{"gene":"ACVR2B","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2015,"finding":"Activin A binds ACVR2A and ACVR2B and antagonizes BMP-6 and BMP-9 signaling through these type II receptors in combination with ALK2, but does not antagonize BMPs that signal through BMPR2 with ALK3/ALK6, establishing ACVR2B as a shared receptor for both activin and select BMP ligands whose competitive occupancy regulates downstream signaling.","method":"Cell-based ligand competition assays using myeloma cell lines with characterized BMP-receptor expression; receptor-specific functional readouts","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assays with multiple ligand/receptor combinations, single lab, two orthogonal approaches (receptor expression characterization + functional antagonism assays)","pmids":["26047946"],"is_preprint":false},{"year":2011,"finding":"BMP3 suppresses osteoblast differentiation of bone marrow stromal cells through interaction with ACVR2B; knockdown of endogenous Acvr2b reduces the suppressive effect of BMP3 on osteoblast differentiation, placing ACVR2B as the receptor mediating BMP3's inhibitory role in skeletal progenitor cells.","method":"In vitro primary bone marrow stromal cell cultures; BMP3 overexpression and loss-of-function; siRNA knockdown of Acvr2b; colony-forming unit assays","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (siRNA) with defined cellular phenotype, overexpression corroboration, single lab","pmids":["22074949"],"is_preprint":false},{"year":2020,"finding":"ACVR2A and ACVR2B are both required in gonadotrope cells for activin-induced FSH production in vivo; gonadotrope-specific double knockout of Acvr2a and Acvr2b leads to profound FSH deficiency, hypogonadism, and sterility in both sexes, while single knockouts produce partial FSH deficiencies.","method":"Conditional knockout using Cre-lox strategy in murine gonadotropes; serum FSH measurement; fertility and gonadal phenotyping","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo conditional knockout with defined hormonal and reproductive phenotype, double and single KO comparison providing epistatic resolution, replicated across sexes","pmids":["32270195"],"is_preprint":false},{"year":2019,"finding":"Systemic blockade of ACVR2B ligands with soluble ACVR2B-Fc antagonizes SMAD2 signaling and cardiomyocyte death under hypoxic stress; ACVR2B-Fc was protective against cardiac ischemia-reperfusion injury in vivo, reducing infarct area and apoptosis, and modifying LV mitochondrial respiration and cardiac metabolism.","method":"In vivo mouse cardiac ischemia-reperfusion model with ACVR2B-Fc treatment; in vitro cardiomyocyte hypoxia assay; echocardiography; SMAD2 phosphorylation assay","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function (ligand blockade) with defined cardiac phenotype plus in vitro mechanistic corroboration (SMAD2 signaling), single lab","pmids":["30765322"],"is_preprint":false},{"year":2023,"finding":"In osteoarthritis, activin A signals through ACVR2B/ACVR1B to activate NOX4-dependent ROS production and amplify SMAD2/3 signaling and catabolic factor expression; NOX4 directly binds the C-terminal binding site on ACVR2B-ACVR1B and amplifies the pathogenic signal for cartilage destruction.","method":"In silico analysis; transgenic and knockout mouse models (Col2a1-Inhba, Inhba+/-, Nox4-/-); shRNA knockdown of ACVR2B; protein-protein interaction studies","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo genetic models plus direct binding studies, single lab, multiple orthogonal methods","pmids":["36950748"],"is_preprint":false},{"year":2024,"finding":"ACVR2B forms stable homomeric complexes that are enhanced by Activin A, whereas ACVR2A requires Activin A for homodimerization; ACVR2B forms heterocomplexes with ALK2-R206H independent of ligand and activates FOP-inducing SMAD1/5/8 signaling without Activin A, while ACVR2A requires Activin A for ALK2-R206H oligomerization and activation.","method":"IgG-mediated receptor immobilization combined with FRAP (fluorescence recovery after photobleaching) to quantify homomeric and heteromeric receptor interactions; pSMAD1/5/8 western blot; BRE-Luc transcriptional reporter assay","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative biophysical method (FRAP) combined with mutagenesis (R206H) and functional signaling readouts (pSMAD1/5/8, reporter), multiple orthogonal methods in single rigorous study","pmids":["38334613"],"is_preprint":false},{"year":2025,"finding":"In zebrafish, maternal-zygotic depletion of Acvr2b receptors abrogates all BMP signaling in dorsoventral patterning, establishing Acvr2b as the primary type II receptor transducing BMP signaling in the gastrula; additionally, Acvr2b dosage restricts hyperactive ACVR1-R206H (FOP mutant) signaling in a dose-dependent manner.","method":"Genetic mutation of all four acvr2a and acvr2b zebrafish genes; maternal-zygotic depletion; BMP signaling readouts; FOP ACVR1-R206H epistasis assay","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous genetic epistasis in zebrafish with complete maternal-zygotic depletion, ortholog study, preprint not yet peer-reviewed","pmids":["41279820"],"is_preprint":true},{"year":2012,"finding":"Sea bream Acvr2b extracellular domain (Acvr2b-ECD), expressed in yeast and N-glycosylated, inhibits recombinant MSTN activity in vitro, demonstrating that the extracellular domain of ACVR2B is sufficient to bind and neutralize myostatin; evidence also found for gene duplication generating two acvr2b paralogs in fish.","method":"Yeast expression of Acvr2b-ECD; CAGA-luciferase reporter in vitro assay; N-glycosylation analysis","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution assay demonstrating direct ligand binding/inhibition, single lab, single method","pmids":["22911153"],"is_preprint":false},{"year":2005,"finding":"Zebrafish acvr2b morpholino depletion produces defects restricted to posterior craniofacial arch structures, including absent/aberrant migration of posterior neural crest cell streams and defects in posterior arch cartilages and pharyngeal tooth development, establishing a distinct role for Acvr2b (vs. Acvr2a) in posterior neural crest patterning.","method":"Morpholino-based targeted protein depletion in zebrafish; phenotypic analysis of neural crest-derived structures","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular and structural phenotype in vivo, ortholog study, comparison to acvr2a morphants providing functional distinction","pmids":["15977175"],"is_preprint":false},{"year":2018,"finding":"Spermidine represses H3K56 acetylation at the ACVR2B promoter, reducing ACVR2B transcription, and lowers the binding affinity of Smad3 to promoters of myogenic genes Myf5 and MyoD in satellite cells, linking ACVR2B promoter chromatin state to downstream myogenic gene regulation.","method":"ChIP assay measuring H3K56ac at ACVR2B promoter and Smad3 binding at Myf5/MyoD promoters in spermidine-treated mouse satellite cells","journal":"Journal of agricultural and food chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP assay, single lab, no direct functional link between ACVR2B promoter acetylation change and downstream phenotype established","pmids":["29224337"],"is_preprint":false},{"year":2024,"finding":"ACVR2B-Fc fusion protein, secreted by iPSC-derived mesenchymal stromal cells, attenuates BMP signaling activated by Activin-A and BMP-9 in FOP patient-derived iMSCs in vitro, and transplantation of these cells reduces primary heterotopic ossification in FOP transgenic mice (ACVR1-R206H), demonstrating ACVR2B-Fc blocks aberrant BMP/Activin signaling in FOP pathogenesis.","method":"In vitro BMP signaling inhibition assay in iMSCs; in vivo transplantation in FOP mouse model; treadmill performance assay","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro signaling assay combined with in vivo functional rescue in disease model, single lab, two orthogonal approaches","pmids":["38500216"],"is_preprint":false},{"year":2021,"finding":"Exosomal miRNAs (let-7a-5p, let-7c-5p, miR-328a-5p, miR-31a-5p) target Acvr2b/Acvr1 and regulate the competitive balance between Bmpr2/Acvr2b signaling, shifting it toward Bmpr-elicited Smad1/5/9 phosphorylation to promote osteoblast differentiation.","method":"miRNA microarray; in vitro pathway verification by gene silencing (siRNA) and miRNA transfection; Smad1/5/9 phosphorylation readout","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene silencing combined with miRNA transfection and downstream SMAD phosphorylation readout, single lab, two orthogonal methods","pmids":["33838528"],"is_preprint":false}],"current_model":"ACVR2B is a type II serine/threonine kinase receptor in the TGF-β superfamily that forms ligand-enhanced homomeric complexes and heteromeric complexes with type I receptors (ALK2/ACVR1, ALK4/ACVR1B) to transduce signals from activins, myostatin, BMP3, and select BMPs (BMP-6, BMP-9) via SMAD2/3 or SMAD1/5/8 phosphorylation; its extracellular domain competitively binds multiple ligands to modulate BMP versus activin signaling balance, it is the primary type II receptor transducing BMP signaling in early vertebrate embryogenesis, it is required with ACVR2A for activin-driven FSH production in gonadotropes, and its ligand-independent homodimerization enables constitutive activation of the FOP-causing ALK2-R206H mutant."},"narrative":{"mechanistic_narrative":"ACVR2B is a type II receptor of the TGF-β superfamily that serves as a shared, ligand-competitive hub transducing signals from activins, myostatin, and select BMPs to determine the balance of downstream SMAD activation [PMID:26047946, PMID:22911153]. Its extracellular domain alone is sufficient to bind and neutralize myostatin, and soluble ACVR2B-Fc traps act as broad ligand antagonists [PMID:22911153]. Activin A binds ACVR2B and, in combination with type I receptors such as ALK2, antagonizes BMP-6 and BMP-9 signaling, so that competitive ligand occupancy of ACVR2B sets the BMP-versus-activin signaling balance [PMID:26047946]; this balance is itself tunable through exosomal miRNA control of receptor levels that shifts signaling toward BMPR2-elicited SMAD1/5/9 phosphorylation during osteoblast differentiation [PMID:33838528]. ACVR2B forms stable homomeric complexes enhanced by Activin A and constitutively assembles ligand-independent heterocomplexes with the FOP-causing ALK2-R206H mutant, enabling its aberrant SMAD1/5/8 activation; ACVR2B receptor dosage dose-dependently restricts this hyperactive ACVR1-R206H signaling [PMID:38334613, PMID:41279820]. In development, ACVR2B is the primary type II receptor transducing BMP signaling in the gastrula and is required for posterior neural crest patterning [PMID:41279820, PMID:15977175]. Physiologically, ACVR2B acts redundantly with ACVR2A to drive activin-dependent FSH production in gonadotropes, with double loss causing FSH deficiency, hypogonadism and sterility [PMID:32270195], and it mediates pathogenic signaling in skeletal and joint tissue, transducing BMP3-dependent suppression of osteoblast differentiation [PMID:22074949] and activin A-driven, NOX4-amplified catabolic SMAD2/3 signaling in osteoarthritic cartilage [PMID:36950748].","teleology":[{"year":2005,"claim":"Established a developmental role for ACVR2B distinct from its paralog by showing it patterns a specific embryonic territory.","evidence":"Morpholino depletion of acvr2b in zebrafish with phenotyping of neural crest-derived structures","pmids":["15977175"],"confidence":"Medium","gaps":["Did not identify the ligand driving posterior neural crest patterning","Morpholino specificity not corroborated by genetic mutant","Downstream SMAD branch not resolved"]},{"year":2011,"claim":"Identified ACVR2B as the receptor through which BMP3 inhibits skeletal progenitor commitment, assigning a defined ligand-receptor function in bone.","evidence":"siRNA knockdown and BMP3 overexpression in primary bone marrow stromal cells with colony-forming assays","pmids":["22074949"],"confidence":"Medium","gaps":["Type I receptor partner not defined","SMAD branch mediating suppression not identified","In vivo relevance not tested"]},{"year":2012,"claim":"Demonstrated that the ACVR2B extracellular domain alone is sufficient to bind and neutralize myostatin, defining the structural basis for ligand-trap antagonism.","evidence":"Yeast-expressed, N-glycosylated Acvr2b-ECD tested in CAGA-luciferase MSTN inhibition assay","pmids":["22911153"],"confidence":"Medium","gaps":["Single in vitro reconstitution assay","Binding affinity and stoichiometry not quantified","Used fish ortholog ECD"]},{"year":2015,"claim":"Showed ACVR2B is a competitive shared receptor for both activin and select BMPs, establishing that ligand occupancy sets the signaling balance.","evidence":"Cell-based ligand competition assays in myeloma lines with characterized receptor expression","pmids":["26047946"],"confidence":"Medium","gaps":["Competition shown functionally, not by direct binding measurement","Did not establish in vivo balance","Type I partner contribution not fully dissected"]},{"year":2018,"claim":"Linked chromatin state at the ACVR2B promoter to receptor transcription and downstream myogenic gene regulation.","evidence":"ChIP for H3K56ac at ACVR2B promoter and Smad3 binding at Myf5/MyoD in spermidine-treated satellite cells","pmids":["29224337"],"confidence":"Low","gaps":["Single ChIP assay with no functional link to phenotype established","Causality between promoter acetylation and ACVR2B output not demonstrated","Effect on receptor protein level not measured"]},{"year":2019,"claim":"Defined a therapeutic context: ligand blockade of ACVR2B dampens SMAD2 signaling and protects the heart from ischemic injury.","evidence":"ACVR2B-Fc treatment in mouse cardiac ischemia-reperfusion model with cardiomyocyte hypoxia assay and pSMAD2 readout","pmids":["30765322"],"confidence":"Medium","gaps":["Specific ligand(s) blocked not pinpointed","On-target receptor contribution vs other ACVR2B ligands not separated","Single lab"]},{"year":2020,"claim":"Resolved the physiological requirement for ACVR2B in reproductive endocrinology and its redundancy with ACVR2A.","evidence":"Gonadotrope-specific conditional single and double knockout of Acvr2a/Acvr2b in mice with FSH and fertility phenotyping","pmids":["32270195"],"confidence":"High","gaps":["Type I receptor partner in gonadotropes not defined","Mechanism of partial vs complete deficiency not molecularly dissected"]},{"year":2021,"claim":"Showed ACVR2B receptor levels are tunable by exosomal miRNAs that shift the Bmpr2/Acvr2b competitive balance toward osteogenic SMAD1/5/9 output.","evidence":"miRNA microarray, siRNA and miRNA transfection with Smad1/5/9 phosphorylation readout in vitro","pmids":["33838528"],"confidence":"Medium","gaps":["Direct miRNA-ACVR2B target binding not validated","In vivo relevance not tested","Quantitative shift in receptor balance not measured"]},{"year":2023,"claim":"Identified a pathogenic signaling amplifier on ACVR2B in joint disease, where NOX4 binds the receptor complex to boost catabolic SMAD2/3 signaling.","evidence":"Transgenic/knockout mouse OA models, shRNA knockdown of ACVR2B, and protein-protein interaction studies","pmids":["36950748"],"confidence":"Medium","gaps":["Structural basis of NOX4 binding to the C-terminal site not resolved","Whether amplification is ACVR2B-specific vs shared with ACVR2A unclear","Single lab"]},{"year":2024,"claim":"Provided the biophysical basis for ACVR2B's role in FOP by showing it homodimerizes and forms ligand-independent complexes with ALK2-R206H to drive constitutive SMAD1/5/8 signaling.","evidence":"FRAP-based receptor interaction quantification with R206H mutagenesis and pSMAD1/5/8 / BRE-Luc readouts","pmids":["38334613"],"confidence":"High","gaps":["Structural detail of the homomeric interface not resolved","Why ACVR2B but not ACVR2A homodimerizes ligand-independently not explained mechanistically"]},{"year":2024,"claim":"Demonstrated translational utility of ACVR2B-Fc traps delivered by engineered cells to suppress aberrant BMP/Activin signaling and heterotopic ossification in FOP.","evidence":"iPSC-derived MSC-secreted ACVR2B-Fc in patient iMSC signaling assays and transplantation into ACVR1-R206H FOP mice","pmids":["38500216"],"confidence":"Medium","gaps":["Durability and dosing not established","Specific ligand contributions to ossification not separated","Single lab"]},{"year":2025,"claim":"Established ACVR2B as the dominant type II receptor for BMP signaling in early vertebrate patterning and as a dose-dependent restrictor of FOP mutant signaling.","evidence":"Complete maternal-zygotic genetic depletion of all acvr2a/acvr2b genes in zebrafish with BMP readouts and ACVR1-R206H epistasis (preprint)","pmids":["41279820"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Mammalian early-embryo dependence not confirmed","Mechanism of dosage restriction of R206H not molecularly defined"]},{"year":null,"claim":"How ACVR2B's homodimerization interface and ligand-selective complex assembly are structurally encoded, and how these determine the activin-versus-BMP signaling balance across tissues, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No atomic structure of ACVR2B homomeric or heteromeric complexes in the corpus","Tissue-specific type I partner choice not systematically mapped","Direct kinase substrate-level mechanism not characterized in the timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,10]}],"complexes":[],"partners":["ACVR1","ACVR1B","ACVR2A","NOX4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13705","full_name":"Activin receptor type-2B","aliases":["Activin receptor type IIB","ACTR-IIB"],"length_aa":512,"mass_kda":57.7,"function":"Transmembrane serine/threonine kinase activin type-2 receptor forming an activin receptor complex with activin type-1 serine/threonine kinase receptors (ACVR1, ACVR1B or ACVR1c). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, the type-2 receptors act as a primary activin receptors (binds activin-A/INHBA, activin-B/INHBB as well as inhibin-A/INHA-INHBA). The type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine-threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C-terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q13705/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACVR2B","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"MVD","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ACVR2B","total_profiled":1310},"omim":[{"mim_id":"613751","title":"HETEROTAXY, VISCERAL, 4, AUTOSOMAL; HTX4","url":"https://www.omim.org/entry/613751"},{"mim_id":"612188","title":"VPS39 SUBUNIT OF HOPS COMPLEX; VPS39","url":"https://www.omim.org/entry/612188"},{"mim_id":"608699","title":"BONE MORPHOGENETIC PROTEIN-BINDING ENDOTHELIAL REGULATOR PROTEIN; BMPER","url":"https://www.omim.org/entry/608699"},{"mim_id":"608021","title":"WAP, FOLLISTATIN, IMMUNOGLOBULIN, KUNITZ, AND NTR DOMAINS-CONTAINING PROTEIN 1; WFIKKN1","url":"https://www.omim.org/entry/608021"},{"mim_id":"604051","title":"ENDO/EXONUCLEASE, ENDOG-LIKE; EXOG","url":"https://www.omim.org/entry/604051"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACVR2B"},"hgnc":{"alias_symbol":["ActR-IIB"],"prev_symbol":[]},"alphafold":{"accession":"Q13705","domains":[{"cath_id":"2.10.60.10","chopping":"27-114","consensus_level":"high","plddt":89.2633,"start":27,"end":114},{"cath_id":"3.30.200.20","chopping":"189-267","consensus_level":"medium","plddt":89.9325,"start":189,"end":267},{"cath_id":"1.10.510.10","chopping":"270-490","consensus_level":"high","plddt":93.5725,"start":270,"end":490}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13705","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13705-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13705-F1-predicted_aligned_error_v6.png","plddt_mean":83.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACVR2B","jax_strain_url":"https://www.jax.org/strain/search?query=ACVR2B"},"sequence":{"accession":"Q13705","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13705.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13705/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13705"}},"corpus_meta":[{"pmid":"33838528","id":"PMC_33838528","title":"Optimized BMSC-derived osteoinductive exosomes immobilized in hierarchical scaffold via lyophilization for bone repair through Bmpr2/Acvr2b competitive receptor-activated Smad pathway.","date":"2021","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/33838528","citation_count":166,"is_preprint":false},{"pmid":"9916847","id":"PMC_9916847","title":"Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB.","date":"1999","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9916847","citation_count":154,"is_preprint":false},{"pmid":"26047946","id":"PMC_26047946","title":"Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B.","date":"2015","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/26047946","citation_count":131,"is_preprint":false},{"pmid":"22431721","id":"PMC_22431721","title":"miR-192, miR-194, miR-215, miR-200c and miR-141 are downregulated and their common target ACVR2B is strongly expressed in renal childhood neoplasms.","date":"2012","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/22431721","citation_count":115,"is_preprint":false},{"pmid":"22074949","id":"PMC_22074949","title":"BMP3 suppresses osteoblast differentiation of bone marrow stromal cells via interaction with Acvr2b.","date":"2011","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/22074949","citation_count":93,"is_preprint":false},{"pmid":"29089584","id":"PMC_29089584","title":"ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29089584","citation_count":56,"is_preprint":false},{"pmid":"29722201","id":"PMC_29722201","title":"Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses.","date":"2018","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/29722201","citation_count":56,"is_preprint":false},{"pmid":"29230965","id":"PMC_29230965","title":"Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle.","date":"2017","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/29230965","citation_count":55,"is_preprint":false},{"pmid":"27666826","id":"PMC_27666826","title":"Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27666826","citation_count":54,"is_preprint":false},{"pmid":"30334578","id":"PMC_30334578","title":"LncRNA MALAT1 modified progression of clear cell kidney carcinoma (KIRC) by regulation of miR-194-5p/ACVR2B signaling.","date":"2018","source":"Molecular 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ACVR2B.","date":"2020","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32270195","citation_count":24,"is_preprint":false},{"pmid":"29224337","id":"PMC_29224337","title":"Spermidine-Activated Satellite Cells Are Associated with Hypoacetylation in ACVR2B and Smad3 Binding to Myogenic Genes in Mice.","date":"2018","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29224337","citation_count":23,"is_preprint":false},{"pmid":"31127166","id":"PMC_31127166","title":"Comparative analysis of silencing expression of myostatin (MSTN) and its two receptors (ACVR2A and ACVR2B) genes affecting growth traits in knock down chicken.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31127166","citation_count":22,"is_preprint":false},{"pmid":"36950748","id":"PMC_36950748","title":"Blockade of Activin Receptor IIB Protects Arthritis Pathogenesis by Non-Amplification of Activin A-ACVR2B-NOX4 Axis 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acvr2b in fish.","date":"2012","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22911153","citation_count":6,"is_preprint":false},{"pmid":"33720451","id":"PMC_33720451","title":"Three SNPs within exons of INHA and ACVR2B genes are significantly associated with litter size in Dazu black goats.","date":"2021","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/33720451","citation_count":5,"is_preprint":false},{"pmid":"38500216","id":"PMC_38500216","title":"iMSC-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.","date":"2024","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38500216","citation_count":4,"is_preprint":false},{"pmid":"11334431","id":"PMC_11334431","title":"No evidence for linkage or for diabetes-associated mutations in the activin type 2B receptor gene (ACVR2B) in French 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and ACVR2A.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38334613","citation_count":2,"is_preprint":false},{"pmid":"40045085","id":"PMC_40045085","title":"lncRNA ACVR2B-AS1 modulates thyroid cancer progression by regulating miR-195-5p.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40045085","citation_count":2,"is_preprint":false},{"pmid":"40416557","id":"PMC_40416557","title":"Combined rapamycin and mesenchymal stem/stromal cells derived from induced pluripotent stem cells-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.","date":"2025","source":"JBMR plus","url":"https://pubmed.ncbi.nlm.nih.gov/40416557","citation_count":1,"is_preprint":false},{"pmid":"40435286","id":"PMC_40435286","title":"Circular RNA profiling reveals an abundant circPTK2 that contributes everolimus-induced endothelial cell dysfunction via regulating 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periodontitis","date":"2025-01-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.19.25320804","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25968,"output_tokens":3428,"usd":0.064662,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10857,"output_tokens":3940,"usd":0.076393,"stage2_stop_reason":"end_turn"},"total_usd":0.141055,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Activin A binds ACVR2A and ACVR2B and antagonizes BMP-6 and BMP-9 signaling through these type II receptors in combination with ALK2, but does not antagonize BMPs that signal through BMPR2 with ALK3/ALK6, establishing ACVR2B as a shared receptor for both activin and select BMP ligands whose competitive occupancy regulates downstream signaling.\",\n      \"method\": \"Cell-based ligand competition assays using myeloma cell lines with characterized BMP-receptor expression; receptor-specific functional readouts\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assays with multiple ligand/receptor combinations, single lab, two orthogonal approaches (receptor expression characterization + functional antagonism assays)\",\n      \"pmids\": [\"26047946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BMP3 suppresses osteoblast differentiation of bone marrow stromal cells through interaction with ACVR2B; knockdown of endogenous Acvr2b reduces the suppressive effect of BMP3 on osteoblast differentiation, placing ACVR2B as the receptor mediating BMP3's inhibitory role in skeletal progenitor cells.\",\n      \"method\": \"In vitro primary bone marrow stromal cell cultures; BMP3 overexpression and loss-of-function; siRNA knockdown of Acvr2b; colony-forming unit assays\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (siRNA) with defined cellular phenotype, overexpression corroboration, single lab\",\n      \"pmids\": [\"22074949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACVR2A and ACVR2B are both required in gonadotrope cells for activin-induced FSH production in vivo; gonadotrope-specific double knockout of Acvr2a and Acvr2b leads to profound FSH deficiency, hypogonadism, and sterility in both sexes, while single knockouts produce partial FSH deficiencies.\",\n      \"method\": \"Conditional knockout using Cre-lox strategy in murine gonadotropes; serum FSH measurement; fertility and gonadal phenotyping\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo conditional knockout with defined hormonal and reproductive phenotype, double and single KO comparison providing epistatic resolution, replicated across sexes\",\n      \"pmids\": [\"32270195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Systemic blockade of ACVR2B ligands with soluble ACVR2B-Fc antagonizes SMAD2 signaling and cardiomyocyte death under hypoxic stress; ACVR2B-Fc was protective against cardiac ischemia-reperfusion injury in vivo, reducing infarct area and apoptosis, and modifying LV mitochondrial respiration and cardiac metabolism.\",\n      \"method\": \"In vivo mouse cardiac ischemia-reperfusion model with ACVR2B-Fc treatment; in vitro cardiomyocyte hypoxia assay; echocardiography; SMAD2 phosphorylation assay\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function (ligand blockade) with defined cardiac phenotype plus in vitro mechanistic corroboration (SMAD2 signaling), single lab\",\n      \"pmids\": [\"30765322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In osteoarthritis, activin A signals through ACVR2B/ACVR1B to activate NOX4-dependent ROS production and amplify SMAD2/3 signaling and catabolic factor expression; NOX4 directly binds the C-terminal binding site on ACVR2B-ACVR1B and amplifies the pathogenic signal for cartilage destruction.\",\n      \"method\": \"In silico analysis; transgenic and knockout mouse models (Col2a1-Inhba, Inhba+/-, Nox4-/-); shRNA knockdown of ACVR2B; protein-protein interaction studies\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo genetic models plus direct binding studies, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36950748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2B forms stable homomeric complexes that are enhanced by Activin A, whereas ACVR2A requires Activin A for homodimerization; ACVR2B forms heterocomplexes with ALK2-R206H independent of ligand and activates FOP-inducing SMAD1/5/8 signaling without Activin A, while ACVR2A requires Activin A for ALK2-R206H oligomerization and activation.\",\n      \"method\": \"IgG-mediated receptor immobilization combined with FRAP (fluorescence recovery after photobleaching) to quantify homomeric and heteromeric receptor interactions; pSMAD1/5/8 western blot; BRE-Luc transcriptional reporter assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative biophysical method (FRAP) combined with mutagenesis (R206H) and functional signaling readouts (pSMAD1/5/8, reporter), multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"38334613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, maternal-zygotic depletion of Acvr2b receptors abrogates all BMP signaling in dorsoventral patterning, establishing Acvr2b as the primary type II receptor transducing BMP signaling in the gastrula; additionally, Acvr2b dosage restricts hyperactive ACVR1-R206H (FOP mutant) signaling in a dose-dependent manner.\",\n      \"method\": \"Genetic mutation of all four acvr2a and acvr2b zebrafish genes; maternal-zygotic depletion; BMP signaling readouts; FOP ACVR1-R206H epistasis assay\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous genetic epistasis in zebrafish with complete maternal-zygotic depletion, ortholog study, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41279820\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sea bream Acvr2b extracellular domain (Acvr2b-ECD), expressed in yeast and N-glycosylated, inhibits recombinant MSTN activity in vitro, demonstrating that the extracellular domain of ACVR2B is sufficient to bind and neutralize myostatin; evidence also found for gene duplication generating two acvr2b paralogs in fish.\",\n      \"method\": \"Yeast expression of Acvr2b-ECD; CAGA-luciferase reporter in vitro assay; N-glycosylation analysis\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution assay demonstrating direct ligand binding/inhibition, single lab, single method\",\n      \"pmids\": [\"22911153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Zebrafish acvr2b morpholino depletion produces defects restricted to posterior craniofacial arch structures, including absent/aberrant migration of posterior neural crest cell streams and defects in posterior arch cartilages and pharyngeal tooth development, establishing a distinct role for Acvr2b (vs. Acvr2a) in posterior neural crest patterning.\",\n      \"method\": \"Morpholino-based targeted protein depletion in zebrafish; phenotypic analysis of neural crest-derived structures\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular and structural phenotype in vivo, ortholog study, comparison to acvr2a morphants providing functional distinction\",\n      \"pmids\": [\"15977175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Spermidine represses H3K56 acetylation at the ACVR2B promoter, reducing ACVR2B transcription, and lowers the binding affinity of Smad3 to promoters of myogenic genes Myf5 and MyoD in satellite cells, linking ACVR2B promoter chromatin state to downstream myogenic gene regulation.\",\n      \"method\": \"ChIP assay measuring H3K56ac at ACVR2B promoter and Smad3 binding at Myf5/MyoD promoters in spermidine-treated mouse satellite cells\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP assay, single lab, no direct functional link between ACVR2B promoter acetylation change and downstream phenotype established\",\n      \"pmids\": [\"29224337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2B-Fc fusion protein, secreted by iPSC-derived mesenchymal stromal cells, attenuates BMP signaling activated by Activin-A and BMP-9 in FOP patient-derived iMSCs in vitro, and transplantation of these cells reduces primary heterotopic ossification in FOP transgenic mice (ACVR1-R206H), demonstrating ACVR2B-Fc blocks aberrant BMP/Activin signaling in FOP pathogenesis.\",\n      \"method\": \"In vitro BMP signaling inhibition assay in iMSCs; in vivo transplantation in FOP mouse model; treadmill performance assay\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro signaling assay combined with in vivo functional rescue in disease model, single lab, two orthogonal approaches\",\n      \"pmids\": [\"38500216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Exosomal miRNAs (let-7a-5p, let-7c-5p, miR-328a-5p, miR-31a-5p) target Acvr2b/Acvr1 and regulate the competitive balance between Bmpr2/Acvr2b signaling, shifting it toward Bmpr-elicited Smad1/5/9 phosphorylation to promote osteoblast differentiation.\",\n      \"method\": \"miRNA microarray; in vitro pathway verification by gene silencing (siRNA) and miRNA transfection; Smad1/5/9 phosphorylation readout\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene silencing combined with miRNA transfection and downstream SMAD phosphorylation readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"33838528\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACVR2B is a type II serine/threonine kinase receptor in the TGF-β superfamily that forms ligand-enhanced homomeric complexes and heteromeric complexes with type I receptors (ALK2/ACVR1, ALK4/ACVR1B) to transduce signals from activins, myostatin, BMP3, and select BMPs (BMP-6, BMP-9) via SMAD2/3 or SMAD1/5/8 phosphorylation; its extracellular domain competitively binds multiple ligands to modulate BMP versus activin signaling balance, it is the primary type II receptor transducing BMP signaling in early vertebrate embryogenesis, it is required with ACVR2A for activin-driven FSH production in gonadotropes, and its ligand-independent homodimerization enables constitutive activation of the FOP-causing ALK2-R206H mutant.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACVR2B is a type II receptor of the TGF-\\u03b2 superfamily that serves as a shared, ligand-competitive hub transducing signals from activins, myostatin, and select BMPs to determine the balance of downstream SMAD activation [#0, #7]. Its extracellular domain alone is sufficient to bind and neutralize myostatin, and soluble ACVR2B-Fc traps act as broad ligand antagonists [#7]. Activin A binds ACVR2B and, in combination with type I receptors such as ALK2, antagonizes BMP-6 and BMP-9 signaling, so that competitive ligand occupancy of ACVR2B sets the BMP-versus-activin signaling balance [#0]; this balance is itself tunable through exosomal miRNA control of receptor levels that shifts signaling toward BMPR2-elicited SMAD1/5/9 phosphorylation during osteoblast differentiation [#11]. ACVR2B forms stable homomeric complexes enhanced by Activin A and constitutively assembles ligand-independent heterocomplexes with the FOP-causing ALK2-R206H mutant, enabling its aberrant SMAD1/5/8 activation; ACVR2B receptor dosage dose-dependently restricts this hyperactive ACVR1-R206H signaling [#5, #6]. In development, ACVR2B is the primary type II receptor transducing BMP signaling in the gastrula and is required for posterior neural crest patterning [#6, #8]. Physiologically, ACVR2B acts redundantly with ACVR2A to drive activin-dependent FSH production in gonadotropes, with double loss causing FSH deficiency, hypogonadism and sterility [#2], and it mediates pathogenic signaling in skeletal and joint tissue, transducing BMP3-dependent suppression of osteoblast differentiation [#1] and activin A-driven, NOX4-amplified catabolic SMAD2/3 signaling in osteoarthritic cartilage [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established a developmental role for ACVR2B distinct from its paralog by showing it patterns a specific embryonic territory.\",\n      \"evidence\": \"Morpholino depletion of acvr2b in zebrafish with phenotyping of neural crest-derived structures\",\n      \"pmids\": [\"15977175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the ligand driving posterior neural crest patterning\", \"Morpholino specificity not corroborated by genetic mutant\", \"Downstream SMAD branch not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified ACVR2B as the receptor through which BMP3 inhibits skeletal progenitor commitment, assigning a defined ligand-receptor function in bone.\",\n      \"evidence\": \"siRNA knockdown and BMP3 overexpression in primary bone marrow stromal cells with colony-forming assays\",\n      \"pmids\": [\"22074949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Type I receptor partner not defined\", \"SMAD branch mediating suppression not identified\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that the ACVR2B extracellular domain alone is sufficient to bind and neutralize myostatin, defining the structural basis for ligand-trap antagonism.\",\n      \"evidence\": \"Yeast-expressed, N-glycosylated Acvr2b-ECD tested in CAGA-luciferase MSTN inhibition assay\",\n      \"pmids\": [\"22911153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vitro reconstitution assay\", \"Binding affinity and stoichiometry not quantified\", \"Used fish ortholog ECD\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed ACVR2B is a competitive shared receptor for both activin and select BMPs, establishing that ligand occupancy sets the signaling balance.\",\n      \"evidence\": \"Cell-based ligand competition assays in myeloma lines with characterized receptor expression\",\n      \"pmids\": [\"26047946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competition shown functionally, not by direct binding measurement\", \"Did not establish in vivo balance\", \"Type I partner contribution not fully dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked chromatin state at the ACVR2B promoter to receptor transcription and downstream myogenic gene regulation.\",\n      \"evidence\": \"ChIP for H3K56ac at ACVR2B promoter and Smad3 binding at Myf5/MyoD in spermidine-treated satellite cells\",\n      \"pmids\": [\"29224337\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single ChIP assay with no functional link to phenotype established\", \"Causality between promoter acetylation and ACVR2B output not demonstrated\", \"Effect on receptor protein level not measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a therapeutic context: ligand blockade of ACVR2B dampens SMAD2 signaling and protects the heart from ischemic injury.\",\n      \"evidence\": \"ACVR2B-Fc treatment in mouse cardiac ischemia-reperfusion model with cardiomyocyte hypoxia assay and pSMAD2 readout\",\n      \"pmids\": [\"30765322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ligand(s) blocked not pinpointed\", \"On-target receptor contribution vs other ACVR2B ligands not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the physiological requirement for ACVR2B in reproductive endocrinology and its redundancy with ACVR2A.\",\n      \"evidence\": \"Gonadotrope-specific conditional single and double knockout of Acvr2a/Acvr2b in mice with FSH and fertility phenotyping\",\n      \"pmids\": [\"32270195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Type I receptor partner in gonadotropes not defined\", \"Mechanism of partial vs complete deficiency not molecularly dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ACVR2B receptor levels are tunable by exosomal miRNAs that shift the Bmpr2/Acvr2b competitive balance toward osteogenic SMAD1/5/9 output.\",\n      \"evidence\": \"miRNA microarray, siRNA and miRNA transfection with Smad1/5/9 phosphorylation readout in vitro\",\n      \"pmids\": [\"33838528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miRNA-ACVR2B target binding not validated\", \"In vivo relevance not tested\", \"Quantitative shift in receptor balance not measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a pathogenic signaling amplifier on ACVR2B in joint disease, where NOX4 binds the receptor complex to boost catabolic SMAD2/3 signaling.\",\n      \"evidence\": \"Transgenic/knockout mouse OA models, shRNA knockdown of ACVR2B, and protein-protein interaction studies\",\n      \"pmids\": [\"36950748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of NOX4 binding to the C-terminal site not resolved\", \"Whether amplification is ACVR2B-specific vs shared with ACVR2A unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the biophysical basis for ACVR2B's role in FOP by showing it homodimerizes and forms ligand-independent complexes with ALK2-R206H to drive constitutive SMAD1/5/8 signaling.\",\n      \"evidence\": \"FRAP-based receptor interaction quantification with R206H mutagenesis and pSMAD1/5/8 / BRE-Luc readouts\",\n      \"pmids\": [\"38334613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the homomeric interface not resolved\", \"Why ACVR2B but not ACVR2A homodimerizes ligand-independently not explained mechanistically\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated translational utility of ACVR2B-Fc traps delivered by engineered cells to suppress aberrant BMP/Activin signaling and heterotopic ossification in FOP.\",\n      \"evidence\": \"iPSC-derived MSC-secreted ACVR2B-Fc in patient iMSC signaling assays and transplantation into ACVR1-R206H FOP mice\",\n      \"pmids\": [\"38500216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Durability and dosing not established\", \"Specific ligand contributions to ossification not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established ACVR2B as the dominant type II receptor for BMP signaling in early vertebrate patterning and as a dose-dependent restrictor of FOP mutant signaling.\",\n      \"evidence\": \"Complete maternal-zygotic genetic depletion of all acvr2a/acvr2b genes in zebrafish with BMP readouts and ACVR1-R206H epistasis (preprint)\",\n      \"pmids\": [\"41279820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Mammalian early-embryo dependence not confirmed\", \"Mechanism of dosage restriction of R206H not molecularly defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ACVR2B's homodimerization interface and ligand-selective complex assembly are structurally encoded, and how these determine the activin-versus-BMP signaling balance across tissues, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic structure of ACVR2B homomeric or heteromeric complexes in the corpus\", \"Tissue-specific type I partner choice not systematically mapped\", \"Direct kinase substrate-level mechanism not characterized in the timeline\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ACVR1\", \"ACVR1B\", \"ACVR2A\", \"NOX4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}