomain alone and in complex with BMP9)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation, multiple structural entities resolved in a single rigorous study\",\n      \"pmids\": [\"28564608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Overexpression of CD105/endoglin in rat myoblasts antagonized TGF-β1-mediated inhibition of cell proliferation and reduced TGF-β1-mediated Smad3/4-dependent transcriptional activity (CAGA-Luc reporter). CD105 reduced serine phosphorylation of Smad3 and inhibited subsequent nuclear translocation of Smad3. CD105 overexpression also led to high phosphorylation of JNK1, which activates c-Jun, a known inhibitor of Smad3 transcriptional activity, suggesting CD105 inhibits TGF-β1/Smad3 signaling partly through JNK1.\",\n      \"method\": \"CD105 transfection in rat myoblasts; luciferase reporter assays (p3TP-Lux, CAGA12-Luc); Western blot for phospho-Smad3; immunofluorescence for Smad3 nuclear translocation; Western blot for phospho-JNK1\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, phosphorylation, nuclear translocation), single lab\",\n      \"pmids\": [\"15274293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD105/endoglin attenuates apoptosis in hypoxic endothelial cells. Hypoxia upregulated CD105 mRNA and protein in human microvascular endothelial cells. Antisense-mediated suppression of CD105 increased apoptosis under hypoxic stress (in the absence of exogenous TGF-β1), and hypoxia plus TGF-β1 synergistically induced apoptosis in CD105-deficient but not control cells. The anti-apoptotic effect correlated with maintenance of Bcl-2/Bax ratio and Bcl-XL/Mcl-1 levels.\",\n      \"method\": \"Antisense oligonucleotide knockdown of CD105; TUNEL assay; Western blot for Bcl-2, Bax, Bcl-XL, Mcl-1, caspase-3/8; hypoxia chamber culture\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined apoptotic phenotype, multiple apoptosis markers measured, single lab\",\n      \"pmids\": [\"12746487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD105/endoglin is required for myelopoiesis and definitive erythropoiesis but not lymphopoiesis during early hematopoiesis from Flk1+ mesodermal precursors. CD105-deficient embryonic stem cells showed severely impaired myeloid and definitive erythroid differentiation in vitro, while lymphoid differentiation was only mildly affected.\",\n      \"method\": \"CD105-knockout murine embryonic stem cell differentiation in vitro; flow cytometry for hematopoietic lineage markers (CD45, Flk1); colony-forming assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined lineage-specific phenotypic readouts, multiple differentiation assays\",\n      \"pmids\": [\"11739167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ENG/endoglin contains an RGD motif within its zona pellucida domain that mediates integrin-based interactions. Endothelial endoglin was shown to interact with leukocyte integrins and is involved in leukocyte trafficking and extravasation. Ectopic endoglin expression also represses the synthesis of several integrin family members and modulates integrin-mediated cell adhesion.\",\n      \"method\": \"Functional and gene/protein expression analysis; RGD motif identification; co-expression and cell adhesion assays (review summarizing experimental findings from multiple cited studies)\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple experimental lines cited but this paper is a review; confidence limited by abstract-level detail\",\n      \"pmids\": [\"25709613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HCV core protein increases endoglin (CD105) cell-surface expression in hepatocytes, activates downstream ALK1-SMAD1/5 phosphorylation and upregulates ID1. Cancer stem-like cell (CSC) generation by HCV core protein was dependent on the endoglin-ALK1 signaling pathway, as shown by blockade with ALK1-Fc and endoglin siRNA knockdown, which abrogated HCV core-induced CSC properties and reduced antiapoptotic (Bcl2), proliferative (cyclin D1), and stemness (Hes1, Notch1, Nanog, Sox2) proteins.\",\n      \"method\": \"HCV core gene transfection in HepG2 and IHH cells; Western blot for phospho-SMAD1/5, ID1, Bcl2, cyclin D1, Nanog, Sox2, Hes1, Notch1; siRNA knockdown of endoglin; ALK1-Fc blocking; flow cytometry for CD105 surface expression\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (siRNA knockdown, pharmacological blockade, western blot, flow cytometry), single lab\",\n      \"pmids\": [\"28794048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Radiation-induced CD105/endoglin signaling (downstream of BMP/TGF-β) was sufficient and necessary for upregulation of SIRT1, which in turn stabilized p53 and activated PGC-1α. This CD105-SIRT1 axis promoted DNA damage repair and metabolic (glycolytic and mitochondrial) recovery after irradiation, conferring radiation resistance in p53-functional prostate cancer cells. Blockade with anti-CD105 antibody TRC105 combined with irradiation depleted ATP stores, caused G2 arrest, delayed DNA damage repair, and reduced tumor growth in xenograft models.\",\n      \"method\": \"Anti-CD105 monoclonal antibody (TRC105) treatment; clonogenic survival assay; Western blot for SIRT1, p53, PGC-1α; DNA damage repair assays (γH2AX foci); xenograft tumor models; p53-null cell comparison\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods, single lab\",\n      \"pmids\": [\"29717261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TGF-β1-induced formation of vascular-like networks by human cardiosphere-derived cells (hCDCs) in hyaluronic acid hydrogels was dependent on the co-activity of CD105/endoglin with TGF-βR2. Knockdown or blockade of CD105 abrogated TGF-β1-induced vascular network formation and associated nitric oxide and VEGF production.\",\n      \"method\": \"CD105 knockdown/blockade in hCDC; TGF-β1 stimulation in HA hydrogels; vascular network formation assay; nitric oxide and VEGF quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined mechanistic pathway placement with loss-of-function, single lab, two orthogonal readouts\",\n      \"pmids\": [\"29566045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Continuous endoglin/CD105 overexpression in endothelial cells disrupts normal angiogenesis by maintaining cells in an active phenotype that impairs endothelium stabilization and mural cell recruitment, resulting in vessels with incomplete mural coverage that permit extravasation and intravasation of tumor cells. In vitro and in vivo sprouting/vascularization models showed that endoglin overexpression does not stimulate sprouting but instead produces abnormal, leaky vessels.\",\n      \"method\": \"Stable endoglin overexpression in endothelial cells; in vitro sprouting assays; in vivo vascularization/tumor models; histological analysis of mural cell coverage and vessel integrity\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo models, single lab, clear gain-of-function phenotype\",\n      \"pmids\": [\"31897911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-6-mediated AR splice variant (AR-V7) expression in prostate cancer cells and associated fibroblasts requires CD105/endoglin-dependent BMP signaling. Chromatin immunoprecipitation showed CD105-dependent ID1- and E2F-mediated expression of RBM38. RNA immunoprecipitation showed RBM38 binds the AR cryptic exon 3 to enable AR-V7 generation. Anti-CD105 antibody carotuximab downregulated AR-V7 expression in vitro and in cancer patients on combination treatment.\",\n      \"method\": \"ChIP for ID1/E2F occupancy; RNA immunoprecipitation (RIP) for RBM38-AR mRNA interaction; CD105 neutralizing antibody (carotuximab); AR-V7 expression by western blot; patient circulating tumor cell analysis\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal molecular methods (ChIP, RIP, antibody blockade) plus translational clinical correlation, single lab\",\n      \"pmids\": [\"36045587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Certain HHT1-causing ENG missense variants (L32R, V105D, P165L, I271N, C363Y) are retained in the endoplasmic reticulum and form heterodimers with wild-type endoglin, reducing its maturation and plasma membrane localization through dominant negative effects, thereby exacerbating loss of endoglin function beyond simple haploinsufficiency.\",\n      \"method\": \"Co-immunoprecipitation of HA-tagged ER-retained mutants with Myc-tagged WT endoglin; surface biotinylation and western blot for plasma membrane localization; endoglycosidase H sensitivity (ER retention assay)\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP demonstrating heterodimer formation, biochemical trafficking assays with multiple variants, mechanistically rigorous single study\",\n      \"pmids\": [\"38272447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"5'UTR mutations in ENG (c.-127C>T and c.-9G>A) cause HHT by reducing endoglin protein levels. In vitro expression studies demonstrated that a construct bearing c.-127C>T alters translation initiation and decreases endoglin protein, and c.-9G>A acts as a hypomorphic mutation reducing protein levels.\",\n      \"method\": \"Sequencing of ENG 5'UTR in HHT patients; in vitro expression constructs with mutations; western blot for endoglin protein levels; linkage analysis\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro expression assays with mutant constructs demonstrating reduced protein, supported by genetic evidence, single lab\",\n      \"pmids\": [\"22192717\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Endoglin (ENG/CD105) is a homodimeric transmembrane co-receptor for TGF-β superfamily ligands (including TGF-β1, TGF-β3, and BMP9) that modulates signaling by interacting with TGF-β type I and II receptors; structurally, BMP9 binds the N-terminal orphan domain of ENG via a hydrophobic interface, and the C-terminal zona pellucida module enables homodimerization that embraces dimeric BMP9; functionally, ENG inhibits TGF-β1/Smad3 signaling (reducing Smad3 phosphorylation and nuclear translocation while activating JNK1/c-Jun), promotes endothelial cell survival under hypoxia through suppression of apoptotic pathways, is required for myeloid and definitive erythroid differentiation from Flk1+ progenitors, mediates leukocyte-endothelial interactions via its RGD motif and integrin binding, supports radiation resistance in prostate cancer through a CD105-BMP-SIRT1-PGC-1α axis, and drives AR-V7 splice variant generation via BMP/ID1/E2F/RBM38 signaling; HHT1-causing mutations can cause ER retention with dominant negative effects on wild-type endoglin trafficking, exacerbating haploinsufficiency.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Endoglin (ENG/CD105) is a homodimeric endothelial transmembrane co-receptor for TGF-β superfamily ligands that shapes angiogenesis, hematopoiesis, and endothelial homeostasis by modulating downstream Smad signaling [#0, #3]. Crystal structures of the ectodomain show that BMP9 docks onto a hydrophobic surface of ENG's N-terminal orphan domain, which adopts a circularly permuted duplicated fold, while the C-terminal zona pellucida (ZP) module mediates the homodimerization that lets two ENG copies embrace dimeric BMP9; this binding mode is compatible with type I but not type II receptor recognition, and the interface coincides with residues mutated in HHT1 [#0]. ENG antagonizes TGF-β1/Smad3 signaling, reducing Smad3 phosphorylation and nuclear translocation while activating JNK1/c-Jun [#1], and acts as a positive co-factor with TGF-βR2 in TGF-β1-driven vascular network formation [#7]. Through its activity it promotes endothelial survival under hypoxic stress by preserving anti-apoptotic Bcl-2/Bcl-XL balance [#2] and is required for myeloid and definitive erythroid differentiation from Flk1+ progenitors [#3]; an RGD motif in the ZP domain mediates integrin engagement during leukocyte–endothelial interactions [#4]. In disease and cancer contexts ENG feeds BMP/ALK1–SMAD1/5–ID1 signaling, supporting HCV-core-induced cancer stem-like cells [#5], a radiation-resistance CD105–SIRT1–p53–PGC-1α axis in prostate cancer [#6], and ID1/E2F/RBM38-dependent generation of the AR-V7 splice variant [#9]. ENG haploinsufficiency causes hereditary hemorrhagic telangiectasia type 1 (HHT1), with certain missense variants retained in the ER where they heterodimerize with wild-type endoglin and block its maturation, exerting dominant-negative effects beyond simple haploinsufficiency [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established a developmental requirement for endoglin in blood cell formation, defining its earliest functional role beyond vascular biology.\",\n      \"evidence\": \"CD105-knockout murine embryonic stem cell differentiation with lineage flow cytometry and colony assays\",\n      \"pmids\": [\"11739167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the ligand/receptor partners driving the lineage defect\", \"In vitro ES differentiation may not reflect in vivo fetal/adult hematopoiesis\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed endoglin is a hypoxia-inducible survival factor for endothelial cells, linking it to apoptosis regulation independent of exogenous TGF-β1.\",\n      \"evidence\": \"Antisense knockdown in microvascular endothelial cells with TUNEL and Bcl-2/Bax/Bcl-XL/Mcl-1 westerns under hypoxia\",\n      \"pmids\": [\"12746487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antisense knockdown specificity not orthogonally confirmed\", \"Signaling link between endoglin and Bcl-2 family regulation not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a mechanism by which endoglin restrains TGF-β1/Smad3 signaling, reframing it as a modulator rather than a simple ligand binder.\",\n      \"evidence\": \"CD105 transfection in rat myoblasts with CAGA/3TP luciferase reporters, phospho-Smad3 westerns, Smad3 nuclear translocation imaging, and phospho-JNK1 westerns\",\n      \"pmids\": [\"15274293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression in myoblasts may not reflect endogenous endothelial stoichiometry\", \"Causal link between JNK1/c-Jun activation and Smad3 inhibition is correlative\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that non-coding 5'UTR mutations cause HHT by lowering endoglin protein, establishing dosage sensitivity at the translational level.\",\n      \"evidence\": \"Patient ENG 5'UTR sequencing plus in vitro mutant expression constructs with endoglin westerns and linkage analysis\",\n      \"pmids\": [\"22192717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative threshold of endoglin loss required for disease not defined\", \"Mechanism of altered translation initiation not resolved at nucleotide level\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified an RGD-integrin functional module in the ZP domain, extending endoglin's role to leukocyte trafficking and adhesion.\",\n      \"evidence\": \"Review summarizing RGD motif identification, integrin co-expression, and cell adhesion assays from multiple cited studies\",\n      \"pmids\": [\"25709613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis without primary experimental detail in this entry\", \"Specific integrin partners and binding affinities not delineated here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the structural basis of ligand recognition, explaining how BMP9 selects ENG and how HHT1 mutations and the TRC105 antibody epitope map onto the binding surface.\",\n      \"evidence\": \"X-ray crystal structures of the ENG ectodomain alone and bound to BMP9\",\n      \"pmids\": [\"28564608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not capture the full ternary complex with type I/II receptors in membrane context\", \"Does not address how ligand binding transduces to intracellular signaling\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed endoglin within an oncogenic ALK1-SMAD1/5-ID1 axis driving cancer stem-like cell generation, expanding its role into BMP-arm signaling and tumorigenesis.\",\n      \"evidence\": \"HCV core transfection in HepG2/IHH cells with phospho-SMAD1/5 and ID1 westerns, endoglin siRNA, ALK1-Fc blockade, and CD105 flow cytometry\",\n      \"pmids\": [\"28794048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking HCV core to increased endoglin surface expression unknown\", \"Single cell-line system, single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed endoglin is a required co-activator with TGF-βR2 for TGF-β1-induced vascular network formation, distinguishing its positive role in vascularization.\",\n      \"evidence\": \"CD105 knockdown/blockade in cardiosphere-derived cells in HA hydrogels with network formation, NO and VEGF readouts\",\n      \"pmids\": [\"29566045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction with TGF-βR2 not demonstrated in this system\", \"Findings in engineered hydrogel may not generalize to native vasculature\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a CD105-SIRT1-p53-PGC-1α axis conferring radiation resistance, connecting endoglin to DNA repair and metabolic recovery in cancer.\",\n      \"evidence\": \"TRC105 antibody blockade, clonogenic survival, SIRT1/p53/PGC-1α westerns, γH2AX foci, and prostate cancer xenografts with p53-null comparison\",\n      \"pmids\": [\"29717261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CD105 signaling upregulates SIRT1 mechanistically not resolved\", \"Dependence restricted to p53-functional cells limits generalizability\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that sustained endoglin overexpression produces abnormal leaky vessels with poor mural coverage, clarifying that endoglin levels must be tightly balanced for normal angiogenesis.\",\n      \"evidence\": \"Stable endoglin overexpression in endothelial cells with in vitro sprouting and in vivo vascularization/tumor models and histological mural coverage analysis\",\n      \"pmids\": [\"31897911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors maintaining the 'active' endothelial phenotype not identified\", \"Overexpression magnitude relative to pathological states not calibrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked endoglin/BMP signaling to androgen receptor splice variant generation via an ID1/E2F/RBM38 cascade, identifying a therapeutic node for resistant prostate cancer.\",\n      \"evidence\": \"ChIP for ID1/E2F, RIP for RBM38-AR cryptic exon binding, carotuximab blockade, AR-V7 westerns, and patient circulating tumor cell analysis\",\n      \"pmids\": [\"36045587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chain from endoglin receptor activation to ID1 induction not fully mapped\", \"Clinical correlation is observational\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that ER-retained HHT1 missense variants act as dominant negatives by heterodimerizing with wild-type endoglin, explaining disease severity beyond haploinsufficiency.\",\n      \"evidence\": \"Reciprocal co-IP of ER-retained mutants with WT endoglin, surface biotinylation, and endoglycosidase H ER-retention assays across multiple variants\",\n      \"pmids\": [\"38272447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of dominant-negative effect versus haploinsufficiency in patients not measured\", \"Whether all HHT1 missense variants behave this way not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How endoglin's ligand-binding and co-receptor function is coupled to selective activation of the Smad2/3 versus Smad1/5 arms in different cell types and disease contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the full ENG–type I/type II receptor signaling complex\", \"Context-dependent switching between TGF-β/Smad3 inhibition and BMP/Smad1/5 promotion not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 10]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BMP9\", \"TGFBR2\", \"ACVRL1\", \"TGFB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}