{"gene":"ACVR2B","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2015,"finding":"Activin A binds ACVR2A and ACVR2B and antagonizes BMP signaling through these receptors in combination with ALK2, but not BMPs signaling through BMPR2 with ALK3/ALK6, establishing that activin A competitively inhibits BMP-ACVR2A/ACVR2B/ALK2 signaling complexes.","method":"Cell-based signaling assays using myeloma cell lines with characterized BMP-receptor expression; ligand competition experiments","journal":"Cell communication and signaling : CCS","confidence":"High","confidence_rationale":"Tier 2 — multiple BMP ligand/receptor combinations tested in well-characterized cell lines, replicated across receptor contexts","pmids":["26047946"],"is_preprint":false},{"year":2011,"finding":"BMP3 suppresses osteoblast differentiation of bone marrow stromal cells through direct interaction with Acvr2b; knockdown of Acvr2b reduces the suppressive effect of BMP3 on osteoblast differentiation, placing BMP3 upstream of Acvr2b in the negative regulation of bone formation.","method":"In vitro cultures of primary bone marrow stromal cells; BMP3 overexpression/loss-of-function; Acvr2b siRNA knockdown; colony-forming unit assays","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via knockdown with defined cellular phenotype, supported by gain- and loss-of-function experiments","pmids":["22074949"],"is_preprint":false},{"year":2024,"finding":"ACVR2B forms stable homomeric complexes (enhanced by Activin A), while ACVR2A requires Activin A for homodimerization. ACVR2B, but not ACVR2A, can activate the FOP-inducing ALK2-R206H mutant in a ligand-independent manner by inducing its oligomerization; ACVR2A requires Activin A to induce ALK2-R206H oligomerization and signaling to SMAD1/5/8.","method":"IgG-mediated receptor immobilization combined with FRAP to measure lateral diffusion and oligomerization; pSMAD1/5/8 western blot; BRE-Luc transcriptional reporter assay","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1 — biophysical quantification of receptor complexes combined with functional signaling assays and mutagenesis (R206H mutant)","pmids":["38334613"],"is_preprint":false},{"year":2019,"finding":"Activin A signals through ACVR2B forming an assembly with ACVR1B and NOX4 in osteoarthritic cartilage; NOX4 directly binds the C-terminal binding site on the ACVR2B-ACVR1B complex and amplifies pathogenic SMAD2/3 signaling for cartilage destruction. ACVR2B knockdown or ligand trapping abrogates this signaling.","method":"In silico analysis; transgenic and knockout mouse models (Col2a1-Inhba Tg, Inhba+/-, Nox4-/-); co-immunoprecipitation; shRNA knockdown; SMAD2/3 phosphorylation assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including genetic mouse models, co-IP of complex components, and signaling readouts","pmids":["36950748"],"is_preprint":false},{"year":2020,"finding":"ACVR2A and ACVR2B are the critical type II receptors through which activins or related TGF-β ligands induce FSH production in gonadotropes in vivo; combined conditional knockout of both receptors causes profound FSH deficiency and sterility in both sexes.","method":"Cre-lox conditional knockout of Acvr2a and/or Acvr2b in murine gonadotropes; serum FSH measurement; fertility and reproductive phenotyping","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with well-defined hormonal and reproductive phenotypes, both single and double KO characterization","pmids":["32270195"],"is_preprint":false},{"year":2025,"finding":"In zebrafish gastrula, Acvr2b is the primary type II receptor transducing BMP signaling for dorsoventral patterning; maternal-zygotic depletion of Acvr2b abrogates all BMP/pSMAD signaling. Additionally, hyperactive ACVR1-R206H (FOP mutant) signaling is restricted in a dose-dependent manner by Acvr2b levels, demonstrating that Acvr2b concentration modulates FOP-associated aberrant signaling.","method":"Genetic mutation of all four acvr2a/acvr2b zebrafish genes; maternal-zygotic mutant analysis; BMP signaling readouts (pSMAD, target gene expression); ACVR1-R206H FOP mutant epistasis","journal":"bioRxiv : the preprint server for biology","confidence":"High","confidence_rationale":"Tier 2 — comprehensive genetic dissection using maternal-zygotic mutants with clear molecular and patterning phenotypes","pmids":["41279820"],"is_preprint":true},{"year":2019,"finding":"Systemic blockade of ACVR2B ligands (including myostatin) using ACVR2B-Fc protects myocardium from ischemia-reperfusion injury by antagonizing SMAD2 signaling and cardiomyocyte death under hypoxic stress, and modifying cardiac metabolism toward physiological hypertrophy.","method":"In vivo mouse myocardial IR injury model with ACVR2B-Fc treatment; in vitro cardiomyocyte hypoxia assay; SMAD2 phosphorylation assays; LV function echocardiography; mitochondrial respiration measurement","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro with defined molecular readout (SMAD2 antagonism), single lab","pmids":["30765322"],"is_preprint":false},{"year":2016,"finding":"Blocking ACVR2B ligand signaling with soluble ACVR2B-Fc (sACVR2B-Fc) prevents chemotherapy (doxorubicin)-induced muscle atrophy by restoring muscle protein synthesis without affecting protein degradation pathways, atrogenes, or mitochondrial oxidative capacity.","method":"In vivo mouse model; sACVR2B-Fc pharmacological treatment; muscle protein synthesis measurement; atrogene expression; mitochondrial function assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — clean in vivo KD with specific molecular mechanism (protein synthesis restoration) identified, single lab","pmids":["27666826"],"is_preprint":false},{"year":2018,"finding":"Spermidine represses H3K56 acetylation at the ACVR2B promoter and reduces Smad3 binding to myogenic gene promoters (Myf5, MyoD), linking ACVR2B transcriptional regulation to satellite cell activation and muscle atrophy.","method":"ChIP assay for H3K56ac and Smad3 at ACVR2B and myogenic gene promoters in mouse muscle; spermidine administration in vivo","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP assays provide direct evidence of epigenetic regulation at ACVR2B locus with functional context, single lab","pmids":["29224337"],"is_preprint":false},{"year":2012,"finding":"ACVR2B extracellular domain (ECD) from sea bream directly inhibits myostatin activity in a CAGA-luciferase reporter assay in A204 cells, demonstrating conserved ligand-binding and inhibitory function of the receptor's extracellular domain. Evidence for N-glycosylation of Acvr2b-ECD was also provided.","method":"In vitro CAGA-luciferase reporter assay in A204 cells; recombinant Acvr2b-ECD expressed in Pichia pastoris; glycosylation analysis","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution assay demonstrating direct ligand inhibition, but in fish ortholog context","pmids":["22911153"],"is_preprint":false},{"year":2021,"finding":"In zebrafish, acvr2b morphant knockdown causes defects restricted to posterior pharyngeal arch structures and aberrant migration of posterior neural crest cell streams, defining a distinct in vivo role for acvr2b versus acvr2a in craniofacial neural crest patterning.","method":"Morpholino-based targeted protein depletion in zebrafish; phenotypic analysis of cartilage, bone, and pharyngeal structures","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"Medium","confidence_rationale":"Tier 2 — morpholino loss-of-function with specific anatomical phenotype, ortholog in zebrafish","pmids":["15977175"],"is_preprint":false},{"year":2024,"finding":"ACVR2B-Fc fusion protein secreted by iPSC-derived mesenchymal stem cells attenuates BMP signaling initiated by Activin-A and BMP-9 in FOP patient-derived iMSCs and reduces heterotopic ossification in a transgenic FOP mouse model (ACVR1-R206H), demonstrating that ACVR2B-Fc acts as a neutralizing decoy receptor for these ligands.","method":"In vitro BMP signaling assays (pSMAD) in FOP-iMSCs; in vivo transplantation into FOP transgenic mice; treadmill performance assay","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo evidence with defined molecular readout, single lab","pmids":["38500216"],"is_preprint":false},{"year":2021,"finding":"Acvr2b is a direct target of miR-132; suppression of Acvr2b by miR-132 attenuates p-Smad2/c-jun signaling pathway activation and reduces neuronal apoptosis in ischemic injury models, placing ACVR2B upstream of Smad2/c-jun in ischemic neuronal death signaling.","method":"Dual-luciferase reporter gene assay confirming miR-132/Acvr2b interaction; loss-of-function assays in OGD-treated neurons; MCAO mouse model; pSmad2 western blot","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 — validated miRNA-target interaction with pathway epistasis, but primarily through overexpression/knockdown approach in a single lab","pmids":["33763412"],"is_preprint":false},{"year":1999,"finding":"Mutations in human ACVR2B are associated with left-right axis malformations, consistent with the known role of mouse Acvr2b in left-right axis development established by targeted disruption studies.","method":"Genomic structure characterization; splice variant analysis; mutation screening in 126 LR axis malformation cases; comparison to 200 control chromosomes","journal":"American journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 — human mutation identification corroborated by mouse targeted disruption data from referenced prior work","pmids":["9916847"],"is_preprint":false},{"year":2021,"finding":"BMSC-derived exosomal miRNAs (let-7a-5p, let-7c-5p, miR-328a-5p, miR-31a-5p) target Acvr2b/Acvr1 to regulate the competitive balance of Bmpr2/Acvr2b, shifting signaling toward BMP receptor-elicited Smad1/5/9 phosphorylation and promoting osteogenesis.","method":"miRNA microarray; gene silencing; miRNA transfection; pathway verification via Smad1/5/9 phosphorylation assays; rat cranial defect model","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro pathway verification with gene silencing and transfection plus in vivo model, single lab","pmids":["33838528"],"is_preprint":false}],"current_model":"ACVR2B is a type II serine/threonine kinase receptor of the TGF-β superfamily that forms ligand-enhanced homomeric and heteromeric complexes with type I receptors (ALK2, ALK4, ACVR1B); it binds activins, myostatin, BMP3, and select BMPs to transduce SMAD2/3 or SMAD1/5/8 signaling, serves as the primary type II receptor for BMP-driven dorsoventral patterning, mediates negative regulation of skeletal muscle mass and osteoblast differentiation, regulates FSH production in gonadotropes, and its ligand-independent homodimerization enables constitutive activation of the FOP-causing ALK2-R206H mutant."},"narrative":{"teleology":[{"year":1999,"claim":"The first human genetic link between ACVR2B and disease was established when mutations in ACVR2B were identified in patients with left–right axis malformations, consistent with prior mouse knockout data showing laterality defects.","evidence":"Mutation screening of 126 human laterality cases versus 200 controls, corroborated by mouse targeted disruption studies","pmids":["9916847"],"confidence":"Medium","gaps":["Functional validation of specific human variants was not performed","Downstream pathway mediating left–right patterning via ACVR2B was not resolved","No structural basis for variant pathogenicity"]},{"year":2011,"claim":"BMP3 was identified as a ligand that acts through ACVR2B to suppress osteoblast differentiation, establishing ACVR2B as a negative regulator of bone formation.","evidence":"Acvr2b siRNA knockdown in primary bone marrow stromal cells combined with BMP3 gain- and loss-of-function","pmids":["22074949"],"confidence":"High","gaps":["Type I receptor partner for BMP3–ACVR2B signaling in osteoblasts was not identified","SMAD branch (SMAD2/3 vs SMAD1/5/8) downstream of BMP3–ACVR2B was not resolved"]},{"year":2012,"claim":"The extracellular domain of ACVR2B was shown to directly inhibit myostatin activity, confirming its ligand-binding specificity and establishing the biochemical basis for soluble decoy receptor strategies.","evidence":"Recombinant ACVR2B-ECD expressed in Pichia pastoris tested in CAGA-luciferase reporter assay against myostatin in A204 cells","pmids":["22911153"],"confidence":"Medium","gaps":["Fish ortholog ECD used; affinity constants for mammalian ACVR2B not determined","Competition with other TGF-β family ligands not systematically tested"]},{"year":2015,"claim":"Activin A was shown to competitively antagonize BMP signaling specifically through ACVR2A/ACVR2B–ALK2 complexes but not BMPR2–ALK3/ALK6, revealing that ligand competition at the type II receptor determines BMP versus activin pathway output.","evidence":"Ligand competition in myeloma cell lines with defined BMP-receptor expression profiles","pmids":["26047946"],"confidence":"High","gaps":["Structural basis for selective activin A displacement of BMPs from ACVR2B–ALK2 was not resolved","Physiological tissue contexts where this competition operates were not identified"]},{"year":2016,"claim":"Blocking ACVR2B ligand signaling in vivo with soluble ACVR2B-Fc prevented chemotherapy-induced muscle atrophy by restoring protein synthesis rather than suppressing degradation, clarifying the anabolic arm of the receptor's muscle regulation.","evidence":"Mouse doxorubicin model with ACVR2B-Fc treatment; muscle protein synthesis measurement and atrogene profiling","pmids":["27666826"],"confidence":"Medium","gaps":["Specific ligand(s) responsible for doxorubicin-induced signaling through ACVR2B were not identified","Downstream translational targets restoring synthesis were not characterized"]},{"year":2019,"claim":"A ternary complex of ACVR2B–ACVR1B–NOX4 was identified in osteoarthritic cartilage, showing that NOX4 binds the receptor complex to amplify pathogenic SMAD2/3 signaling, expanding the receptor's known effector repertoire beyond SMADs.","evidence":"Co-immunoprecipitation, genetic mouse models (Col2a1-Inhba Tg, Nox4 KO), ACVR2B knockdown, and pSMAD2/3 readouts","pmids":["36950748"],"confidence":"High","gaps":["Stoichiometry and structural interface of NOX4 binding to ACVR2B–ACVR1B not determined","Whether NOX4 association occurs with other type II receptor complexes was not tested"]},{"year":2019,"claim":"Systemic ACVR2B ligand blockade was shown to protect against myocardial ischemia-reperfusion injury by antagonizing SMAD2 signaling, extending ACVR2B's role beyond skeletal muscle to cardiac stress responses.","evidence":"Mouse IR injury model with ACVR2B-Fc; in vitro cardiomyocyte hypoxia; echocardiography and mitochondrial respiration","pmids":["30765322"],"confidence":"Medium","gaps":["Specific cardiomyocyte-expressed ligand driving pathogenic SMAD2 activation not identified","Single lab finding; independent replication not available"]},{"year":2020,"claim":"Conditional knockout in gonadotropes demonstrated that ACVR2A and ACVR2B are jointly required for activin-dependent FSH production, with combined loss causing profound FSH deficiency and sterility.","evidence":"Cre-lox conditional knockout of Acvr2a/Acvr2b in murine gonadotropes; serum FSH, fertility phenotyping","pmids":["32270195"],"confidence":"High","gaps":["Relative individual contributions of ACVR2A versus ACVR2B to FSH regulation in single KOs were partially redundant and not fully disentangled","Downstream transcriptional program linking receptor signaling to FSHβ gene expression not fully characterized"]},{"year":2024,"claim":"Biophysical studies revealed that ACVR2B, unlike ACVR2A, forms stable homomeric complexes constitutively and can activate the FOP-causing ALK2-R206H mutant in a ligand-independent manner, providing a mechanistic explanation for differential receptor contributions to aberrant signaling in FOP.","evidence":"FRAP-based receptor immobilization/diffusion measurements; pSMAD1/5/8 and BRE-Luc reporter in cells expressing wild-type or R206H ALK2","pmids":["38334613"],"confidence":"High","gaps":["Structural basis for constitutive ACVR2B homodimerization versus ACVR2A's ligand dependence not resolved","Whether ligand-independent activation of ALK2-R206H by ACVR2B occurs in patient tissues not demonstrated"]},{"year":null,"claim":"Key unresolved questions include the structural determinants of ACVR2B's constitutive oligomerization, the full repertoire of ACVR2B type I receptor pairings in specific tissues, and how competition among activins, myostatin, and BMPs for ACVR2B is spatiotemporally regulated in vivo.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of a full-length ACVR2B homomeric or heteromeric signaling complex","Tissue-specific type I receptor partnerships remain largely inferred from expression data","Quantitative in vivo ligand competition dynamics at ACVR2B are uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,4,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,10,13]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[4]}],"complexes":["ACVR2B–ALK2 complex","ACVR2B–ACVR1B–NOX4 complex"],"partners":["ALK2","ACVR1B","NOX4","ACVR2A","SMAD2","SMAD3"],"other_free_text":[]},"mechanistic_narrative":"ACVR2B is a type II serine/threonine kinase receptor of the TGF-β superfamily that binds activins, myostatin, BMP3, and select BMPs to transduce SMAD2/3 and SMAD1/5/8 signaling across diverse developmental and homeostatic contexts. ACVR2B forms ligand-enhanced homomeric complexes and assembles with type I receptors including ALK2 and ACVR1B; its constitutive homodimerization enables ligand-independent activation of the FOP-causing ALK2-R206H mutant, linking receptor oligomerization directly to disease pathogenesis [PMID:38334613]. In skeletal muscle, ACVR2B mediates myostatin and activin signaling to negatively regulate muscle mass via SMAD2/3, and ligand trapping with soluble ACVR2B-Fc prevents muscle atrophy by restoring protein synthesis [PMID:27666826, PMID:22911153]. ACVR2B also functions as the primary type II receptor for BMP-driven dorsoventral patterning, is required with ACVR2A for activin-dependent FSH production in gonadotropes, participates in BMP3-mediated suppression of osteoblast differentiation, and harbors mutations associated with left–right axis malformations in humans [PMID:32270195, PMID:22074949, PMID:9916847]."},"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":161,"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":129,"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":"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":"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":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 carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/30334578","citation_count":38,"is_preprint":false},{"pmid":"17347381","id":"PMC_17347381","title":"Activin-type II receptor B (ACVR2B) and follistatin haplotype associations with muscle mass and strength in humans.","date":"2007","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/17347381","citation_count":35,"is_preprint":false},{"pmid":"21864452","id":"PMC_21864452","title":"Mutations in ZIC3 and ACVR2B are a common cause of heterotaxy and associated cardiovascular anomalies.","date":"2011","source":"Cardiology in the young","url":"https://pubmed.ncbi.nlm.nih.gov/21864452","citation_count":32,"is_preprint":false},{"pmid":"33200567","id":"PMC_33200567","title":"ACVR2B antagonism as a countermeasure to multi-organ perturbations in metastatic colorectal cancer cachexia.","date":"2020","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/33200567","citation_count":32,"is_preprint":false},{"pmid":"30765322","id":"PMC_30765322","title":"Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury.","date":"2019","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30765322","citation_count":28,"is_preprint":false},{"pmid":"15977175","id":"PMC_15977175","title":"Zebrafish acvr2a and acvr2b exhibit distinct roles in craniofacial development.","date":"2005","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/15977175","citation_count":24,"is_preprint":false},{"pmid":"32270195","id":"PMC_32270195","title":"Murine FSH Production Depends on the Activin Type II Receptors ACVR2A and ACVR2B.","date":"2020","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32270195","citation_count":22,"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":"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":20,"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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ADAMTS19 is associated with premature ovarian failure.","date":"2015","source":"Menopause (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25051287","citation_count":13,"is_preprint":false},{"pmid":"32427381","id":"PMC_32427381","title":"Systemic blockade of ACVR2B ligands attenuates muscle wasting in ischemic heart failure without compromising cardiac function.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32427381","citation_count":10,"is_preprint":false},{"pmid":"36781583","id":"PMC_36781583","title":"Circ_0000566 contributes oxygen-glucose deprivation and reoxygenation (OGD/R)-induced human brain microvascular endothelial cell injury via regulating miR-18a-5p/ACVR2B axis.","date":"2023","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/36781583","citation_count":8,"is_preprint":false},{"pmid":"30120850","id":"PMC_30120850","title":"Expression of TGFBR1, TGFBR2, TGFBR3, ACVR1B and ACVR2B is altered in ovaries of cows with cystic ovarian disease.","date":"2019","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/30120850","citation_count":8,"is_preprint":false},{"pmid":"26848890","id":"PMC_26848890","title":"Genetic Variant in ACVR2B Is Associated with Lean Mass.","date":"2016","source":"Medicine and science in sports and exercise","url":"https://pubmed.ncbi.nlm.nih.gov/26848890","citation_count":8,"is_preprint":false},{"pmid":"39254854","id":"PMC_39254854","title":"LncRNA ACVR2B-as1 interacts with ALDOA to regulate the self-renewal and apoptosis of human spermatogonial stem cells by controlling glycolysis activity.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39254854","citation_count":7,"is_preprint":false},{"pmid":"34302448","id":"PMC_34302448","title":"The association between sarcopenia susceptibility and polymorphisms of FTO, ACVR2B, and IRS1 in Tibetans.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34302448","citation_count":6,"is_preprint":false},{"pmid":"38851743","id":"PMC_38851743","title":"Sponging of five tumour suppressor miRNAs by lncRNA-KCNQ1OT1 activates BMPR1A/BMPR1B-ACVR2A/ACVR2B signalling and promotes chemoresistance in hepatocellular carcinoma.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38851743","citation_count":6,"is_preprint":false},{"pmid":"22911153","id":"PMC_22911153","title":"Structural and functional characterizations of activin type 2B receptor (acvr2b) ortholog from the marine fish, gilthead sea bream, Sparus aurata: evidence for gene duplication of 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 patients with mature-onset diabetes of the young or type 2 diabetes.","date":"2001","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/11334431","citation_count":4,"is_preprint":false},{"pmid":"33706404","id":"PMC_33706404","title":"Activin A and Acvr2b mRNA from Umbilical Cord Blood Are Not Reliable Markers of Mild or Moderate Neonatal Hypoxic-Ischemic Encephalopathy.","date":"2021","source":"Neuropediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/33706404","citation_count":3,"is_preprint":false},{"pmid":"38334613","id":"PMC_38334613","title":"The Activation of the Fibrodysplasia Ossificans Progressiva-Inducing ALK2-R206H Mutant Depends on the Distinct Homo-Oligomerization Patterns of ACVR2B and ACVR2A.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38334613","citation_count":2,"is_preprint":false},{"pmid":"39533028","id":"PMC_39533028","title":"ACVR2B polymorphism, Adiponectin, and GDF-15 levels as biomarkers for cachexia in gastrointestinal 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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":25204,"output_tokens":3862,"usd":0.066771},"stage2":{"model":"claude-opus-4-6","input_tokens":7271,"output_tokens":2788,"usd":0.159082},"total_usd":0.225853,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","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 signaling through these receptors in combination with ALK2, but not BMPs signaling through BMPR2 with ALK3/ALK6, establishing that activin A competitively inhibits BMP-ACVR2A/ACVR2B/ALK2 signaling complexes.\",\n      \"method\": \"Cell-based signaling assays using myeloma cell lines with characterized BMP-receptor expression; ligand competition experiments\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple BMP ligand/receptor combinations tested in well-characterized cell lines, replicated across receptor contexts\",\n      \"pmids\": [\"26047946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BMP3 suppresses osteoblast differentiation of bone marrow stromal cells through direct interaction with Acvr2b; knockdown of Acvr2b reduces the suppressive effect of BMP3 on osteoblast differentiation, placing BMP3 upstream of Acvr2b in the negative regulation of bone formation.\",\n      \"method\": \"In vitro cultures of primary bone marrow stromal cells; BMP3 overexpression/loss-of-function; Acvr2b siRNA knockdown; colony-forming unit assays\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via knockdown with defined cellular phenotype, supported by gain- and loss-of-function experiments\",\n      \"pmids\": [\"22074949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2B forms stable homomeric complexes (enhanced by Activin A), while ACVR2A requires Activin A for homodimerization. ACVR2B, but not ACVR2A, can activate the FOP-inducing ALK2-R206H mutant in a ligand-independent manner by inducing its oligomerization; ACVR2A requires Activin A to induce ALK2-R206H oligomerization and signaling to SMAD1/5/8.\",\n      \"method\": \"IgG-mediated receptor immobilization combined with FRAP to measure lateral diffusion and oligomerization; pSMAD1/5/8 western blot; BRE-Luc transcriptional reporter assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biophysical quantification of receptor complexes combined with functional signaling assays and mutagenesis (R206H mutant)\",\n      \"pmids\": [\"38334613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Activin A signals through ACVR2B forming an assembly with ACVR1B and NOX4 in osteoarthritic cartilage; NOX4 directly binds the C-terminal binding site on the ACVR2B-ACVR1B complex and amplifies pathogenic SMAD2/3 signaling for cartilage destruction. ACVR2B knockdown or ligand trapping abrogates this signaling.\",\n      \"method\": \"In silico analysis; transgenic and knockout mouse models (Col2a1-Inhba Tg, Inhba+/-, Nox4-/-); co-immunoprecipitation; shRNA knockdown; SMAD2/3 phosphorylation assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genetic mouse models, co-IP of complex components, and signaling readouts\",\n      \"pmids\": [\"36950748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACVR2A and ACVR2B are the critical type II receptors through which activins or related TGF-β ligands induce FSH production in gonadotropes in vivo; combined conditional knockout of both receptors causes profound FSH deficiency and sterility in both sexes.\",\n      \"method\": \"Cre-lox conditional knockout of Acvr2a and/or Acvr2b in murine gonadotropes; serum FSH measurement; fertility and reproductive phenotyping\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with well-defined hormonal and reproductive phenotypes, both single and double KO characterization\",\n      \"pmids\": [\"32270195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish gastrula, Acvr2b is the primary type II receptor transducing BMP signaling for dorsoventral patterning; maternal-zygotic depletion of Acvr2b abrogates all BMP/pSMAD signaling. Additionally, hyperactive ACVR1-R206H (FOP mutant) signaling is restricted in a dose-dependent manner by Acvr2b levels, demonstrating that Acvr2b concentration modulates FOP-associated aberrant signaling.\",\n      \"method\": \"Genetic mutation of all four acvr2a/acvr2b zebrafish genes; maternal-zygotic mutant analysis; BMP signaling readouts (pSMAD, target gene expression); ACVR1-R206H FOP mutant epistasis\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive genetic dissection using maternal-zygotic mutants with clear molecular and patterning phenotypes\",\n      \"pmids\": [\"41279820\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Systemic blockade of ACVR2B ligands (including myostatin) using ACVR2B-Fc protects myocardium from ischemia-reperfusion injury by antagonizing SMAD2 signaling and cardiomyocyte death under hypoxic stress, and modifying cardiac metabolism toward physiological hypertrophy.\",\n      \"method\": \"In vivo mouse myocardial IR injury model with ACVR2B-Fc treatment; in vitro cardiomyocyte hypoxia assay; SMAD2 phosphorylation assays; LV function echocardiography; mitochondrial respiration measurement\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro with defined molecular readout (SMAD2 antagonism), single lab\",\n      \"pmids\": [\"30765322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Blocking ACVR2B ligand signaling with soluble ACVR2B-Fc (sACVR2B-Fc) prevents chemotherapy (doxorubicin)-induced muscle atrophy by restoring muscle protein synthesis without affecting protein degradation pathways, atrogenes, or mitochondrial oxidative capacity.\",\n      \"method\": \"In vivo mouse model; sACVR2B-Fc pharmacological treatment; muscle protein synthesis measurement; atrogene expression; mitochondrial function assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KD with specific molecular mechanism (protein synthesis restoration) identified, single lab\",\n      \"pmids\": [\"27666826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Spermidine represses H3K56 acetylation at the ACVR2B promoter and reduces Smad3 binding to myogenic gene promoters (Myf5, MyoD), linking ACVR2B transcriptional regulation to satellite cell activation and muscle atrophy.\",\n      \"method\": \"ChIP assay for H3K56ac and Smad3 at ACVR2B and myogenic gene promoters in mouse muscle; spermidine administration in vivo\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP assays provide direct evidence of epigenetic regulation at ACVR2B locus with functional context, single lab\",\n      \"pmids\": [\"29224337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ACVR2B extracellular domain (ECD) from sea bream directly inhibits myostatin activity in a CAGA-luciferase reporter assay in A204 cells, demonstrating conserved ligand-binding and inhibitory function of the receptor's extracellular domain. Evidence for N-glycosylation of Acvr2b-ECD was also provided.\",\n      \"method\": \"In vitro CAGA-luciferase reporter assay in A204 cells; recombinant Acvr2b-ECD expressed in Pichia pastoris; glycosylation analysis\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution assay demonstrating direct ligand inhibition, but in fish ortholog context\",\n      \"pmids\": [\"22911153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In zebrafish, acvr2b morphant knockdown causes defects restricted to posterior pharyngeal arch structures and aberrant migration of posterior neural crest cell streams, defining a distinct in vivo role for acvr2b versus acvr2a in craniofacial neural crest patterning.\",\n      \"method\": \"Morpholino-based targeted protein depletion in zebrafish; phenotypic analysis of cartilage, bone, and pharyngeal structures\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — morpholino loss-of-function with specific anatomical phenotype, ortholog in zebrafish\",\n      \"pmids\": [\"15977175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2B-Fc fusion protein secreted by iPSC-derived mesenchymal stem cells attenuates BMP signaling initiated by Activin-A and BMP-9 in FOP patient-derived iMSCs and reduces heterotopic ossification in a transgenic FOP mouse model (ACVR1-R206H), demonstrating that ACVR2B-Fc acts as a neutralizing decoy receptor for these ligands.\",\n      \"method\": \"In vitro BMP signaling assays (pSMAD) in FOP-iMSCs; in vivo transplantation into FOP transgenic mice; treadmill performance assay\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo evidence with defined molecular readout, single lab\",\n      \"pmids\": [\"38500216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Acvr2b is a direct target of miR-132; suppression of Acvr2b by miR-132 attenuates p-Smad2/c-jun signaling pathway activation and reduces neuronal apoptosis in ischemic injury models, placing ACVR2B upstream of Smad2/c-jun in ischemic neuronal death signaling.\",\n      \"method\": \"Dual-luciferase reporter gene assay confirming miR-132/Acvr2b interaction; loss-of-function assays in OGD-treated neurons; MCAO mouse model; pSmad2 western blot\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — validated miRNA-target interaction with pathway epistasis, but primarily through overexpression/knockdown approach in a single lab\",\n      \"pmids\": [\"33763412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mutations in human ACVR2B are associated with left-right axis malformations, consistent with the known role of mouse Acvr2b in left-right axis development established by targeted disruption studies.\",\n      \"method\": \"Genomic structure characterization; splice variant analysis; mutation screening in 126 LR axis malformation cases; comparison to 200 control chromosomes\",\n      \"journal\": \"American journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — human mutation identification corroborated by mouse targeted disruption data from referenced prior work\",\n      \"pmids\": [\"9916847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BMSC-derived exosomal miRNAs (let-7a-5p, let-7c-5p, miR-328a-5p, miR-31a-5p) target Acvr2b/Acvr1 to regulate the competitive balance of Bmpr2/Acvr2b, shifting signaling toward BMP receptor-elicited Smad1/5/9 phosphorylation and promoting osteogenesis.\",\n      \"method\": \"miRNA microarray; gene silencing; miRNA transfection; pathway verification via Smad1/5/9 phosphorylation assays; rat cranial defect model\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro pathway verification with gene silencing and transfection plus in vivo model, single lab\",\n      \"pmids\": [\"33838528\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACVR2B is a type II serine/threonine kinase receptor of the TGF-β superfamily that forms ligand-enhanced homomeric and heteromeric complexes with type I receptors (ALK2, ALK4, ACVR1B); it binds activins, myostatin, BMP3, and select BMPs to transduce SMAD2/3 or SMAD1/5/8 signaling, serves as the primary type II receptor for BMP-driven dorsoventral patterning, mediates negative regulation of skeletal muscle mass and osteoblast differentiation, regulates FSH production in gonadotropes, and its ligand-independent homodimerization enables constitutive activation of the FOP-causing ALK2-R206H mutant.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ACVR2B is a type II serine/threonine kinase receptor of the TGF-β superfamily that binds activins, myostatin, BMP3, and select BMPs to transduce SMAD2/3 and SMAD1/5/8 signaling across diverse developmental and homeostatic contexts. ACVR2B forms ligand-enhanced homomeric complexes and assembles with type I receptors including ALK2 and ACVR1B; its constitutive homodimerization enables ligand-independent activation of the FOP-causing ALK2-R206H mutant, linking receptor oligomerization directly to disease pathogenesis [PMID:38334613]. In skeletal muscle, ACVR2B mediates myostatin and activin signaling to negatively regulate muscle mass via SMAD2/3, and ligand trapping with soluble ACVR2B-Fc prevents muscle atrophy by restoring protein synthesis [PMID:27666826, PMID:22911153]. ACVR2B also functions as the primary type II receptor for BMP-driven dorsoventral patterning, is required with ACVR2A for activin-dependent FSH production in gonadotropes, participates in BMP3-mediated suppression of osteoblast differentiation, and harbors mutations associated with left–right axis malformations in humans [PMID:32270195, PMID:22074949, PMID:9916847].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The first human genetic link between ACVR2B and disease was established when mutations in ACVR2B were identified in patients with left–right axis malformations, consistent with prior mouse knockout data showing laterality defects.\",\n      \"evidence\": \"Mutation screening of 126 human laterality cases versus 200 controls, corroborated by mouse targeted disruption studies\",\n      \"pmids\": [\"9916847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional validation of specific human variants was not performed\",\n        \"Downstream pathway mediating left–right patterning via ACVR2B was not resolved\",\n        \"No structural basis for variant pathogenicity\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"BMP3 was identified as a ligand that acts through ACVR2B to suppress osteoblast differentiation, establishing ACVR2B as a negative regulator of bone formation.\",\n      \"evidence\": \"Acvr2b siRNA knockdown in primary bone marrow stromal cells combined with BMP3 gain- and loss-of-function\",\n      \"pmids\": [\"22074949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Type I receptor partner for BMP3–ACVR2B signaling in osteoblasts was not identified\",\n        \"SMAD branch (SMAD2/3 vs SMAD1/5/8) downstream of BMP3–ACVR2B was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The extracellular domain of ACVR2B was shown to directly inhibit myostatin activity, confirming its ligand-binding specificity and establishing the biochemical basis for soluble decoy receptor strategies.\",\n      \"evidence\": \"Recombinant ACVR2B-ECD expressed in Pichia pastoris tested in CAGA-luciferase reporter assay against myostatin in A204 cells\",\n      \"pmids\": [\"22911153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Fish ortholog ECD used; affinity constants for mammalian ACVR2B not determined\",\n        \"Competition with other TGF-β family ligands not systematically tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Activin A was shown to competitively antagonize BMP signaling specifically through ACVR2A/ACVR2B–ALK2 complexes but not BMPR2–ALK3/ALK6, revealing that ligand competition at the type II receptor determines BMP versus activin pathway output.\",\n      \"evidence\": \"Ligand competition in myeloma cell lines with defined BMP-receptor expression profiles\",\n      \"pmids\": [\"26047946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for selective activin A displacement of BMPs from ACVR2B–ALK2 was not resolved\",\n        \"Physiological tissue contexts where this competition operates were not identified\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Blocking ACVR2B ligand signaling in vivo with soluble ACVR2B-Fc prevented chemotherapy-induced muscle atrophy by restoring protein synthesis rather than suppressing degradation, clarifying the anabolic arm of the receptor's muscle regulation.\",\n      \"evidence\": \"Mouse doxorubicin model with ACVR2B-Fc treatment; muscle protein synthesis measurement and atrogene profiling\",\n      \"pmids\": [\"27666826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific ligand(s) responsible for doxorubicin-induced signaling through ACVR2B were not identified\",\n        \"Downstream translational targets restoring synthesis were not characterized\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A ternary complex of ACVR2B–ACVR1B–NOX4 was identified in osteoarthritic cartilage, showing that NOX4 binds the receptor complex to amplify pathogenic SMAD2/3 signaling, expanding the receptor's known effector repertoire beyond SMADs.\",\n      \"evidence\": \"Co-immunoprecipitation, genetic mouse models (Col2a1-Inhba Tg, Nox4 KO), ACVR2B knockdown, and pSMAD2/3 readouts\",\n      \"pmids\": [\"36950748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and structural interface of NOX4 binding to ACVR2B–ACVR1B not determined\",\n        \"Whether NOX4 association occurs with other type II receptor complexes was not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Systemic ACVR2B ligand blockade was shown to protect against myocardial ischemia-reperfusion injury by antagonizing SMAD2 signaling, extending ACVR2B's role beyond skeletal muscle to cardiac stress responses.\",\n      \"evidence\": \"Mouse IR injury model with ACVR2B-Fc; in vitro cardiomyocyte hypoxia; echocardiography and mitochondrial respiration\",\n      \"pmids\": [\"30765322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific cardiomyocyte-expressed ligand driving pathogenic SMAD2 activation not identified\",\n        \"Single lab finding; independent replication not available\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conditional knockout in gonadotropes demonstrated that ACVR2A and ACVR2B are jointly required for activin-dependent FSH production, with combined loss causing profound FSH deficiency and sterility.\",\n      \"evidence\": \"Cre-lox conditional knockout of Acvr2a/Acvr2b in murine gonadotropes; serum FSH, fertility phenotyping\",\n      \"pmids\": [\"32270195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative individual contributions of ACVR2A versus ACVR2B to FSH regulation in single KOs were partially redundant and not fully disentangled\",\n        \"Downstream transcriptional program linking receptor signaling to FSHβ gene expression not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Biophysical studies revealed that ACVR2B, unlike ACVR2A, forms stable homomeric complexes constitutively and can activate the FOP-causing ALK2-R206H mutant in a ligand-independent manner, providing a mechanistic explanation for differential receptor contributions to aberrant signaling in FOP.\",\n      \"evidence\": \"FRAP-based receptor immobilization/diffusion measurements; pSMAD1/5/8 and BRE-Luc reporter in cells expressing wild-type or R206H ALK2\",\n      \"pmids\": [\"38334613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for constitutive ACVR2B homodimerization versus ACVR2A's ligand dependence not resolved\",\n        \"Whether ligand-independent activation of ALK2-R206H by ACVR2B occurs in patient tissues not demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural determinants of ACVR2B's constitutive oligomerization, the full repertoire of ACVR2B type I receptor pairings in specific tissues, and how competition among activins, myostatin, and BMPs for ACVR2B is spatiotemporally regulated in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of a full-length ACVR2B homomeric or heteromeric signaling complex\",\n        \"Tissue-specific type I receptor partnerships remain largely inferred from expression data\",\n        \"Quantitative in vivo ligand competition dynamics at ACVR2B are uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 10, 13]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"ACVR2B–ALK2 complex\",\n      \"ACVR2B–ACVR1B–NOX4 complex\"\n    ],\n    \"partners\": [\n      \"ALK2\",\n      \"ACVR1B\",\n      \"NOX4\",\n      \"ACVR2A\",\n      \"SMAD2\",\n      \"SMAD3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}