{"gene":"ACVR1","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":1999,"finding":"ActRIA/ALK2 is required for gastrulation; it functions in extraembryonic visceral endoderm to support mesoderm formation, and its absence reduces HNF4 expression. Chimera analyses showed that ActRIA in extraembryonic cells (not embryonic cells) is the critical locus of function during early gastrulation.","method":"Gene targeting (knockout), reciprocal chimera analyses, molecular marker analysis (HNF4)","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, reciprocal chimera rescue experiment, replicated across two deletion alleles","pmids":["10226013"],"is_preprint":false},{"year":1999,"finding":"ALK2 mediates a BMP/Smad signaling pathway on the right side of the Xenopus embryo that antagonizes left-sided Vg1 activity to control cardiac looping. Truncated (dominant-negative) or constitutively active ALK2 on inappropriate sides causes heart reversals; Smad1 and Smad7 are downstream modulators of this pathway.","method":"RNA injection into Xenopus embryos (dominant-negative and constitutively active constructs), epistasis with Vg1, Smad1, Smad7","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic constructs and epistasis experiments defining pathway position, consistent results across multiple manipulations","pmids":["10556046"],"is_preprint":false},{"year":2001,"finding":"ALK2 acts as the type I receptor for Müllerian inhibiting substance (MIS) signaling in the mesenchyme surrounding the Müllerian duct, activating a BMP-like pathway through SMAD1 (not SMAD2) and inducing SMAD6 expression. Dominant-negative ALK2 blocked MIS-induced signaling and Müllerian duct regression; ALK6 was not required.","method":"Reporter assays (Tlx2-luc, Gal4DBD-Smad1 fusion), dominant-negative ALK2, antisense knockdown, organ culture regression assay, expression analysis, ALK6 knockout mouse analysis","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated in two independent papers (PMID 11376113, 11376112) using multiple orthogonal methods including reporter assays, dominant-negative constructs, antisense, and ex vivo organ culture","pmids":["11376113","11376112"],"is_preprint":false},{"year":2003,"finding":"ALK2 functions as a BMP type I receptor in chondrocytes and, when constitutively activated, induces Indian hedgehog (Ihh) expression in a maturation-independent manner in vitro and in vivo, linking BMP signaling to the Ihh/PTHrP axis during skeletal development.","method":"Overexpression of constitutively active ALK2 in chick chondrocytes (in vitro) and chick limb bud (in vivo retroviral infection), gene expression analysis","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — constitutively active receptor overexpression with defined downstream targets in both in vitro and in vivo settings, single lab","pmids":["12968668"],"is_preprint":false},{"year":2004,"finding":"Neural crest cell-autonomous ALK2 signaling is required for cardiac outflow tract formation and aortic arch development; neural crest-specific deletion impairs migration to the outflow tract, deficient smooth muscle differentiation around aortic arch arteries, and loss of Msx1 expression.","method":"Cre/loxP neural crest-specific conditional knockout (Wnt1-Cre), histology, molecular marker analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout with defined cellular phenotype and downstream marker loss, well-controlled in vivo genetic experiment","pmids":["15226263"],"is_preprint":false},{"year":2005,"finding":"Endothelial-cell-autonomous ALK2 is required for endocardial cushion formation; endothelial-specific Alk2 deletion impairs endothelial-to-mesenchymal transdifferentiation in the AV canal, reduces Msx1 and Snail expression, and decreases phosphorylation of both BMP and TGF-β Smads.","method":"Cre/loxP endothelial-specific conditional knockout (Tie2-Cre), AV canal explant delamination assay, immunostaining for pSmad","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout with defined cellular phenotype, ex vivo explant assay, downstream signaling readout","pmids":["16140292"],"is_preprint":false},{"year":2007,"finding":"In silico modeling predicts that the FOP R206H mutation disrupts a salt bridge between R206 and an invariant aspartate in the GS activation domain, creating a pH-sensitive switch that promotes ligand-independent ACVR1 activation; only histidine (not conservative substitutions) creates this effect.","method":"Homology modeling of wild-type and mutant ACVR1 based on TβRI crystal structure","journal":"Clinical orthopaedics and related research","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational structural prediction only, no in vitro or in vivo functional validation in this study","pmids":["17572636"],"is_preprint":false},{"year":2007,"finding":"Endoglin activates the ALK2-Smad1 pathway to inhibit prostate cancer cell motility; knockdown of ALK2 (but not ALK5) abolished endoglin-mediated reduction of motility, and constitutively active ALK2 restored low-motility phenotype in endoglin-deficient cells.","method":"siRNA knockdown, constitutively active ALK2 overexpression, Smad-specific phosphorylation and promoter activity assays, cell motility assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown and constitutively active rescue with defined phenotypic readout, single lab, multiple methods","pmids":["17496924"],"is_preprint":false},{"year":2008,"finding":"ALK2 R206H (FOP mutation) constitutively activates BMP signaling (pSmad1/5 phosphorylation) without ligand binding; R206H shows decreased binding to FKBP12, leading to leaky BMP signal activation and altered subcellular distribution (plasma membrane localization regardless of BMP-2 stimulation).","method":"Overexpression in C2C12 and HEK293 cells, co-immunoprecipitation for FKBP12 binding, Smad phosphorylation assays, subcellular fractionation/immunofluorescence","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (signaling assay, binding assay, localization), replicated across multiple studies","pmids":["18684712"],"is_preprint":false},{"year":2009,"finding":"R206H ACVR1 activates BMP signaling in the absence of BMP ligand and mediates BMP-independent chondrogenesis; the mutant exhibits reduced binding to FKBP1A, accounting for increased BMP pathway activity. In zebrafish, R206H causes BMP-independent hyperactivation of BMP signaling and embryonic ventralization.","method":"In vitro assays in multiple mammalian cell lines and chick limb bud micromass cultures; COS-7 co-immunoprecipitation for FKBP1A binding; zebrafish embryo injection","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal in vitro and in vivo methods, FKBP1A binding confirmed biochemically, replicated across species","pmids":["19855136"],"is_preprint":false},{"year":2009,"finding":"ALK2 endoglin phosphorylation: ALK2 (and ALK5) phosphorylate endoglin on cytosolic domain threonine residues in prostate cancer cells; constitutively active ALK2 abrogated endoglin's inhibition of cell migration, demonstrating that ALK2-mediated endoglin phosphorylation is a Smad-independent mechanism regulating cell migration.","method":"Co-immunoprecipitation, phosphorylation assays with constitutively active ALK2, cell migration assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical phosphorylation assay plus functional migration readout, single lab","pmids":["19736306"],"is_preprint":false},{"year":2009,"finding":"ALK2 is required for cardiac looping: dominant-negative ALK2 L343P allele, identified in a patient with atrioventricular septal defects, has impaired kinase activity and dominant-interfering activity in vivo in zebrafish, causing improper AV canal formation.","method":"In vitro kinase assay, BMP-specific transcriptional reporter assay, zebrafish embryo RNA injection","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus in vivo zebrafish functional validation, single lab","pmids":["19506109"],"is_preprint":false},{"year":2010,"finding":"ALK2 R206H confers constitutive activity to the BMP receptor, leading to increased Smad1 phosphorylation and BMP transcriptional activity; unlike wild-type ALK2, FOP-ALK2 is not inhibited by FKBP12. Mesenchymal cells expressing R206H are hypersensitized to BMP-induced osteoblast differentiation and mineralization in vitro and form increased bone in vivo.","method":"Smad1 phosphorylation assay, BMP transcriptional reporter assay, overexpression of inhibitory Smads, FKBP12 binding assay, osteoblast differentiation assay, in vivo implantation of hMSCs in nude mice","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including binding assay, signaling assay, differentiation assay, and in vivo bone formation model","pmids":["19929436"],"is_preprint":false},{"year":2010,"finding":"ACVR1 R206H shows weak constitutive BMP pathway activation (pSmad1/5/8), distinct from the strong constitutive Q207D mutant; it shows decreased FKBP1A binding affinity leading to leaky BMP signaling and decreased steady-state R206H protein levels. Wild-type ACVR1 and FKBP1A localize to the plasma membrane upon BMP-2 stimulation, while R206H localizes to the plasma membrane regardless of stimulation.","method":"Smad phosphorylation assays, co-immunoprecipitation (FKBP1A binding), immunofluorescence/subcellular localization in C2C12 and HEK293 cells","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and cell biological methods, consistent with other published work","pmids":["20463014"],"is_preprint":false},{"year":2011,"finding":"Loss of ACVR1 in osteoblasts increases bone mass by activating canonical Wnt signaling; osteoblast-specific Acvr1 knockout upregulates Wnt signaling and suppresses Wnt inhibitors SOST and DKK1. BMP7 dose-dependently upregulates SOST and DKK1 in vitro, defining a BMP7-ACVR1-SOST/DKK1 axis that normally inhibits osteogenesis.","method":"Inducible Cre-loxP osteoblast-specific knockout, micro-CT bone analysis, Wnt pathway and gene expression analysis, in vitro BMP7 treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined molecular pathway, in vitro mechanistic validation, single lab","pmids":["21945937"],"is_preprint":false},{"year":2012,"finding":"The R206H knock-in mouse (Acvr1R206H/+) recapitulates FOP: first digit malformations and postnatal heterotopic endochondral bone formation. Lesions show inflammatory infiltration followed by robust heterotopic bone formation. Tie2+ lineage progenitor cells contribute to endochondral osteogenesis, and both wild-type and mutant cells contribute to ectopic bone.","method":"Gene targeting (knock-in mouse model), radiographic analysis, histology, lineage tracing (Tie2-Cre)","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — first direct in vivo evidence using knock-in model with histological, radiographic, and lineage-tracing validation","pmids":["22508565"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of ALK2 kinase domain in complex with FKBP12 and dorsomorphin reveals that FOP mutations break critical interactions stabilizing the inactive kinase state, reducing FKBP12 binding and promoting GS-loop and αC-helix rearrangements that enable kinase activation.","method":"X-ray crystallography (crystal structure of ALK2 cytoplasmic domain in complex with FKBP12 and dorsomorphin)","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with structural analysis of disease mutations, mechanistically defines FKBP12-ALK2 interaction and inhibitory mechanism","pmids":["22977237"],"is_preprint":false},{"year":2012,"finding":"Constitutively active ALK2 GS-domain mutants require type II BMP receptors (BmpRII and ActRIIa) for signaling and heterotopic ossification in vivo; the type II receptor contribution is independent of their ligand-binding or kinase function but requires an intact cytoplasmic domain, suggesting a nonenzymatic scaffolding role.","method":"Genetic ablation of BmpRII and ActRIIa in cells, rescue by type II receptor expression constructs (kinase-dead, ligand-binding-dead mutants), in vivo HO mouse model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic ablation and rescue experiments defining minimal signaling complex requirements, in vitro and in vivo validation","pmids":["23572558"],"is_preprint":false},{"year":2012,"finding":"STIP1 (stress-induced phosphoprotein 1) binds ALK2 and activates the SMAD-ID3 signaling pathway to promote ovarian cancer cell proliferation; STIP1 binding to ALK2 (not prion protein) was necessary and sufficient for this proliferative effect.","method":"Co-immunoprecipitation, siRNA knockdown, transcriptional reporter assays, cell proliferation assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assay and knockdown with defined signaling pathway, single lab","pmids":["22884369"],"is_preprint":false},{"year":2012,"finding":"Pathogenic FOP ALK2 mutation inhibits iPSC reprogramming and maintenance through constitutive ALK2 activation; specific suppression of ALK2 expression or ALK2 inhibitor treatment rescued iPSC generation, confirming that constitutive ALK2 kinase activity is causally responsible for the reprogramming block.","method":"iPSC generation from FOP fibroblasts, ALK2 siRNA knockdown, ALK2 kinase inhibitor treatment","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic rescue of defined cellular phenotype, single lab","pmids":["22949078"],"is_preprint":false},{"year":2013,"finding":"LDN-212854, a selective ALK2-biased BMP type I receptor kinase inhibitor, potently inhibits ALK2 with ~4 orders of magnitude selectivity for BMP over TGF-β/Activin type I receptors and some preference for ALK2 over ALK1 and ALK3; it inhibits heterotopic ossification in a mutant ALK2 transgenic mouse model.","method":"In vitro kinase selectivity profiling, cell-based BMP signaling assays, in vivo HO mouse model","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus in vivo efficacy, single lab","pmids":["23547776"],"is_preprint":false},{"year":2014,"finding":"ACVR1 mutations in DIPG (same residues mutated in FOP) are constitutively activating, leading to SMAD phosphorylation and increased expression of ID1 and ID2 in tumor cells.","method":"Whole-genome sequencing for mutation identification; functional assays showing SMAD phosphorylation and downstream target expression in tumor cells","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional demonstration of constitutive signaling in tumor cells, replicated in two independent Nature Genetics papers (PMID 24705254, 24705250)","pmids":["24705254","24705250"],"is_preprint":false},{"year":2014,"finding":"Alk2 R206H mutation accelerates chondrogenic differentiation in mouse embryonic fibroblasts, due in part to enhanced BMP ligand sensitivity; loss of Alk2 severely impairs chondrogenesis despite expression of other BMP type I receptors, demonstrating Alk2 as a direct regulator of early chondrogenic commitment.","method":"Acvr1R206H/+ and Acvr1CKO (loss-of-function) mouse embryonic fibroblast chondrogenesis assays, in vivo HEO recruitment assay","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function genetic experiments with defined chondrogenic phenotype, both in vitro and in vivo","pmids":["24449086"],"is_preprint":false},{"year":2015,"finding":"FOP-ACVR1 (R206H) displays neofunction: it abnormally transduces BMP signaling in response to Activin A (which normally only activates TGF-β signaling), enhancing chondrogenesis via aberrant BMP signaling activation in FOP-iPSC-derived mesenchymal stromal cells in vitro and inducing endochondral ossification in vivo.","method":"FOP patient-derived iPSC differentiation to mesenchymal stromal cells, BMP/TGF-β pathway reporter assays with Activin A stimulation, in vivo implantation of FOP-iMSCs","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — patient-derived iPSC model with in vitro signaling pathway dissection and in vivo validation, endogenous locus mutation","pmids":["26621707"],"is_preprint":false},{"year":2015,"finding":"ACVR1/ALK2 is required for chondrocyte proliferation and differentiation particularly in craniofacial and axial skeleton; cartilage-specific Acvr1 conditional knockout mice show shortened cranial base, hypoplastic cervical vertebrae, progressive kyphosis, and decreased Smad1/5 and p38 activation. Double knockouts of Acvr1/Bmpr1a or Acvr1/Bmpr1b show perinatal lethal chondrodysplasia, demonstrating coordinated function.","method":"Cre/loxP cartilage-specific conditional knockout, skeletal analysis, signaling assays (pSmad, p38), double mutant analysis","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — well-controlled tissue-specific knockout with defined molecular and phenotypic readouts, genetic epistasis via double mutants","pmids":["25413979"],"is_preprint":false},{"year":2017,"finding":"FKBP12 preferentially targets ALK2 in hepatocytes to inhibit hepcidin expression; sequestration of FKBP12 (by rapamycin or tacrolimus) activates hepcidin via BMP-SMAD signaling. ALK2 mutants defective in FKBP12 binding increase hepcidin ligand-independently, and ALK2 free of FKBP12 becomes responsive to the noncanonical inflammatory ligand Activin A.","method":"Pharmacologic and genetic FKBP12 manipulation in hepatocytes and mice, ALK2 FKBP12-binding mutants, hepcidin expression assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological and genetic methods in vitro and in vivo, FKBP12-binding mutants used to establish mechanism, multiple orthogonal readouts","pmids":["28864813"],"is_preprint":false},{"year":2017,"finding":"Momelotinib directly inhibits ACVR1 kinase, reducing hepatocyte hepcidin production via suppression of BMP-SMAD signaling, leading to increased iron mobilization and erythropoiesis; this mechanism (not JAK2-mediated ferroportin regulation) explains momelotinib's anemia benefit.","method":"In vitro kinase inhibition assay, rat model of anemia of chronic disease, hepcidin assays, myeloid-specific JAK2 deletion for negative control","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, animal model, genetic negative control (JAK2 deletion), multiple orthogonal methods","pmids":["28188131"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of ALK2 in complex with LDN-212854 shows type I ATP-competitive inhibitor binding to the kinase hinge region via a single hydrogen bond to His286; specificity arises from the 5-quinoline moiety interacting with water-mediated hydrogen bonds involving Lys235 and Glu248 in the inactive ALK2 conformation.","method":"X-ray crystallography","journal":"Bone","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure defining atomic-level binding interactions","pmids":["28918311"],"is_preprint":false},{"year":2017,"finding":"FOP ACVR1 mutations in the kinase domain show greater sensitivity to low BMP levels than GS-domain mutations; FOP mutant receptors respond to both BMP and Activin A; constructs lacking the ligand-binding domain retain increased BMP-pSmad1/5/8 pathway activation relative to wild-type, supporting ligand-independent signaling by the mutant receptors.","method":"Cell-based signaling assays with various ACVR1 mutant constructs including ligand-binding-domain deletions, dose-response to BMP and Activin A","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutant constructs with defined signaling readouts, single lab","pmids":["29097342"],"is_preprint":false},{"year":2017,"finding":"AMPK activation (by metformin/aspirin) downregulates ALK2 by enhancing the interaction between Smad6 and Smurf1, leading to Smurf1-mediated K48-linked ubiquitination and proteasomal degradation of ALK2; knockdown of Smad6 or Smurf1 prevented metformin-induced ALK2 reduction.","method":"Pharmacological AMPK activation/inhibition, dominant-negative/constitutively-active AMPK, siRNA knockdown of Smad6/Smurf1, co-immunoprecipitation, ubiquitination assay, FOP-iPSC osteogenic differentiation","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and biochemical methods including co-IP and ubiquitination assay, single lab","pmids":["28847510"],"is_preprint":false},{"year":2018,"finding":"ACVR1 R206H mutation (FOP) causes a proinflammatory state through NF-κB and p38MAPK pathway activation in primary monocytes/macrophages; FOP monocytes show prolonged NF-κB activation and abnormal cytokine secretion after LPS stimulation; SMAD phosphorylation was not significantly altered in these immune cells.","method":"Primary blood/monocyte/macrophage samples from FOP and control subjects, multiplex cytokine assays, gene expression analysis, NF-κB and p38MAPK pathway assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary human cells from patients, multiple pathway assays, single lab but rigorous","pmids":["30429363"],"is_preprint":false},{"year":2018,"finding":"BMPR2 inhibits ALK2-mediated activin A and BMP signaling via wild-type ALK2 by preventing ALK2 from oligomerizing with the type II receptors ACVR2A and ACVR2B that are necessary for ALK2 activation; knockdown of BMPR2 potentiates activin A/B-induced SMAD1/5/8 activation through endogenous wild-type ALK2.","method":"siRNA knockdown of BMPR2 in multiple myeloma and HepG2 cells, SMAD1/5/8 phosphorylation assays, cell death assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined signaling readout in two cell lines, single lab","pmids":["29739878"],"is_preprint":false},{"year":2019,"finding":"ACVR1 R206H and G328V mutations in DIPG promote tumor initiation by arresting glial/oligodendroglial differentiation and activate STAT3 signaling in vitro; in vivo, ACVR1 R206H with H3.1K27M and p53 deletion in combination with PDGFA signaling significantly decreases survival and increases tumor incidence.","method":"In vitro signaling assays, in vivo mouse glioma model (intracranial injection), genetic epistasis, ACVR1 inhibitor treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with defined tumor phenotype and signaling readouts, in vitro epistasis, single lab","pmids":["30833574"],"is_preprint":false},{"year":2019,"finding":"Acvr1 G328V mutation arrests oligodendroglial lineage cell differentiation, driving tumorigenesis in a mouse model of DIPG; mechanistically, mutant Acvr1 upregulates transcription factors controlling differentiation and tumor cell fitness. E6201 was identified as a dual ACVR1/MEK1/2 inhibitor effective against tumor cells in vivo.","method":"Mouse models of gliomagenesis, differentiation assays, transcription factor expression analysis, in vivo drug treatment","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model plus transcriptional mechanistic analysis, single lab","pmids":["32142668"],"is_preprint":false},{"year":2019,"finding":"PSMD14 deubiquitinase stabilizes ALK2 by removing K48-linked ubiquitin chains (mediated by Smurf1 E3 ligase), thereby positively regulating initiation of the BMP6 signaling pathway; PSMD14 or ALK2 depletion reduces colorectal cancer tumorigenesis and cancer stemness.","method":"DUB siRNA library screen, immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo xenograft model","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitination assay and in vivo functional validation, single lab","pmids":["31685442"],"is_preprint":false},{"year":2020,"finding":"FOP-ACVR1 mutants R206H and G328R signal through multiple modalities in zebrafish: they do not require their ligand-binding domain for ligand-independent BMP signaling; however, intact R206H can respond to both Bmp7 and Activin A. The normal type I BMP receptor BMPR1 is dispensable for FOP-ACVR1-mediated signaling.","method":"Zebrafish DV patterning assay, injection of FOP-ACVR1 deletion constructs (ligand-binding domain removed), genetic epistasis with BMPR1","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple ACVR1 mutant constructs tested in vivo in zebrafish with epistasis analysis, clear mechanistic dissection","pmids":["32897189"],"is_preprint":false},{"year":2021,"finding":"ACVR1R206H is activated by two distinct mechanisms: (1) wild-type ACVR1 is activated by upstream ACVR1B/C kinases; (2) ACVR1R206H activation does not require upstream kinases but is predominantly activated via Activin A-induced receptor clustering that causes auto-activation. Activin A-induced clustering requires type II receptors ACVR2A/B.","method":"Optogenetics, live-imaging of receptor clustering, phospho-SMAD1/5 signaling assays, kinase-dead constructs, ACVR2A/B knockdown","journal":"EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including optogenetics, live imaging, and signaling assays, mechanistically rigorous dissection of activation mechanism","pmids":["34003511"],"is_preprint":false},{"year":2021,"finding":"Structural basis for ALK2/BMPR2 signaling: the kinase domain of type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes; this heterodimer is essential for ligand-induced receptor signaling and serves as the scaffold for the active tetrameric receptor complex that enables GS domain phosphorylation and SMAD activation.","method":"Hydrogen-deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS), molecular dynamics simulations, SMAD signaling assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple structural methods (HDX-MS, SAXS, MD) combined with functional SMAD signaling validation, rigorous mechanistic study","pmids":["34400635"],"is_preprint":false},{"year":2021,"finding":"FOP-macrophages (ACVR1R206H) show prolonged inflammatory cytokine production and higher Activin A production after M1-like polarization, dampening responses to additional LPS stimulation; macrophages are identified as a source of Activin A that may drive heterotopic ossification.","method":"hiPSC-derived macrophages from FOP patients, cytokine multiplex assays, phagocytosis assays, M1/M2 polarization assays","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived iPSC macrophage model with functional assays, single lab","pmids":["34311122"],"is_preprint":false},{"year":2022,"finding":"Anti-ACVR1 bivalent antibodies that block ligand binding paradoxically stimulate heterotopic ossification in FOP by activating FOP-mutant ACVR1 through antibody-mediated receptor dimerization; this property is specific to FOP-mutant ACVR1, while wild-type ACVR1 is inhibited by the same antibodies.","method":"Anti-ACVR1 monoclonal antibody generation, in vivo FOP mouse models, signaling assays comparing wild-type and mutant ACVR1","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent FOP mouse models, mechanistic explanation (dimerization) validated biochemically, confirmed by two simultaneous independent studies (PMID 35511419, 35503416)","pmids":["35511419","35503416"],"is_preprint":false},{"year":2022,"finding":"ACVR1 R206H mutation in sensory neurons causes ACVR1-dependent hyperexcitability and enhanced responses to TRPV1 and TRPA1 agonists in iPSC-derived nociceptive neurons, providing a mechanism for neuropathic pain hypersensitivity observed in FOP patients.","method":"Quantitative sensory testing in FOP patients, iPSC-derived sensory neuron differentiation, intracellular and extracellular electrophysiology, TRPV1/TRPA1 agonist response assays, ACVR1 inhibitor treatment","journal":"Pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived iPSC neurons with electrophysiology and pharmacological validation, novel cellular context, single lab","pmids":["35442931"],"is_preprint":false},{"year":2024,"finding":"BRCC3 deubiquitinase activates ALK2 by removing K63-linked ubiquitin from Lys-472 and Lys-475 on ALK2, stabilizing/activating the receptor; this activates SMAD1/5/9 and downstream BMP-PPARγ/p53/Id1 signaling in pulmonary artery smooth muscle cells. BRCC3 downregulation in PAH reduces ALK2-BMP signaling, and overexpression of BRCC3 or de-ubiquitin-mimetic ALK2-K472/475R attenuates PASMC proliferation and experimental pulmonary hypertension in mice.","method":"Bioinformatic analysis, co-immunoprecipitation, ubiquitination assay, overexpression/knockdown in PASMCs, SM22α-BRCC3-Tg mouse and Brcc3-/- mouse models, patient samples","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical ubiquitination site mapping at specific lysines, gain- and loss-of-function genetic mouse models, human patient samples, multiple orthogonal methods","pmids":["38557054"],"is_preprint":false},{"year":2018,"finding":"ACVR1R206H mutation alters mechanosensing: mutant Acvr1R206H/+ cells inappropriately respond to soft substrates with a spread morphology typical of stiff-substrate responses and pre-osteoblastic differentiation; this is associated with increased RhoA activation and nuclear localization of RUNX2 on soft substrates, demonstrating altered mechanosensing thresholds downstream of increased BMP signaling.","method":"Acvr1R206H/+ mouse model, in vitro substrate stiffness assays, RhoA activity assay, RUNX2 nuclear localization imaging, fibroproliferative tissue stiffness measurement","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse cells with defined mechanobiology readouts, single lab","pmids":["30379592"],"is_preprint":false},{"year":2016,"finding":"ACVR1R206H mutation has cell-type specific effects in human endothelial cells: FOP iPSC-derived endothelial cells show increased SMAD1/5/8 phosphorylation upon BMP4 stimulation but, unlike FOP iPSCs, do not show increased SMAD1/5/8 phosphorylation upon Activin A stimulation; they express more fibrogenic matrix proteins (Collagen 1/2) and can form in low-BMP conditions. Cell-type differences in ACVR1 and type II receptor expression explain context-specific signaling.","method":"hiPSC-derived endothelial cell differentiation protocol, SMAD1/5/8 phosphorylation assays with BMP4 and Activin A, gene expression analysis, mineralization assays","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived iPSC model at endogenous locus, multiple ligand and signaling assays, single lab","pmids":["27530160"],"is_preprint":false},{"year":2016,"finding":"ACVR1R206H has an altered ligand response: wild-type ACVR1 inhibits BMP2/BMP4 signaling from other BMP type I receptors in a ligand-binding-domain-independent manner, whereas R206H enhances it. BMP6/BMP7 activate wild-type ACVR1 and cause hyper-activation of R206H. Activin A neofunction via R206H requires an intact ligand-binding domain.","method":"Reporter assays with wild-type and mutant ACVR1 constructs (including ligand-binding domain deletions), co-expression with BMPR1A/BMPR1B","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple receptor constructs and ligands tested with defined reporter readouts, single lab","pmids":["27713089"],"is_preprint":false},{"year":2008,"finding":"ALK2 G356D mutation (atypical FOP) constitutively activates BMP signaling (pSmad1/5/8, Id1-luc, alkaline phosphatase), but not p38/ERK1/2 or TGF-β/CAGA signaling; its activity is weaker than R206H, which may explain the milder phenotype, and is suppressed by BMP-Smad pathway inhibitors.","method":"Overexpression in myoblasts, pSmad1/5/8 assay, Id1-luciferase reporter, alkaline phosphatase assay, pharmacological inhibition","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling assays comparing mutant and wild-type receptors, single lab","pmids":["18952055"],"is_preprint":false},{"year":2018,"finding":"FKBP12 suppresses signaling of most ALK2 mutants associated with FOP/DIPG to varying extents; co-expression of BMP type II receptors or ligand stimulation relieves FKBP12 suppression by disrupting the mutant ALK2-FKBP12 interaction. The PF197-8L mutant is uniquely resistant to FKBP12 suppression due to a steric clash between L197 and D36 of FKBP12.","method":"Overexpression of 14 ALK2 mutants with/without FKBP12, BMP signaling assays, structural modeling of FKBP12-ALK2 interaction","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic analysis of 14 ALK2 mutants with defined signaling readout and structural rationale, single lab","pmids":["29551750"],"is_preprint":false},{"year":2018,"finding":"ALK3 undergoes ligand-independent homodimerization, while ALK2 does not homodimerize; ALK2 forms heterodimers with ALK3 in a BMP2/BMP6-dependent manner; both ALK3-ALK3 and ALK2-ALK3 receptor complexes functionally induce hepcidin expression in Huh7 cells.","method":"Co-immunoprecipitation in Huh7 cells with/without BMP2/BMP6, hepcidin expression assays, Alk2/3 double knockout mice","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with multiple conditions, functional hepcidin assay, in vivo double knockout, single lab","pmids":["30227271"],"is_preprint":false},{"year":2017,"finding":"ALK2/ACVR1 and ALK3/BMPR1A, together with BMPR2, mediate pro-angiogenic BMP signaling required for retinal angiogenesis; endothelial-specific deletion of either Alk2/acvr1 or Alk3/Bmpr1a causes delayed radial vascular expansion reminiscent of BMPR2 deletion phenotype.","method":"Endothelial-specific inducible Cre/loxP deletion of Alk2, Alk3, and Bmpr2, retinal vascular phenotype analysis","journal":"Arteriosclerosis thrombosis and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific conditional knockouts with defined vascular phenotype, single lab","pmids":["28232325"],"is_preprint":false}],"current_model":"ACVR1/ALK2 is a TGF-β superfamily BMP type I serine/threonine kinase receptor that forms heterotetrameric signaling complexes with type II receptors (BMPR2, ACVR2A/B) via kinase domain C-lobe dimerization; upon BMP ligand binding or constitutive activation, it phosphorylates the GS domain and downstream SMAD1/5/8 transcription factors (with SMAD-independent p38 and RhoA signaling also documented); its activity is negatively regulated by FKBP12 binding to the GS domain, by K48-ubiquitination via Smurf1 (reversed by PSMD14), and by K63-ubiquitination (reversed by BRCC3 at Lys-472/475); the recurrent FOP gain-of-function mutation R206H reduces FKBP12 binding, locks the receptor at the plasma membrane, enables Activin A-dependent activation via receptor clustering and auto-phosphorylation, and in DIPG cooperates with H3.1K27M and other oncogenic lesions to arrest glial differentiation through STAT3 and transcription factor upregulation; in physiological contexts ACVR1 transduces MIS/AMH signaling through SMAD1, regulates hepcidin expression in hepatocytes (BMP6-ACVR1-SMAD-hepcidin axis governing iron homeostasis), controls cardiac outflow tract, aortic valve, and neural crest development, and mediates chondrogenesis and retinal angiogenesis."},"narrative":{"mechanistic_narrative":"ACVR1/ALK2 is a BMP type I serine/threonine kinase receptor that transduces TGF-β superfamily signals to control mesoderm formation, cardiac and craniofacial development, skeletal chondrogenesis, iron homeostasis, and angiogenesis [PMID:10226013, PMID:11376113, PMID:11376112, PMID:25413979, PMID:28864813, PMID:28232325]. Signaling proceeds through a tetrameric receptor complex in which the ALK2 kinase domain heterodimerizes with the type II receptor BMPR2 via their C-terminal lobes, a scaffold required for ligand-induced GS-domain phosphorylation and downstream SMAD1/5/8 activation [PMID:34400635]; type II receptors ACVR2A/B and BMPR2 are obligate partners, with BMPR2 also restraining activin/BMP signaling by preventing premature ALK2 oligomerization [PMID:23572558, PMID:29739878]. ACVR1 activity is held in check by FKBP12 binding to the GS domain, which stabilizes the inactive kinase, and by ubiquitin turnover: Smurf1-mediated K48 ubiquitination (promoted by AMPK via Smad6 and reversed by the deubiquitinase PSMD14) and BRCC3-reversed K63 ubiquitination at Lys-472/475 tune receptor stability and output [PMID:22977237, PMID:28847510, PMID:31685442, PMID:38557054]. Physiologically, ALK2 serves as the type I receptor for Müllerian inhibiting substance signaling through SMAD1 [PMID:11376113, PMID:11376112], drives a BMP6-ALK2-SMAD axis governing hepatocyte hepcidin expression and systemic iron handling [PMID:28864813, PMID:30227271], and is required cell-autonomously in neural crest and endocardial cells for outflow tract, aortic arch, and endocardial cushion development [PMID:15226263, PMID:16140292]. The recurrent fibrodysplasia ossificans progressiva (FOP) gain-of-function mutation R206H reduces FKBP12 binding, locks the receptor at the plasma membrane, and confers ligand-independent SMAD1/5/8 activation plus a neofunctional response to Activin A driven by Activin-induced receptor clustering and auto-activation, recapitulating heterotopic endochondral ossification in knock-in mice [PMID:18684712, PMID:19855136, PMID:22508565, PMID:26621707, PMID:34003511]. The identical activating residues are mutated in DIPG, where ACVR1 mutants arrest glial differentiation and engage STAT3 and ID transcription factors to promote tumorigenesis [PMID:24705254, PMID:24705250, PMID:30833574, PMID:32142668].","teleology":[{"year":1999,"claim":"Established that ALK2 is a developmentally essential receptor by showing its loss blocks gastrulation through a requirement in extraembryonic visceral endoderm.","evidence":"Gene targeting and reciprocal chimera analyses in mouse with HNF4 marker readout","pmids":["10226013"],"confidence":"High","gaps":["Did not identify the ligand or downstream SMAD effectors in this context","Embryonic versus extraembryonic mechanistic basis of mesoderm support not resolved"]},{"year":2001,"claim":"Defined ALK2 as the type I receptor transmitting MIS/AMH signaling via SMAD1, placing it in BMP-like rather than TGF-β/SMAD2 signaling.","evidence":"Reporter assays, dominant-negative ALK2, antisense knockdown, and ex vivo Müllerian duct regression assay","pmids":["11376113","11376112"],"confidence":"High","gaps":["Type II receptor partner in MIS signaling not defined here","Direct ligand-receptor binding not demonstrated"]},{"year":2005,"claim":"Showed ALK2 acts cell-autonomously in distinct lineages — neural crest and endocardial endothelium — for cardiac development, linking it to EMT and downstream Msx1/Snail.","evidence":"Wnt1-Cre and Tie2-Cre tissue-specific conditional knockouts with explant assays and pSmad immunostaining","pmids":["15226263","16140292"],"confidence":"High","gaps":["Specific BMP ligand driving each lineage not identified","Relative contribution of SMAD versus non-SMAD output unresolved"]},{"year":2009,"claim":"Identified the mechanistic basis of the FOP R206H mutation as reduced FKBP12/FKBP1A binding causing ligand-independent constitutive BMP signaling and aberrant plasma membrane retention.","evidence":"Overexpression in C2C12/HEK293, co-IP for FKBP12 binding, SMAD phosphorylation, subcellular localization, and zebrafish ventralization","pmids":["18684712","19855136"],"confidence":"High","gaps":["Did not explain how reduced FKBP12 binding mechanistically unlocks the kinase","Endogenous-level consequences not yet tested"]},{"year":2012,"claim":"Provided structural and in vivo proof: the ALK2-FKBP12 crystal structure showed FOP mutations break inactivating contacts, and an R206H knock-in mouse recapitulated heterotopic endochondral ossification.","evidence":"X-ray crystallography of ALK2 kinase domain with FKBP12/dorsomorphin, and Acvr1R206H/+ knock-in mouse with lineage tracing","pmids":["22977237","22508565"],"confidence":"High","gaps":["Cellular origin of all ossifying progenitors not fully resolved","Inflammatory trigger of lesions not mechanistically defined"]},{"year":2012,"claim":"Defined the minimal active receptor complex by showing constitutively active ALK2 still requires type II receptors BMPR2/ACVR2A via a nonenzymatic scaffolding role.","evidence":"Genetic ablation and rescue with kinase-dead and ligand-binding-dead type II receptor constructs, plus in vivo HO model","pmids":["23572558"],"confidence":"High","gaps":["Atomic basis of the scaffolding contribution not defined in this study","Stoichiometry of the active complex unresolved here"]},{"year":2014,"claim":"Showed the FOP-activating residues are recurrently mutated in DIPG and drive constitutive SMAD signaling and ID1/ID2 upregulation in tumor cells, extending ACVR1 from skeletal disease into oncogenesis.","evidence":"Whole-genome sequencing and functional SMAD/target expression assays in tumor cells","pmids":["24705254","24705250"],"confidence":"Medium","gaps":["Did not establish how SMAD output drives the differentiation block","Cooperating lesions not yet defined at this stage"]},{"year":2015,"claim":"Demonstrated the neofunction of FOP-ACVR1: the mutant aberrantly transduces BMP signaling in response to Activin A, which normally only drives TGF-β signaling, explaining ligand-driven heterotopic ossification.","evidence":"FOP patient-derived iPSC mesenchymal stromal cells with Activin A reporter assays and in vivo implantation","pmids":["26621707"],"confidence":"High","gaps":["Did not resolve the conformational mechanism of Activin A neofunction","Cell-type specificity of the neofunction not fully mapped"]},{"year":2017,"claim":"Connected ACVR1 to systemic iron homeostasis by showing FKBP12 preferentially restrains ALK2 in hepatocytes to limit hepcidin, and that this axis is pharmacologically druggable.","evidence":"Pharmacologic/genetic FKBP12 manipulation, FKBP12-binding mutants, hepcidin assays, and the kinase inhibitor momelotinib in an anemia model","pmids":["28864813","28188131"],"confidence":"High","gaps":["Physiological ligand integrating inflammatory signals into the hepatic axis not fully resolved","Type II receptor usage in hepatocytes addressed only partially"]},{"year":2019,"claim":"Defined how ACVR1 mutations drive DIPG by arresting oligodendroglial differentiation through STAT3 and transcription-factor upregulation, cooperating with H3K27M and PDGFA, and nominated dual ACVR1/MEK inhibition.","evidence":"In vivo mouse glioma models with genetic epistasis, differentiation and transcription-factor analyses, and inhibitor treatment","pmids":["30833574","32142668"],"confidence":"Medium","gaps":["Direct SMAD-dependence of the differentiation arrest not isolated","Single-lab in vivo models"]},{"year":2021,"claim":"Resolved the activation mechanism: wild-type ALK2 requires upstream ACVR1B/C kinases, whereas R206H bypasses this and is instead activated by Activin A-induced, type-II-receptor-dependent receptor clustering and auto-activation.","evidence":"Optogenetics, live-imaging of receptor clustering, phospho-SMAD assays, kinase-dead constructs, and ACVR2A/B knockdown","pmids":["34003511"],"confidence":"High","gaps":["Quantitative threshold of clustering needed for auto-activation not defined","Generalizability across all FOP/DIPG mutants not tested"]},{"year":2021,"claim":"Provided the structural framework for signaling, showing the ALK2 and BMPR2 kinase domains heterodimerize via C-terminal lobes to scaffold the active tetrameric complex enabling GS-domain phosphorylation.","evidence":"HDX-MS, SAXS, molecular dynamics, and SMAD signaling assays","pmids":["34400635"],"confidence":"High","gaps":["Full ligand-bound tetramer at high resolution not obtained","How disease mutations alter this heterodimer geometry not addressed"]},{"year":2024,"claim":"Extended ACVR1 regulation to deubiquitination control, showing BRCC3 removes K63 ubiquitin at Lys-472/475 to activate ALK2-SMAD-BMP signaling in pulmonary artery smooth muscle, with disease relevance to pulmonary hypertension.","evidence":"Ubiquitination site mapping, co-IP, gain/loss-of-function in PASMCs, BRCC3-Tg and Brcc3-/- mouse models, and patient samples","pmids":["38557054"],"confidence":"High","gaps":["Interplay between K63 (BRCC3) and K48 (Smurf1/PSMD14) ubiquitin regulation not integrated","Upstream signals controlling BRCC3 activity not defined"]},{"year":null,"claim":"How the diverse regulatory inputs — FKBP12 occupancy, K48 and K63 ubiquitin codes, type II receptor scaffolding, and ligand-induced clustering — are quantitatively integrated to set tissue-specific ACVR1 output thresholds remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking ubiquitin regulation to clustering-based activation","Cell-type determinants of Activin A neofunction not fully mapped","Structural basis of the active ligand-bound tetramer not yet defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,10,16,37]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[10,11,37]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,36,44]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[11,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8,9,37]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,4,5,24,48]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,21,32,41]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[29,34,41]}],"complexes":["ALK2-BMPR2 type I/type II receptor heterotetramer","ALK2-FKBP12 inhibitory complex"],"partners":["FKBP12","BMPR2","ACVR2A","ACVR2B","SMURF1","PSMD14","BRCC3","STIP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q04771","full_name":"Activin receptor type-1","aliases":["Activin receptor type I","ACTR-I","Activin receptor-like kinase 2","ALK-2","Serine/threonine-protein kinase receptor R1","SKR1","TGF-B superfamily receptor type I","TSR-I"],"length_aa":509,"mass_kda":57.2,"function":"Bone morphogenetic protein (BMP) type I receptor that is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation (PubMed:20628059, PubMed:22977237). As a type I receptor, forms heterotetrameric receptor complexes with the type II receptors AMHR2, ACVR2A or ACVR2B (PubMed:17911401). Upon binding of ligands such as BMP7 or GDF2/BMP9 to the heteromeric complexes, type II receptors transphosphorylate ACVR1 intracellular domain (PubMed:25354296). In turn, ACVR1 kinase domain is activated and subsequently phosphorylates SMAD1/5/8 proteins that transduce the signal (PubMed:9748228). In addition to its role in mediating BMP pathway-specific signaling, suppresses TGFbeta/activin pathway signaling by interfering with the binding of activin to its type II receptor (PubMed:17911401). Besides canonical SMAD signaling, can activate non-canonical pathways such as p38 mitogen-activated protein kinases/MAPKs (By similarity). May promote the expression of HAMP, potentially via its interaction with BMP6 (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q04771/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACVR1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACVR1","total_profiled":1310},"omim":[{"mim_id":"615886","title":"SCAFFOLDING CK1-ANCHORING PROTEIN G; SACK1G","url":"https://www.omim.org/entry/615886"},{"mim_id":"606215","title":"ATRIOVENTRICULAR SEPTAL DEFECT; AVSD","url":"https://www.omim.org/entry/606215"},{"mim_id":"603295","title":"SMAD FAMILY MEMBER 9; SMAD9","url":"https://www.omim.org/entry/603295"},{"mim_id":"603248","title":"BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE IB; BMPR1B","url":"https://www.omim.org/entry/603248"},{"mim_id":"602991","title":"NOGGIN; NOG","url":"https://www.omim.org/entry/602991"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACVR1"},"hgnc":{"alias_symbol":["SKR1","ALK2","ACVR1A"],"prev_symbol":["ACVRLK2"]},"alphafold":{"accession":"Q04771","domains":[{"cath_id":"2.10.60.10","chopping":"32-93","consensus_level":"high","plddt":86.9437,"start":32,"end":93},{"cath_id":"3.30.200.20","chopping":"194-285","consensus_level":"medium","plddt":87.4597,"start":194,"end":285},{"cath_id":"1.10.510.10","chopping":"290-509","consensus_level":"medium","plddt":94.2364,"start":290,"end":509}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04771","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q04771-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q04771-F1-predicted_aligned_error_v6.png","plddt_mean":83.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACVR1","jax_strain_url":"https://www.jax.org/strain/search?query=ACVR1"},"sequence":{"accession":"Q04771","fasta_url":"https://rest.uniprot.org/uniprotkb/Q04771.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q04771/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04771"}},"corpus_meta":[{"pmid":"24705254","id":"PMC_24705254","title":"Genomic 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Chimera analyses showed that ActRIA in extraembryonic cells (not embryonic cells) is the critical locus of function during early gastrulation.\",\n      \"method\": \"Gene targeting (knockout), reciprocal chimera analyses, molecular marker analysis (HNF4)\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, reciprocal chimera rescue experiment, replicated across two deletion alleles\",\n      \"pmids\": [\"10226013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ALK2 mediates a BMP/Smad signaling pathway on the right side of the Xenopus embryo that antagonizes left-sided Vg1 activity to control cardiac looping. Truncated (dominant-negative) or constitutively active ALK2 on inappropriate sides causes heart reversals; Smad1 and Smad7 are downstream modulators of this pathway.\",\n      \"method\": \"RNA injection into Xenopus embryos (dominant-negative and constitutively active constructs), epistasis with Vg1, Smad1, Smad7\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic constructs and epistasis experiments defining pathway position, consistent results across multiple manipulations\",\n      \"pmids\": [\"10556046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ALK2 acts as the type I receptor for Müllerian inhibiting substance (MIS) signaling in the mesenchyme surrounding the Müllerian duct, activating a BMP-like pathway through SMAD1 (not SMAD2) and inducing SMAD6 expression. Dominant-negative ALK2 blocked MIS-induced signaling and Müllerian duct regression; ALK6 was not required.\",\n      \"method\": \"Reporter assays (Tlx2-luc, Gal4DBD-Smad1 fusion), dominant-negative ALK2, antisense knockdown, organ culture regression assay, expression analysis, ALK6 knockout mouse analysis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated in two independent papers (PMID 11376113, 11376112) using multiple orthogonal methods including reporter assays, dominant-negative constructs, antisense, and ex vivo organ culture\",\n      \"pmids\": [\"11376113\", \"11376112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ALK2 functions as a BMP type I receptor in chondrocytes and, when constitutively activated, induces Indian hedgehog (Ihh) expression in a maturation-independent manner in vitro and in vivo, linking BMP signaling to the Ihh/PTHrP axis during skeletal development.\",\n      \"method\": \"Overexpression of constitutively active ALK2 in chick chondrocytes (in vitro) and chick limb bud (in vivo retroviral infection), gene expression analysis\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — constitutively active receptor overexpression with defined downstream targets in both in vitro and in vivo settings, single lab\",\n      \"pmids\": [\"12968668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Neural crest cell-autonomous ALK2 signaling is required for cardiac outflow tract formation and aortic arch development; neural crest-specific deletion impairs migration to the outflow tract, deficient smooth muscle differentiation around aortic arch arteries, and loss of Msx1 expression.\",\n      \"method\": \"Cre/loxP neural crest-specific conditional knockout (Wnt1-Cre), histology, molecular marker analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout with defined cellular phenotype and downstream marker loss, well-controlled in vivo genetic experiment\",\n      \"pmids\": [\"15226263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Endothelial-cell-autonomous ALK2 is required for endocardial cushion formation; endothelial-specific Alk2 deletion impairs endothelial-to-mesenchymal transdifferentiation in the AV canal, reduces Msx1 and Snail expression, and decreases phosphorylation of both BMP and TGF-β Smads.\",\n      \"method\": \"Cre/loxP endothelial-specific conditional knockout (Tie2-Cre), AV canal explant delamination assay, immunostaining for pSmad\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout with defined cellular phenotype, ex vivo explant assay, downstream signaling readout\",\n      \"pmids\": [\"16140292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In silico modeling predicts that the FOP R206H mutation disrupts a salt bridge between R206 and an invariant aspartate in the GS activation domain, creating a pH-sensitive switch that promotes ligand-independent ACVR1 activation; only histidine (not conservative substitutions) creates this effect.\",\n      \"method\": \"Homology modeling of wild-type and mutant ACVR1 based on TβRI crystal structure\",\n      \"journal\": \"Clinical orthopaedics and related research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational structural prediction only, no in vitro or in vivo functional validation in this study\",\n      \"pmids\": [\"17572636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Endoglin activates the ALK2-Smad1 pathway to inhibit prostate cancer cell motility; knockdown of ALK2 (but not ALK5) abolished endoglin-mediated reduction of motility, and constitutively active ALK2 restored low-motility phenotype in endoglin-deficient cells.\",\n      \"method\": \"siRNA knockdown, constitutively active ALK2 overexpression, Smad-specific phosphorylation and promoter activity assays, cell motility assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown and constitutively active rescue with defined phenotypic readout, single lab, multiple methods\",\n      \"pmids\": [\"17496924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ALK2 R206H (FOP mutation) constitutively activates BMP signaling (pSmad1/5 phosphorylation) without ligand binding; R206H shows decreased binding to FKBP12, leading to leaky BMP signal activation and altered subcellular distribution (plasma membrane localization regardless of BMP-2 stimulation).\",\n      \"method\": \"Overexpression in C2C12 and HEK293 cells, co-immunoprecipitation for FKBP12 binding, Smad phosphorylation assays, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (signaling assay, binding assay, localization), replicated across multiple studies\",\n      \"pmids\": [\"18684712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"R206H ACVR1 activates BMP signaling in the absence of BMP ligand and mediates BMP-independent chondrogenesis; the mutant exhibits reduced binding to FKBP1A, accounting for increased BMP pathway activity. In zebrafish, R206H causes BMP-independent hyperactivation of BMP signaling and embryonic ventralization.\",\n      \"method\": \"In vitro assays in multiple mammalian cell lines and chick limb bud micromass cultures; COS-7 co-immunoprecipitation for FKBP1A binding; zebrafish embryo injection\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal in vitro and in vivo methods, FKBP1A binding confirmed biochemically, replicated across species\",\n      \"pmids\": [\"19855136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ALK2 endoglin phosphorylation: ALK2 (and ALK5) phosphorylate endoglin on cytosolic domain threonine residues in prostate cancer cells; constitutively active ALK2 abrogated endoglin's inhibition of cell migration, demonstrating that ALK2-mediated endoglin phosphorylation is a Smad-independent mechanism regulating cell migration.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays with constitutively active ALK2, cell migration assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical phosphorylation assay plus functional migration readout, single lab\",\n      \"pmids\": [\"19736306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ALK2 is required for cardiac looping: dominant-negative ALK2 L343P allele, identified in a patient with atrioventricular septal defects, has impaired kinase activity and dominant-interfering activity in vivo in zebrafish, causing improper AV canal formation.\",\n      \"method\": \"In vitro kinase assay, BMP-specific transcriptional reporter assay, zebrafish embryo RNA injection\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus in vivo zebrafish functional validation, single lab\",\n      \"pmids\": [\"19506109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ALK2 R206H confers constitutive activity to the BMP receptor, leading to increased Smad1 phosphorylation and BMP transcriptional activity; unlike wild-type ALK2, FOP-ALK2 is not inhibited by FKBP12. Mesenchymal cells expressing R206H are hypersensitized to BMP-induced osteoblast differentiation and mineralization in vitro and form increased bone in vivo.\",\n      \"method\": \"Smad1 phosphorylation assay, BMP transcriptional reporter assay, overexpression of inhibitory Smads, FKBP12 binding assay, osteoblast differentiation assay, in vivo implantation of hMSCs in nude mice\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including binding assay, signaling assay, differentiation assay, and in vivo bone formation model\",\n      \"pmids\": [\"19929436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ACVR1 R206H shows weak constitutive BMP pathway activation (pSmad1/5/8), distinct from the strong constitutive Q207D mutant; it shows decreased FKBP1A binding affinity leading to leaky BMP signaling and decreased steady-state R206H protein levels. Wild-type ACVR1 and FKBP1A localize to the plasma membrane upon BMP-2 stimulation, while R206H localizes to the plasma membrane regardless of stimulation.\",\n      \"method\": \"Smad phosphorylation assays, co-immunoprecipitation (FKBP1A binding), immunofluorescence/subcellular localization in C2C12 and HEK293 cells\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and cell biological methods, consistent with other published work\",\n      \"pmids\": [\"20463014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of ACVR1 in osteoblasts increases bone mass by activating canonical Wnt signaling; osteoblast-specific Acvr1 knockout upregulates Wnt signaling and suppresses Wnt inhibitors SOST and DKK1. BMP7 dose-dependently upregulates SOST and DKK1 in vitro, defining a BMP7-ACVR1-SOST/DKK1 axis that normally inhibits osteogenesis.\",\n      \"method\": \"Inducible Cre-loxP osteoblast-specific knockout, micro-CT bone analysis, Wnt pathway and gene expression analysis, in vitro BMP7 treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined molecular pathway, in vitro mechanistic validation, single lab\",\n      \"pmids\": [\"21945937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The R206H knock-in mouse (Acvr1R206H/+) recapitulates FOP: first digit malformations and postnatal heterotopic endochondral bone formation. Lesions show inflammatory infiltration followed by robust heterotopic bone formation. Tie2+ lineage progenitor cells contribute to endochondral osteogenesis, and both wild-type and mutant cells contribute to ectopic bone.\",\n      \"method\": \"Gene targeting (knock-in mouse model), radiographic analysis, histology, lineage tracing (Tie2-Cre)\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — first direct in vivo evidence using knock-in model with histological, radiographic, and lineage-tracing validation\",\n      \"pmids\": [\"22508565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of ALK2 kinase domain in complex with FKBP12 and dorsomorphin reveals that FOP mutations break critical interactions stabilizing the inactive kinase state, reducing FKBP12 binding and promoting GS-loop and αC-helix rearrangements that enable kinase activation.\",\n      \"method\": \"X-ray crystallography (crystal structure of ALK2 cytoplasmic domain in complex with FKBP12 and dorsomorphin)\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with structural analysis of disease mutations, mechanistically defines FKBP12-ALK2 interaction and inhibitory mechanism\",\n      \"pmids\": [\"22977237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Constitutively active ALK2 GS-domain mutants require type II BMP receptors (BmpRII and ActRIIa) for signaling and heterotopic ossification in vivo; the type II receptor contribution is independent of their ligand-binding or kinase function but requires an intact cytoplasmic domain, suggesting a nonenzymatic scaffolding role.\",\n      \"method\": \"Genetic ablation of BmpRII and ActRIIa in cells, rescue by type II receptor expression constructs (kinase-dead, ligand-binding-dead mutants), in vivo HO mouse model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic ablation and rescue experiments defining minimal signaling complex requirements, in vitro and in vivo validation\",\n      \"pmids\": [\"23572558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STIP1 (stress-induced phosphoprotein 1) binds ALK2 and activates the SMAD-ID3 signaling pathway to promote ovarian cancer cell proliferation; STIP1 binding to ALK2 (not prion protein) was necessary and sufficient for this proliferative effect.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, transcriptional reporter assays, cell proliferation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assay and knockdown with defined signaling pathway, single lab\",\n      \"pmids\": [\"22884369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Pathogenic FOP ALK2 mutation inhibits iPSC reprogramming and maintenance through constitutive ALK2 activation; specific suppression of ALK2 expression or ALK2 inhibitor treatment rescued iPSC generation, confirming that constitutive ALK2 kinase activity is causally responsible for the reprogramming block.\",\n      \"method\": \"iPSC generation from FOP fibroblasts, ALK2 siRNA knockdown, ALK2 kinase inhibitor treatment\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic rescue of defined cellular phenotype, single lab\",\n      \"pmids\": [\"22949078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LDN-212854, a selective ALK2-biased BMP type I receptor kinase inhibitor, potently inhibits ALK2 with ~4 orders of magnitude selectivity for BMP over TGF-β/Activin type I receptors and some preference for ALK2 over ALK1 and ALK3; it inhibits heterotopic ossification in a mutant ALK2 transgenic mouse model.\",\n      \"method\": \"In vitro kinase selectivity profiling, cell-based BMP signaling assays, in vivo HO mouse model\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus in vivo efficacy, single lab\",\n      \"pmids\": [\"23547776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ACVR1 mutations in DIPG (same residues mutated in FOP) are constitutively activating, leading to SMAD phosphorylation and increased expression of ID1 and ID2 in tumor cells.\",\n      \"method\": \"Whole-genome sequencing for mutation identification; functional assays showing SMAD phosphorylation and downstream target expression in tumor cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional demonstration of constitutive signaling in tumor cells, replicated in two independent Nature Genetics papers (PMID 24705254, 24705250)\",\n      \"pmids\": [\"24705254\", \"24705250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Alk2 R206H mutation accelerates chondrogenic differentiation in mouse embryonic fibroblasts, due in part to enhanced BMP ligand sensitivity; loss of Alk2 severely impairs chondrogenesis despite expression of other BMP type I receptors, demonstrating Alk2 as a direct regulator of early chondrogenic commitment.\",\n      \"method\": \"Acvr1R206H/+ and Acvr1CKO (loss-of-function) mouse embryonic fibroblast chondrogenesis assays, in vivo HEO recruitment assay\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function genetic experiments with defined chondrogenic phenotype, both in vitro and in vivo\",\n      \"pmids\": [\"24449086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOP-ACVR1 (R206H) displays neofunction: it abnormally transduces BMP signaling in response to Activin A (which normally only activates TGF-β signaling), enhancing chondrogenesis via aberrant BMP signaling activation in FOP-iPSC-derived mesenchymal stromal cells in vitro and inducing endochondral ossification in vivo.\",\n      \"method\": \"FOP patient-derived iPSC differentiation to mesenchymal stromal cells, BMP/TGF-β pathway reporter assays with Activin A stimulation, in vivo implantation of FOP-iMSCs\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — patient-derived iPSC model with in vitro signaling pathway dissection and in vivo validation, endogenous locus mutation\",\n      \"pmids\": [\"26621707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ACVR1/ALK2 is required for chondrocyte proliferation and differentiation particularly in craniofacial and axial skeleton; cartilage-specific Acvr1 conditional knockout mice show shortened cranial base, hypoplastic cervical vertebrae, progressive kyphosis, and decreased Smad1/5 and p38 activation. Double knockouts of Acvr1/Bmpr1a or Acvr1/Bmpr1b show perinatal lethal chondrodysplasia, demonstrating coordinated function.\",\n      \"method\": \"Cre/loxP cartilage-specific conditional knockout, skeletal analysis, signaling assays (pSmad, p38), double mutant analysis\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-controlled tissue-specific knockout with defined molecular and phenotypic readouts, genetic epistasis via double mutants\",\n      \"pmids\": [\"25413979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FKBP12 preferentially targets ALK2 in hepatocytes to inhibit hepcidin expression; sequestration of FKBP12 (by rapamycin or tacrolimus) activates hepcidin via BMP-SMAD signaling. ALK2 mutants defective in FKBP12 binding increase hepcidin ligand-independently, and ALK2 free of FKBP12 becomes responsive to the noncanonical inflammatory ligand Activin A.\",\n      \"method\": \"Pharmacologic and genetic FKBP12 manipulation in hepatocytes and mice, ALK2 FKBP12-binding mutants, hepcidin expression assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological and genetic methods in vitro and in vivo, FKBP12-binding mutants used to establish mechanism, multiple orthogonal readouts\",\n      \"pmids\": [\"28864813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Momelotinib directly inhibits ACVR1 kinase, reducing hepatocyte hepcidin production via suppression of BMP-SMAD signaling, leading to increased iron mobilization and erythropoiesis; this mechanism (not JAK2-mediated ferroportin regulation) explains momelotinib's anemia benefit.\",\n      \"method\": \"In vitro kinase inhibition assay, rat model of anemia of chronic disease, hepcidin assays, myeloid-specific JAK2 deletion for negative control\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, animal model, genetic negative control (JAK2 deletion), multiple orthogonal methods\",\n      \"pmids\": [\"28188131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of ALK2 in complex with LDN-212854 shows type I ATP-competitive inhibitor binding to the kinase hinge region via a single hydrogen bond to His286; specificity arises from the 5-quinoline moiety interacting with water-mediated hydrogen bonds involving Lys235 and Glu248 in the inactive ALK2 conformation.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure defining atomic-level binding interactions\",\n      \"pmids\": [\"28918311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOP ACVR1 mutations in the kinase domain show greater sensitivity to low BMP levels than GS-domain mutations; FOP mutant receptors respond to both BMP and Activin A; constructs lacking the ligand-binding domain retain increased BMP-pSmad1/5/8 pathway activation relative to wild-type, supporting ligand-independent signaling by the mutant receptors.\",\n      \"method\": \"Cell-based signaling assays with various ACVR1 mutant constructs including ligand-binding-domain deletions, dose-response to BMP and Activin A\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutant constructs with defined signaling readouts, single lab\",\n      \"pmids\": [\"29097342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AMPK activation (by metformin/aspirin) downregulates ALK2 by enhancing the interaction between Smad6 and Smurf1, leading to Smurf1-mediated K48-linked ubiquitination and proteasomal degradation of ALK2; knockdown of Smad6 or Smurf1 prevented metformin-induced ALK2 reduction.\",\n      \"method\": \"Pharmacological AMPK activation/inhibition, dominant-negative/constitutively-active AMPK, siRNA knockdown of Smad6/Smurf1, co-immunoprecipitation, ubiquitination assay, FOP-iPSC osteogenic differentiation\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and biochemical methods including co-IP and ubiquitination assay, single lab\",\n      \"pmids\": [\"28847510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ACVR1 R206H mutation (FOP) causes a proinflammatory state through NF-κB and p38MAPK pathway activation in primary monocytes/macrophages; FOP monocytes show prolonged NF-κB activation and abnormal cytokine secretion after LPS stimulation; SMAD phosphorylation was not significantly altered in these immune cells.\",\n      \"method\": \"Primary blood/monocyte/macrophage samples from FOP and control subjects, multiplex cytokine assays, gene expression analysis, NF-κB and p38MAPK pathway assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary human cells from patients, multiple pathway assays, single lab but rigorous\",\n      \"pmids\": [\"30429363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BMPR2 inhibits ALK2-mediated activin A and BMP signaling via wild-type ALK2 by preventing ALK2 from oligomerizing with the type II receptors ACVR2A and ACVR2B that are necessary for ALK2 activation; knockdown of BMPR2 potentiates activin A/B-induced SMAD1/5/8 activation through endogenous wild-type ALK2.\",\n      \"method\": \"siRNA knockdown of BMPR2 in multiple myeloma and HepG2 cells, SMAD1/5/8 phosphorylation assays, cell death assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined signaling readout in two cell lines, single lab\",\n      \"pmids\": [\"29739878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ACVR1 R206H and G328V mutations in DIPG promote tumor initiation by arresting glial/oligodendroglial differentiation and activate STAT3 signaling in vitro; in vivo, ACVR1 R206H with H3.1K27M and p53 deletion in combination with PDGFA signaling significantly decreases survival and increases tumor incidence.\",\n      \"method\": \"In vitro signaling assays, in vivo mouse glioma model (intracranial injection), genetic epistasis, ACVR1 inhibitor treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with defined tumor phenotype and signaling readouts, in vitro epistasis, single lab\",\n      \"pmids\": [\"30833574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Acvr1 G328V mutation arrests oligodendroglial lineage cell differentiation, driving tumorigenesis in a mouse model of DIPG; mechanistically, mutant Acvr1 upregulates transcription factors controlling differentiation and tumor cell fitness. E6201 was identified as a dual ACVR1/MEK1/2 inhibitor effective against tumor cells in vivo.\",\n      \"method\": \"Mouse models of gliomagenesis, differentiation assays, transcription factor expression analysis, in vivo drug treatment\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model plus transcriptional mechanistic analysis, single lab\",\n      \"pmids\": [\"32142668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMD14 deubiquitinase stabilizes ALK2 by removing K48-linked ubiquitin chains (mediated by Smurf1 E3 ligase), thereby positively regulating initiation of the BMP6 signaling pathway; PSMD14 or ALK2 depletion reduces colorectal cancer tumorigenesis and cancer stemness.\",\n      \"method\": \"DUB siRNA library screen, immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo xenograft model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitination assay and in vivo functional validation, single lab\",\n      \"pmids\": [\"31685442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOP-ACVR1 mutants R206H and G328R signal through multiple modalities in zebrafish: they do not require their ligand-binding domain for ligand-independent BMP signaling; however, intact R206H can respond to both Bmp7 and Activin A. The normal type I BMP receptor BMPR1 is dispensable for FOP-ACVR1-mediated signaling.\",\n      \"method\": \"Zebrafish DV patterning assay, injection of FOP-ACVR1 deletion constructs (ligand-binding domain removed), genetic epistasis with BMPR1\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple ACVR1 mutant constructs tested in vivo in zebrafish with epistasis analysis, clear mechanistic dissection\",\n      \"pmids\": [\"32897189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACVR1R206H is activated by two distinct mechanisms: (1) wild-type ACVR1 is activated by upstream ACVR1B/C kinases; (2) ACVR1R206H activation does not require upstream kinases but is predominantly activated via Activin A-induced receptor clustering that causes auto-activation. Activin A-induced clustering requires type II receptors ACVR2A/B.\",\n      \"method\": \"Optogenetics, live-imaging of receptor clustering, phospho-SMAD1/5 signaling assays, kinase-dead constructs, ACVR2A/B knockdown\",\n      \"journal\": \"EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including optogenetics, live imaging, and signaling assays, mechanistically rigorous dissection of activation mechanism\",\n      \"pmids\": [\"34003511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Structural basis for ALK2/BMPR2 signaling: the kinase domain of type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes; this heterodimer is essential for ligand-induced receptor signaling and serves as the scaffold for the active tetrameric receptor complex that enables GS domain phosphorylation and SMAD activation.\",\n      \"method\": \"Hydrogen-deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS), molecular dynamics simulations, SMAD signaling assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple structural methods (HDX-MS, SAXS, MD) combined with functional SMAD signaling validation, rigorous mechanistic study\",\n      \"pmids\": [\"34400635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOP-macrophages (ACVR1R206H) show prolonged inflammatory cytokine production and higher Activin A production after M1-like polarization, dampening responses to additional LPS stimulation; macrophages are identified as a source of Activin A that may drive heterotopic ossification.\",\n      \"method\": \"hiPSC-derived macrophages from FOP patients, cytokine multiplex assays, phagocytosis assays, M1/M2 polarization assays\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived iPSC macrophage model with functional assays, single lab\",\n      \"pmids\": [\"34311122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Anti-ACVR1 bivalent antibodies that block ligand binding paradoxically stimulate heterotopic ossification in FOP by activating FOP-mutant ACVR1 through antibody-mediated receptor dimerization; this property is specific to FOP-mutant ACVR1, while wild-type ACVR1 is inhibited by the same antibodies.\",\n      \"method\": \"Anti-ACVR1 monoclonal antibody generation, in vivo FOP mouse models, signaling assays comparing wild-type and mutant ACVR1\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent FOP mouse models, mechanistic explanation (dimerization) validated biochemically, confirmed by two simultaneous independent studies (PMID 35511419, 35503416)\",\n      \"pmids\": [\"35511419\", \"35503416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACVR1 R206H mutation in sensory neurons causes ACVR1-dependent hyperexcitability and enhanced responses to TRPV1 and TRPA1 agonists in iPSC-derived nociceptive neurons, providing a mechanism for neuropathic pain hypersensitivity observed in FOP patients.\",\n      \"method\": \"Quantitative sensory testing in FOP patients, iPSC-derived sensory neuron differentiation, intracellular and extracellular electrophysiology, TRPV1/TRPA1 agonist response assays, ACVR1 inhibitor treatment\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived iPSC neurons with electrophysiology and pharmacological validation, novel cellular context, single lab\",\n      \"pmids\": [\"35442931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRCC3 deubiquitinase activates ALK2 by removing K63-linked ubiquitin from Lys-472 and Lys-475 on ALK2, stabilizing/activating the receptor; this activates SMAD1/5/9 and downstream BMP-PPARγ/p53/Id1 signaling in pulmonary artery smooth muscle cells. BRCC3 downregulation in PAH reduces ALK2-BMP signaling, and overexpression of BRCC3 or de-ubiquitin-mimetic ALK2-K472/475R attenuates PASMC proliferation and experimental pulmonary hypertension in mice.\",\n      \"method\": \"Bioinformatic analysis, co-immunoprecipitation, ubiquitination assay, overexpression/knockdown in PASMCs, SM22α-BRCC3-Tg mouse and Brcc3-/- mouse models, patient samples\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical ubiquitination site mapping at specific lysines, gain- and loss-of-function genetic mouse models, human patient samples, multiple orthogonal methods\",\n      \"pmids\": [\"38557054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ACVR1R206H mutation alters mechanosensing: mutant Acvr1R206H/+ cells inappropriately respond to soft substrates with a spread morphology typical of stiff-substrate responses and pre-osteoblastic differentiation; this is associated with increased RhoA activation and nuclear localization of RUNX2 on soft substrates, demonstrating altered mechanosensing thresholds downstream of increased BMP signaling.\",\n      \"method\": \"Acvr1R206H/+ mouse model, in vitro substrate stiffness assays, RhoA activity assay, RUNX2 nuclear localization imaging, fibroproliferative tissue stiffness measurement\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse cells with defined mechanobiology readouts, single lab\",\n      \"pmids\": [\"30379592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ACVR1R206H mutation has cell-type specific effects in human endothelial cells: FOP iPSC-derived endothelial cells show increased SMAD1/5/8 phosphorylation upon BMP4 stimulation but, unlike FOP iPSCs, do not show increased SMAD1/5/8 phosphorylation upon Activin A stimulation; they express more fibrogenic matrix proteins (Collagen 1/2) and can form in low-BMP conditions. Cell-type differences in ACVR1 and type II receptor expression explain context-specific signaling.\",\n      \"method\": \"hiPSC-derived endothelial cell differentiation protocol, SMAD1/5/8 phosphorylation assays with BMP4 and Activin A, gene expression analysis, mineralization assays\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived iPSC model at endogenous locus, multiple ligand and signaling assays, single lab\",\n      \"pmids\": [\"27530160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ACVR1R206H has an altered ligand response: wild-type ACVR1 inhibits BMP2/BMP4 signaling from other BMP type I receptors in a ligand-binding-domain-independent manner, whereas R206H enhances it. BMP6/BMP7 activate wild-type ACVR1 and cause hyper-activation of R206H. Activin A neofunction via R206H requires an intact ligand-binding domain.\",\n      \"method\": \"Reporter assays with wild-type and mutant ACVR1 constructs (including ligand-binding domain deletions), co-expression with BMPR1A/BMPR1B\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple receptor constructs and ligands tested with defined reporter readouts, single lab\",\n      \"pmids\": [\"27713089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ALK2 G356D mutation (atypical FOP) constitutively activates BMP signaling (pSmad1/5/8, Id1-luc, alkaline phosphatase), but not p38/ERK1/2 or TGF-β/CAGA signaling; its activity is weaker than R206H, which may explain the milder phenotype, and is suppressed by BMP-Smad pathway inhibitors.\",\n      \"method\": \"Overexpression in myoblasts, pSmad1/5/8 assay, Id1-luciferase reporter, alkaline phosphatase assay, pharmacological inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling assays comparing mutant and wild-type receptors, single lab\",\n      \"pmids\": [\"18952055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FKBP12 suppresses signaling of most ALK2 mutants associated with FOP/DIPG to varying extents; co-expression of BMP type II receptors or ligand stimulation relieves FKBP12 suppression by disrupting the mutant ALK2-FKBP12 interaction. The PF197-8L mutant is uniquely resistant to FKBP12 suppression due to a steric clash between L197 and D36 of FKBP12.\",\n      \"method\": \"Overexpression of 14 ALK2 mutants with/without FKBP12, BMP signaling assays, structural modeling of FKBP12-ALK2 interaction\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic analysis of 14 ALK2 mutants with defined signaling readout and structural rationale, single lab\",\n      \"pmids\": [\"29551750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ALK3 undergoes ligand-independent homodimerization, while ALK2 does not homodimerize; ALK2 forms heterodimers with ALK3 in a BMP2/BMP6-dependent manner; both ALK3-ALK3 and ALK2-ALK3 receptor complexes functionally induce hepcidin expression in Huh7 cells.\",\n      \"method\": \"Co-immunoprecipitation in Huh7 cells with/without BMP2/BMP6, hepcidin expression assays, Alk2/3 double knockout mice\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with multiple conditions, functional hepcidin assay, in vivo double knockout, single lab\",\n      \"pmids\": [\"30227271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ALK2/ACVR1 and ALK3/BMPR1A, together with BMPR2, mediate pro-angiogenic BMP signaling required for retinal angiogenesis; endothelial-specific deletion of either Alk2/acvr1 or Alk3/Bmpr1a causes delayed radial vascular expansion reminiscent of BMPR2 deletion phenotype.\",\n      \"method\": \"Endothelial-specific inducible Cre/loxP deletion of Alk2, Alk3, and Bmpr2, retinal vascular phenotype analysis\",\n      \"journal\": \"Arteriosclerosis thrombosis and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific conditional knockouts with defined vascular phenotype, single lab\",\n      \"pmids\": [\"28232325\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACVR1/ALK2 is a TGF-β superfamily BMP type I serine/threonine kinase receptor that forms heterotetrameric signaling complexes with type II receptors (BMPR2, ACVR2A/B) via kinase domain C-lobe dimerization; upon BMP ligand binding or constitutive activation, it phosphorylates the GS domain and downstream SMAD1/5/8 transcription factors (with SMAD-independent p38 and RhoA signaling also documented); its activity is negatively regulated by FKBP12 binding to the GS domain, by K48-ubiquitination via Smurf1 (reversed by PSMD14), and by K63-ubiquitination (reversed by BRCC3 at Lys-472/475); the recurrent FOP gain-of-function mutation R206H reduces FKBP12 binding, locks the receptor at the plasma membrane, enables Activin A-dependent activation via receptor clustering and auto-phosphorylation, and in DIPG cooperates with H3.1K27M and other oncogenic lesions to arrest glial differentiation through STAT3 and transcription factor upregulation; in physiological contexts ACVR1 transduces MIS/AMH signaling through SMAD1, regulates hepcidin expression in hepatocytes (BMP6-ACVR1-SMAD-hepcidin axis governing iron homeostasis), controls cardiac outflow tract, aortic valve, and neural crest development, and mediates chondrogenesis and retinal angiogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACVR1/ALK2 is a BMP type I serine/threonine kinase receptor that transduces TGF-β superfamily signals to control mesoderm formation, cardiac and craniofacial development, skeletal chondrogenesis, iron homeostasis, and angiogenesis [#0, #2, #24, #25, #48]. Signaling proceeds through a tetrameric receptor complex in which the ALK2 kinase domain heterodimerizes with the type II receptor BMPR2 via their C-terminal lobes, a scaffold required for ligand-induced GS-domain phosphorylation and downstream SMAD1/5/8 activation [#37]; type II receptors ACVR2A/B and BMPR2 are obligate partners, with BMPR2 also restraining activin/BMP signaling by preventing premature ALK2 oligomerization [#17, #31]. ACVR1 activity is held in check by FKBP12 binding to the GS domain, which stabilizes the inactive kinase, and by ubiquitin turnover: Smurf1-mediated K48 ubiquitination (promoted by AMPK via Smad6 and reversed by the deubiquitinase PSMD14) and BRCC3-reversed K63 ubiquitination at Lys-472/475 tune receptor stability and output [#16, #29, #34, #41]. Physiologically, ALK2 serves as the type I receptor for Müllerian inhibiting substance signaling through SMAD1 [#2], drives a BMP6-ALK2-SMAD axis governing hepatocyte hepcidin expression and systemic iron handling [#25, #47], and is required cell-autonomously in neural crest and endocardial cells for outflow tract, aortic arch, and endocardial cushion development [#4, #5]. The recurrent fibrodysplasia ossificans progressiva (FOP) gain-of-function mutation R206H reduces FKBP12 binding, locks the receptor at the plasma membrane, and confers ligand-independent SMAD1/5/8 activation plus a neofunctional response to Activin A driven by Activin-induced receptor clustering and auto-activation, recapitulating heterotopic endochondral ossification in knock-in mice [#8, #9, #15, #23, #36]. The identical activating residues are mutated in DIPG, where ACVR1 mutants arrest glial differentiation and engage STAT3 and ID transcription factors to promote tumorigenesis [#21, #32, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that ALK2 is a developmentally essential receptor by showing its loss blocks gastrulation through a requirement in extraembryonic visceral endoderm.\",\n      \"evidence\": \"Gene targeting and reciprocal chimera analyses in mouse with HNF4 marker readout\",\n      \"pmids\": [\"10226013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the ligand or downstream SMAD effectors in this context\", \"Embryonic versus extraembryonic mechanistic basis of mesoderm support not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined ALK2 as the type I receptor transmitting MIS/AMH signaling via SMAD1, placing it in BMP-like rather than TGF-β/SMAD2 signaling.\",\n      \"evidence\": \"Reporter assays, dominant-negative ALK2, antisense knockdown, and ex vivo Müllerian duct regression assay\",\n      \"pmids\": [\"11376113\", \"11376112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Type II receptor partner in MIS signaling not defined here\", \"Direct ligand-receptor binding not demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed ALK2 acts cell-autonomously in distinct lineages — neural crest and endocardial endothelium — for cardiac development, linking it to EMT and downstream Msx1/Snail.\",\n      \"evidence\": \"Wnt1-Cre and Tie2-Cre tissue-specific conditional knockouts with explant assays and pSmad immunostaining\",\n      \"pmids\": [\"15226263\", \"16140292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific BMP ligand driving each lineage not identified\", \"Relative contribution of SMAD versus non-SMAD output unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the mechanistic basis of the FOP R206H mutation as reduced FKBP12/FKBP1A binding causing ligand-independent constitutive BMP signaling and aberrant plasma membrane retention.\",\n      \"evidence\": \"Overexpression in C2C12/HEK293, co-IP for FKBP12 binding, SMAD phosphorylation, subcellular localization, and zebrafish ventralization\",\n      \"pmids\": [\"18684712\", \"19855136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how reduced FKBP12 binding mechanistically unlocks the kinase\", \"Endogenous-level consequences not yet tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided structural and in vivo proof: the ALK2-FKBP12 crystal structure showed FOP mutations break inactivating contacts, and an R206H knock-in mouse recapitulated heterotopic endochondral ossification.\",\n      \"evidence\": \"X-ray crystallography of ALK2 kinase domain with FKBP12/dorsomorphin, and Acvr1R206H/+ knock-in mouse with lineage tracing\",\n      \"pmids\": [\"22977237\", \"22508565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular origin of all ossifying progenitors not fully resolved\", \"Inflammatory trigger of lesions not mechanistically defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the minimal active receptor complex by showing constitutively active ALK2 still requires type II receptors BMPR2/ACVR2A via a nonenzymatic scaffolding role.\",\n      \"evidence\": \"Genetic ablation and rescue with kinase-dead and ligand-binding-dead type II receptor constructs, plus in vivo HO model\",\n      \"pmids\": [\"23572558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of the scaffolding contribution not defined in this study\", \"Stoichiometry of the active complex unresolved here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed the FOP-activating residues are recurrently mutated in DIPG and drive constitutive SMAD signaling and ID1/ID2 upregulation in tumor cells, extending ACVR1 from skeletal disease into oncogenesis.\",\n      \"evidence\": \"Whole-genome sequencing and functional SMAD/target expression assays in tumor cells\",\n      \"pmids\": [\"24705254\", \"24705250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish how SMAD output drives the differentiation block\", \"Cooperating lesions not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated the neofunction of FOP-ACVR1: the mutant aberrantly transduces BMP signaling in response to Activin A, which normally only drives TGF-β signaling, explaining ligand-driven heterotopic ossification.\",\n      \"evidence\": \"FOP patient-derived iPSC mesenchymal stromal cells with Activin A reporter assays and in vivo implantation\",\n      \"pmids\": [\"26621707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the conformational mechanism of Activin A neofunction\", \"Cell-type specificity of the neofunction not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected ACVR1 to systemic iron homeostasis by showing FKBP12 preferentially restrains ALK2 in hepatocytes to limit hepcidin, and that this axis is pharmacologically druggable.\",\n      \"evidence\": \"Pharmacologic/genetic FKBP12 manipulation, FKBP12-binding mutants, hepcidin assays, and the kinase inhibitor momelotinib in an anemia model\",\n      \"pmids\": [\"28864813\", \"28188131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological ligand integrating inflammatory signals into the hepatic axis not fully resolved\", \"Type II receptor usage in hepatocytes addressed only partially\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined how ACVR1 mutations drive DIPG by arresting oligodendroglial differentiation through STAT3 and transcription-factor upregulation, cooperating with H3K27M and PDGFA, and nominated dual ACVR1/MEK inhibition.\",\n      \"evidence\": \"In vivo mouse glioma models with genetic epistasis, differentiation and transcription-factor analyses, and inhibitor treatment\",\n      \"pmids\": [\"30833574\", \"32142668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SMAD-dependence of the differentiation arrest not isolated\", \"Single-lab in vivo models\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the activation mechanism: wild-type ALK2 requires upstream ACVR1B/C kinases, whereas R206H bypasses this and is instead activated by Activin A-induced, type-II-receptor-dependent receptor clustering and auto-activation.\",\n      \"evidence\": \"Optogenetics, live-imaging of receptor clustering, phospho-SMAD assays, kinase-dead constructs, and ACVR2A/B knockdown\",\n      \"pmids\": [\"34003511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative threshold of clustering needed for auto-activation not defined\", \"Generalizability across all FOP/DIPG mutants not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural framework for signaling, showing the ALK2 and BMPR2 kinase domains heterodimerize via C-terminal lobes to scaffold the active tetrameric complex enabling GS-domain phosphorylation.\",\n      \"evidence\": \"HDX-MS, SAXS, molecular dynamics, and SMAD signaling assays\",\n      \"pmids\": [\"34400635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full ligand-bound tetramer at high resolution not obtained\", \"How disease mutations alter this heterodimer geometry not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended ACVR1 regulation to deubiquitination control, showing BRCC3 removes K63 ubiquitin at Lys-472/475 to activate ALK2-SMAD-BMP signaling in pulmonary artery smooth muscle, with disease relevance to pulmonary hypertension.\",\n      \"evidence\": \"Ubiquitination site mapping, co-IP, gain/loss-of-function in PASMCs, BRCC3-Tg and Brcc3-/- mouse models, and patient samples\",\n      \"pmids\": [\"38557054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between K63 (BRCC3) and K48 (Smurf1/PSMD14) ubiquitin regulation not integrated\", \"Upstream signals controlling BRCC3 activity not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse regulatory inputs — FKBP12 occupancy, K48 and K63 ubiquitin codes, type II receptor scaffolding, and ligand-induced clustering — are quantitatively integrated to set tissue-specific ACVR1 output thresholds remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking ubiquitin regulation to clustering-based activation\", \"Cell-type determinants of Activin A neofunction not fully mapped\", \"Structural basis of the active ligand-bound tetramer not yet defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 10, 16, 37]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [10, 11, 37]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 36, 44]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [11, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 9, 37]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 4, 5, 24, 48]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 21, 32, 41]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [29, 34, 41]}\n    ],\n    \"complexes\": [\n      \"ALK2-BMPR2 type I/type II receptor heterotetramer\",\n      \"ALK2-FKBP12 inhibitory complex\"\n    ],\n    \"partners\": [\n      \"FKBP12\",\n      \"BMPR2\",\n      \"ACVR2A\",\n      \"ACVR2B\",\n      \"SMURF1\",\n      \"PSMD14\",\n      \"BRCC3\",\n      \"STIP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}