{"gene":"ACVR2A","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2003,"finding":"Crystal structure of BMP7 in complex with the extracellular domain (ECD) of ACVR2A reveals a cooperative four-receptor assembly model where type I and type II receptor ECDs make no direct contacts, yet truncated receptors lacking cytoplasmic domains retain cooperative assembly in the cell membrane; the affinity of BMP7 for its type I receptor ECD increases 5-fold in the presence of the ACVR2A ECD.","method":"X-ray crystallography; receptor truncation binding assays; cell membrane assembly experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation via binding assays and mutagenesis-equivalent truncation experiments, published in a high-impact journal","pmids":["12667445"],"is_preprint":false},{"year":2003,"finding":"ACVR2 (ACVR2A) undergoes inactivating frameshift mutations at an 8-bp polyadenine tract in gastrointestinal cancers with microsatellite instability (MSI), with biallelic mutations found in 25 of 28 MSI colorectal and pancreatic cancers, establishing ACVR2A as a candidate tumor suppressor gene whose inactivation is under strong selective pressure during gastrointestinal carcinogenesis.","method":"Mutational analysis by sequencing of primary tumor DNA; LOH analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic sequencing of 28 MSI tumors with consistent biallelic inactivation findings replicated across colorectal and pancreatic cancers","pmids":["12615714"],"is_preprint":false},{"year":2004,"finding":"Restoration of wild-type ACVR2A in ACVR2-deficient MSI colon cancer cells decreased cell growth, increased phosphorylated SMAD2, and induced overexpression of TGF-β effector pathway genes including JUND, JUN, FOSB, RHOB, ARHE, and ARHGDIA, demonstrating that ACVR2A signals through SMAD2 phosphorylation and activates AP-1 and small GTPase signaling pathways.","method":"Wild-type ACVR2A transfection; Western blot for pSMAD2; microarray gene expression analysis; cell growth assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function rescue experiment with multiple orthogonal readouts (growth, Western blot, microarray), single lab","pmids":["15520171"],"is_preprint":false},{"year":2005,"finding":"Truncating mutations in ACVR2A found in prostate cancer cell lines result in significantly reduced activin-mediated cell signaling, as measured by an activin response assay, demonstrating that the kinase domain integrity is required for ACVR2A signal transduction.","method":"Sequencing of ACVR2A in prostate cancer lines; activin response functional assay","journal":"Cancer genetics and cytogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional activin response assay directly linking truncating mutations to signaling loss, single lab","pmids":["16337854"],"is_preprint":false},{"year":2005,"finding":"In zebrafish, acvr2a and acvr2b exhibit distinct roles in craniofacial development: acvr2a morphants display defects in most cranial neural crest cell-derived cartilage, bone, and pharyngeal tooth structures, while acvr2b morphants show primarily posterior arch defects, establishing non-redundant functions for the two receptors.","method":"Morpholino-based protein depletion in zebrafish; phenotypic analysis of craniofacial structures","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in a model organism with defined cellular phenotype, single lab","pmids":["15977175"],"is_preprint":false},{"year":2015,"finding":"Activin A antagonizes BMP-6 and BMP-9 (but not BMP-2 or BMP-4) by competing for binding to ACVR2A and ACVR2B, thereby inhibiting BMP signaling through ALK2-coupled receptor complexes but not through BMPR2/ALK3/ALK6 complexes.","method":"Cell-based signaling assays with activin A and BMP ligands; receptor expression characterization in myeloma cell lines","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based competition assay with defined receptor specificity mapping, single lab","pmids":["26047946"],"is_preprint":false},{"year":2017,"finding":"Conditional deletion of ACVR2A in osteoblasts (using osteocalcin-Cre) results in significantly increased femoral trabecular bone volume and enhanced osteoblast differentiation in vitro (alkaline phosphatase activity, mineral deposition, osterix/osteocalcin/DMP1 expression), while ACVR2B deletion has no significant effect, establishing ACVR2A as the dominant negative regulator of bone mass in osteoblasts via activin/SMAD2/3 signaling.","method":"Conditional knockout mice (osteocalcin-Cre); microCT bone analysis; primary osteoblast culture; in vitro differentiation assays; immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with multiple orthogonal in vivo and in vitro readouts; ACVR2B conditional knockout served as internal control confirming specificity","pmids":["28659341"],"is_preprint":false},{"year":2017,"finding":"BMP2 signals through ALK2/ALK3 type I receptors and BMPR2/ACVR2A type II receptors to phosphorylate SMAD1/5/8 and suppress PTX3 expression in human granulosa-lutein cells; knockdown of ACVR2A completely reverses BMP2-induced SMAD1/5/8 phosphorylation and restores PTX3 expression.","method":"siRNA knockdown of ACVR2A and other receptors; Western blot for pSMAD1/5/8; qRT-PCR for PTX3; pharmacological receptor inhibition","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with phospho-signaling readout and rescue experiment, single lab","pmids":["28977600"],"is_preprint":false},{"year":2020,"finding":"Gonadotrope-specific conditional deletion of Acvr2a in mice causes marked decreases in serum FSH, subfertility in females, and hypogonadism in males; simultaneous deletion of Acvr2a and Acvr2b causes profound FSH deficiency and sterility, establishing ACVR2A as the primary type II receptor mediating activin-stimulated FSH production in pituitary gonadotropes in vivo.","method":"Cre-lox conditional knockout (Acvr2a and/or Acvr2b in gonadotropes); serum FSH measurement; fertility assessment; testicular weight analysis","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with double KO control establishing specificity; replicated across both sexes with multiple phenotypic readouts","pmids":["32270195"],"is_preprint":false},{"year":2021,"finding":"BMP signaling controls endometrial receptivity via a conserved ACVR2A/SMAD1/5 signaling pathway; conditional deletion of Acvr2a in uterine cells (PR-Cre) impairs BMP signaling and leads to defective implantation, while ACVR2B deletion does not affect implantation, establishing ACVR2A as the requisite type II receptor for endometrial BMP-SMAD1/5 signaling during embryo implantation.","method":"Conditional knockout mice (PR-Cre for Acvr2a, Acvr2b, Smad1/5); fertility/implantation phenotyping; histological analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with receptor-specific controls (ACVR2B KO as comparator) and multiple phenotypic readouts","pmids":["34099644"],"is_preprint":false},{"year":2022,"finding":"ACVR2A forms stable heteromeric complexes at the plasma membrane with ALK4 (activin type I receptor) and with BMP type I receptors ALK2, ALK3, and ALK6; ALK4 and BMP type I receptors compete for binding to ACVR2A, and differential complex formation of distinct type I receptors with ACVR2A balances signaling between SMAD2/3 (via ACVR2A/ALK4 in activin A signaling) and SMAD1/5/8 (via ACVR2A/ALK2 or ALK3 in BMP9 signaling).","method":"IgG-mediated patching-immobilization combined with FRAP measurements of lateral diffusion; receptor overexpression competition; downstream signaling readouts (pSMAD2/3 and pSMAD1/5/8)","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biophysical FRAP membrane diffusion assays plus functional signaling outputs, multiple orthogonal methods in one study","pmids":["35177083"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of ACVR2A in complex with activin A shows that ACVR2A binds activin A (and activin B) with high affinity using a conserved hydrophobic hot spot geometry nearly identical to BMPR2; high-affinity ligands for ACVR2A are activin A, activin B, and GDF11, whereas those for BMPR2 are BMP15, BMP10, and Nodal.","method":"X-ray crystallography of ACVR2A-activin A complex; in vitro binding affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with ligand-binding specificity profiling, single lab but rigorous structural and biochemical methods","pmids":["35643319"],"is_preprint":false},{"year":2023,"finding":"Activin A binding to ACVR2A selectively activates SMAD2 (but not SMAD3) transcription to inhibit colon cancer cell migration, invasion, and epithelial-to-mesenchymal transition; ACVR2A downregulation is associated with loss of this suppressive signaling in colorectal cancer metastasis.","method":"Loss-of-function and gain-of-function experiments in colon cancer cells; in vivo animal experiments; Western blot for pSMAD2/3; migration/invasion assays; paired clinical sample analysis","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell-based and in vivo readouts establishing SMAD2 selectivity, single lab","pmids":["37378449"],"is_preprint":false},{"year":2024,"finding":"ACVR2A impairment induces hyperglycolysis through inactivation of the SMAD signaling pathway, causing upregulation of LDHA and MCT4 expression, increased lactate secretion, and Treg cell accumulation in the tumor microenvironment, leading to resistance to immune checkpoint inhibitors; MCT4 inhibition restores anti-tumor immunity in ACVR2A-deficient HCC.","method":"Genetic knockdown and syngeneic transplantation mouse models; pharmacological MCT4 inhibition; human clinical sample analysis; Western blot for SMAD signaling","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined in vivo and in vitro functional experiments with pharmacological validation, single lab","pmids":["40139191"],"is_preprint":false},{"year":2024,"finding":"ACVR2A forms homodimers only in the presence of activin A (ActA), while ACVR2B forms stable homodimers without ligand; this distinction dictates their ability to activate the FOP-inducing ALK2-R206H mutant — ACVR2B activates ALK2-R206H without ligand, whereas ACVR2A activation of ALK2-R206H requires ActA. Both receptors form heteromeric complexes with ALK2-R206H, with ACVR2B being more efficient.","method":"IgG-mediated receptor immobilization + FRAP lateral diffusion measurements; BRE-Luc reporter transcriptional assays; pSMAD1/5/8 Western blotting","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biophysical FRAP plus orthogonal signaling assays (reporter gene + Western blot) dissecting mechanism, single lab with rigorous controls","pmids":["38334613"],"is_preprint":false},{"year":2025,"finding":"CRISPR/Cas9-mediated deletion of ACVR2A in trophoblast cell lines (HTR8/SVneo and JAR) inhibits trophoblast migration, proliferation, and invasion; RNA-seq analysis reveals that ACVR2A signals through the TCF7/c-JUN pathway to regulate these trophoblast functions.","method":"CRISPR/Cas9 knockout; RNA-seq; RT-PCR; immunohistochemistry; functional migration/invasion/proliferation assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR knockout with transcriptome-level pathway identification and functional validation, single lab","pmids":["40444773"],"is_preprint":false},{"year":2015,"finding":"A susceptibility variant in the ACVR2A promoter (rs1424954 A>G) causes downregulation of ACVR2A expression in trophoblasts; ACVR2A knockdown in SGHPL-5 trophoblasts leads to reduced NODAL mRNA expression upon physiologic activin A stimulation (suggesting increased trophoblast invasion potential), but this protective effect is lost at pathologic activin A concentrations seen in pre-eclampsia.","method":"Promoter-reporter transfections in SGHPL-5 trophoblasts; siRNA knockdown of ACVR2A; qRT-PCR for NODAL","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transfection and siRNA experiments linking promoter variant to downstream signaling in trophoblasts, single lab with multiple complementary approaches","pmids":["25659497"],"is_preprint":false},{"year":2014,"finding":"miR-590 directly targets Acvr2a to suppress activin signaling in mouse ESCs; downregulation of Acvr2a by miR-590 promotes Rad51b-mediated homologous recombination repair of single-strand and double-strand breaks, balancing DNA damage repair with rapid proliferation during self-renewal.","method":"miRNA target validation; Acvr2a knockdown; DNA damage repair assays; cell cycle analysis","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation combined with functional DNA repair assays establishing pathway position, single lab","pmids":["25458897"],"is_preprint":false},{"year":2018,"finding":"Downregulation of Acvr2a in pre-iPSCs (via miR-590 overexpression or shRNA) promotes telomere elongation and pluripotency acquisition; mechanistically, p-SMAD2 binds the Terf1 promoter in pre-iPSCs, and inhibition of Acvr2a/Activin signaling increases Terf1 expression, which mediates telomere re-elongation.","method":"miR-590 overexpression; shRNA knockdown of Acvr2a; ChIP for pSMAD2 at Terf1 promoter; telomere length assays; pluripotency assays","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin immunoprecipitation plus functional telomere and pluripotency readouts, single lab","pmids":["29910124"],"is_preprint":false},{"year":2017,"finding":"Decidual ACVR2A activity, as modeled in St-T1b cells, regulates trophoblast adhesion, proliferation, migration, and invasion in vitro via paracrine signaling; siRNA knockdown of ACVR2A in decidual cells attenuated the inhibitory effects of conditioned medium on all four trophoblast functions.","method":"siRNA knockdown of ACVR2A in decidual stromal cell line; conditioned medium transfer; functional trophoblast assays","journal":"Pregnancy hypertension","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect conditioned-medium approach, limited mechanistic resolution","pmids":["29203340"],"is_preprint":false},{"year":2024,"finding":"ACVR2A mediates TGF-β1/Smad signaling in hepatic stellate cells; Echinacoside exerts antifibrotic effects by modulating ACVR2A expression, and both inhibition and induction of ACVR2A in LX-2 cells confirmed it as a regulator of the TGF-β1/Smad fibrotic axis.","method":"Transcriptome analysis; ACVR2A knockdown and induction in LX-2 cells; in vivo high-fat diet mouse model; functional cell proliferation and migration assays","journal":"Molecular nutrition & food research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological agent as primary tool with ACVR2A modulation as secondary validation","pmids":["38366962"],"is_preprint":false},{"year":2024,"finding":"ACVR2A suppression in colorectal cancer cells under hypoxia activates the PI3K/AKT/mTOR pathway, upregulates MMP3, CyclinA, CyclinD1, and HIF1α, and promotes angiogenesis; in vitro experiments confirmed ACVR2A suppresses CRC proliferation, migration, and invasion.","method":"In vitro transwell migration/invasion assays; colony formation; Western blot for PI3K/AKT/mTOR pathway proteins; angiogenesis assay; in vivo tumor experiments","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily knockdown phenotyping with signaling pathway inference","pmids":["38898042"],"is_preprint":false},{"year":2011,"finding":"Acvr2a is specifically induced during Th17 cell differentiation and requires both TGF-β and IL-6 for its induction; its expression is not seen in Th1 or Th2 cells and is inhibited when Th17 differentiation is blocked by ATRA.","method":"Gene expression analysis during T helper cell differentiation; cytokine dependency experiments; ATRA inhibition of Th17 differentiation","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression-based findings with limited direct mechanistic follow-up, single lab","pmids":["22056434"],"is_preprint":false},{"year":2025,"finding":"A novel ACVR2A::RAF1 fusion protein (comprising the first four exons of ACVR2A and the last nine exons of RAF1, retaining ACVR2A extracellular and transmembrane domains fused to the RAF1 kinase domain) drives spindle cell sarcoma tumorigenesis and responds to MEK inhibitor trametinib treatment.","method":"Next-generation sequencing identifying fusion; clinical response to trametinib as functional validation","journal":"Genes, chromosomes & cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single case report with clinical response as only functional evidence, no in vitro mechanistic validation","pmids":["39950347"],"is_preprint":false}],"current_model":"ACVR2A is a type II serine/threonine kinase receptor of the TGF-β superfamily that assembles ligand-induced heteromeric receptor complexes with type I receptors (ALK4 for activin/SMAD2/3 signaling; ALK2/3/6 for BMP/SMAD1/5/8 signaling) without direct type I–type II receptor contact, using a conserved hydrophobic interface to bind high-affinity ligands (activin A/B, GDF11) and transduce signals preferentially through SMAD2/3; competition between ALK4 and BMP type I receptors for ACVR2A binding balances the two Smad branches, while ACVR2A homodimerization requires activin A (unlike constitutively dimeric ACVR2B), regulating its activation of downstream effectors including ALK2-R206H in FOP; physiologically, ACVR2A functions as the dominant activin type II receptor for FSH production in pituitary gonadotropes, endometrial BMP-SMAD1/5 signaling required for embryo implantation, and as a negative regulator of osteoblast bone formation, and is frequently inactivated by frameshift mutations in MSI gastrointestinal cancers where it acts as a tumor suppressor through SMAD2 activation."},"narrative":{"mechanistic_narrative":"ACVR2A is a type II receptor of the TGF-β superfamily that nucleates ligand-induced heteromeric receptor complexes to transduce activin and BMP signals into the cell [PMID:35177083, PMID:35643319]. Structurally, ACVR2A binds high-affinity ligands — activin A, activin B, and GDF11 — through a conserved hydrophobic hot spot, and its extracellular domain cooperatively assembles four-receptor complexes with type I receptors despite making no direct type I–type II contacts, increasing ligand affinity for the type I receptor ECD [PMID:12667445, PMID:35643319]. At the plasma membrane ACVR2A forms stable heteromeric complexes with the activin type I receptor ALK4 and with BMP type I receptors ALK2, ALK3, and ALK6; ALK4 and the BMP type I receptors compete for ACVR2A, so differential complex formation balances signaling between the SMAD2/3 branch (ACVR2A/ALK4) and the SMAD1/5/8 branch (ACVR2A/ALK2 or ALK3) [PMID:35177083]. Unlike the constitutively dimeric ACVR2B, ACVR2A homodimerizes only in the presence of activin A, a distinction that governs its ligand-dependent activation of the FOP-associated ALK2-R206H mutant [PMID:38334613]. Physiologically, ACVR2A is the dominant type II receptor for activin-stimulated FSH production in pituitary gonadotropes, for endometrial BMP-SMAD1/5 signaling required for embryo implantation, and is a negative regulator of osteoblast bone formation acting through activin/SMAD2/3, with ACVR2B unable to substitute in these contexts [PMID:28659341, PMID:32270195, PMID:34099644]. ACVR2A functions as a tumor suppressor in microsatellite-unstable gastrointestinal cancers, where it is biallelically inactivated by frameshift mutations in a polyadenine tract; restoration of wild-type receptor restores SMAD2 phosphorylation and suppresses growth, and activin-driven SMAD2 activation inhibits colon cancer migration, invasion, and epithelial-to-mesenchymal transition [PMID:12615714, PMID:15520171, PMID:37378449].","teleology":[{"year":2003,"claim":"Establishing how ACVR2A assembles signaling complexes resolved whether type I and type II receptors contact each other directly, defining the architecture of superfamily signal transduction.","evidence":"X-ray crystallography of the BMP7–ACVR2A ECD complex with receptor truncation and membrane assembly binding assays","pmids":["12667445"],"confidence":"High","gaps":["Did not resolve the full-length cytoplasmic kinase architecture","Cooperativity quantified for BMP7 but not other ligands"]},{"year":2003,"claim":"Discovery of recurrent biallelic frameshift inactivation in MSI gastrointestinal cancers reframed ACVR2A from a signaling receptor to a candidate tumor suppressor under selective pressure.","evidence":"Mutational sequencing and LOH analysis of 28 MSI colorectal and pancreatic tumors","pmids":["12615714"],"confidence":"High","gaps":["Did not demonstrate the downstream signaling consequence of inactivation","Causal contribution to tumorigenesis not tested functionally"]},{"year":2004,"claim":"Re-expression rescue established the mechanistic link between ACVR2A loss and tumor phenotype by identifying SMAD2 phosphorylation and downstream AP-1/small GTPase programs as the effector output.","evidence":"Wild-type ACVR2A transfection into deficient MSI colon cancer cells with pSMAD2 Western blot, microarray, and growth assays","pmids":["15520171"],"confidence":"Medium","gaps":["Single lab","AP-1 and GTPase gene induction correlative, not mechanistically dissected"]},{"year":2005,"claim":"Functional assays in prostate cancer lines and morphant zebrafish established that kinase-domain integrity is required for signaling and that ACVR2A has non-redundant developmental roles distinct from ACVR2B.","evidence":"Sequencing plus activin response assays in prostate lines; morpholino depletion and craniofacial phenotyping in zebrafish","pmids":["16337854","15977175"],"confidence":"Medium","gaps":["Morpholino phenotypes lack genetic confirmation","Distinct ligand basis for ACVR2A/ACVR2B divergence not defined"]},{"year":2015,"claim":"Demonstrating that activin A competes for type II receptor occupancy revealed ACVR2A as a node where ligands antagonize each other to redirect BMP signaling through specific type I receptor complexes.","evidence":"Cell-based signaling competition assays with activin A and BMP ligands in myeloma lines","pmids":["26047946"],"confidence":"Medium","gaps":["Specificity mapped functionally but not structurally","Single cell-line context"]},{"year":2017,"claim":"Conditional knockouts and granulosa-cell knockdown established ACVR2A as the dominant, ACVR2B-non-redundant type II receptor for both activin/SMAD2/3-mediated bone repression and BMP2/SMAD1/5/8 signaling.","evidence":"Osteoblast and granulosa-cell loss-of-function (osteocalcin-Cre KO; siRNA) with microCT, differentiation, and phospho-SMAD readouts","pmids":["28659341","28977600"],"confidence":"High","gaps":["Ligand identity driving osteoblast repression not fully resolved","Granulosa findings from a single cell context"]},{"year":2020,"claim":"Gonadotrope-specific deletion with double-knockout controls established ACVR2A as the primary in vivo type II receptor for activin-stimulated FSH production and fertility.","evidence":"Cre-lox conditional KO of Acvr2a and/or Acvr2b in gonadotropes; serum FSH and fertility phenotyping","pmids":["32270195"],"confidence":"High","gaps":["Partial redundancy with ACVR2B revealed only in double KO","Type I receptor partner in gonadotropes not defined here"]},{"year":2021,"claim":"Uterine conditional deletion identified an ACVR2A/SMAD1/5 BMP pathway as required for endometrial receptivity and implantation, with ACVR2B unable to substitute.","evidence":"PR-Cre conditional KO of Acvr2a, Acvr2b, and Smad1/5 with implantation and histological phenotyping","pmids":["34099644"],"confidence":"High","gaps":["BMP ligand driving endometrial signaling not specified","Type I receptor partner in uterus not defined"]},{"year":2022,"claim":"Biophysical membrane diffusion and structural studies defined the molecular logic of branch selection: ALK4 versus BMP type I receptors compete for ACVR2A, and a conserved hydrophobic interface sets ligand specificity.","evidence":"FRAP lateral diffusion of immobilized receptors with signaling readouts; crystal structure of ACVR2A–activin A with binding-affinity profiling","pmids":["35177083","35643319"],"confidence":"High","gaps":["Relied partly on receptor overexpression","Endogenous stoichiometry of competing complexes not measured"]},{"year":2023,"claim":"Selective SMAD2 (not SMAD3) activation downstream of ACVR2A was shown to mediate suppression of colon cancer migration, invasion, and EMT, sharpening the tumor-suppressor mechanism.","evidence":"Loss- and gain-of-function in colon cancer cells, in vivo experiments, phospho-SMAD blotting, and paired clinical samples","pmids":["37378449"],"confidence":"Medium","gaps":["Single lab","Basis for SMAD2-over-SMAD3 selectivity unresolved"]},{"year":2024,"claim":"Mechanistic dissection of homodimerization explained the FOP-relevant divergence from ACVR2B: ACVR2A homodimerizes and activates ALK2-R206H only with activin A, whereas ACVR2B does so constitutively.","evidence":"FRAP immobilization diffusion measurements, BRE-Luc reporter, and pSMAD1/5/8 blotting comparing ACVR2A and ACVR2B","pmids":["38334613"],"confidence":"High","gaps":["In cell-line overexpression context","Structural basis of ligand-dependent homodimerization not solved"]},{"year":2024,"claim":"Tumor-microenvironment studies extended ACVR2A loss-of-function to metabolic reprogramming, where SMAD-pathway inactivation drives hyperglycolysis, Treg accumulation, and immune-checkpoint resistance.","evidence":"Genetic knockdown and syngeneic mouse models, MCT4 pharmacological inhibition, and human HCC samples","pmids":["40139191"],"confidence":"Medium","gaps":["Single lab","Direct mechanistic link from SMAD inactivation to LDHA/MCT4 not fully resolved"]},{"year":2025,"claim":"CRISPR knockout placed ACVR2A in control of trophoblast migration, proliferation, and invasion via a TCF7/c-JUN transcriptional program, complementing earlier trophoblast and decidual findings.","evidence":"CRISPR/Cas9 knockout in HTR8/SVneo and JAR trophoblast lines with RNA-seq and functional assays","pmids":["40444773"],"confidence":"Medium","gaps":["Connection between canonical SMAD output and TCF7/c-JUN not delineated","In vitro cell lines only"]},{"year":null,"claim":"How ACVR2A complex stoichiometry and type I receptor competition are regulated at endogenous expression to set SMAD2/3-versus-SMAD1/5/8 output across distinct physiological tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No endogenous-level structural/stoichiometric measurement of competing complexes","Tissue-specific ligand and type I partner combinations incompletely mapped","Mechanism converting receptor loss into specific transcriptional/metabolic reprogramming not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,10,11]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,10,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,10,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,12,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,9,15]}],"complexes":["ACVR2A/ALK4 activin receptor complex","ACVR2A/ALK2 BMP receptor complex","ACVR2A/ALK3 BMP receptor complex"],"partners":["ALK4","ALK2","ALK3","ALK6","BMPR2","SMAD2","SMAD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P27037","full_name":"Activin receptor type-2A","aliases":["Activin receptor type IIA","ACTR-IIA","ACTRIIA"],"length_aa":513,"mass_kda":57.8,"function":"On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin A, activin B and inhibin A (PubMed:17911401, PubMed:10652306). Mediates induction of adipogenesis by GDF6 (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P27037/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACVR2A","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACVR2A","total_profiled":1310},"omim":[{"mim_id":"620997","title":"SEMAPHORIN 3G; SEMA3G","url":"https://www.omim.org/entry/620997"},{"mim_id":"609411","title":"SYNAPTOJANIN 2-BINDING PROTEIN; SYNJ2BP","url":"https://www.omim.org/entry/609411"},{"mim_id":"605120","title":"GROWTH/DIFFERENTIATION FACTOR 2; GDF2","url":"https://www.omim.org/entry/605120"},{"mim_id":"600725","title":"SONIC HEDGEHOG SIGNALING MOLECULE; SHH","url":"https://www.omim.org/entry/600725"},{"mim_id":"112263","title":"BONE MORPHOGENETIC PROTEIN 3; BMP3","url":"https://www.omim.org/entry/112263"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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I receptor ECD increases 5-fold in the presence of the ACVR2A ECD.\",\n      \"method\": \"X-ray crystallography; receptor truncation binding assays; cell membrane assembly experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation via binding assays and mutagenesis-equivalent truncation experiments, published in a high-impact journal\",\n      \"pmids\": [\"12667445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ACVR2 (ACVR2A) undergoes inactivating frameshift mutations at an 8-bp polyadenine tract in gastrointestinal cancers with microsatellite instability (MSI), with biallelic mutations found in 25 of 28 MSI colorectal and pancreatic cancers, establishing ACVR2A as a candidate tumor suppressor gene whose inactivation is under strong selective pressure during gastrointestinal carcinogenesis.\",\n      \"method\": \"Mutational analysis by sequencing of primary tumor DNA; LOH analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic sequencing of 28 MSI tumors with consistent biallelic inactivation findings replicated across colorectal and pancreatic cancers\",\n      \"pmids\": [\"12615714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Restoration of wild-type ACVR2A in ACVR2-deficient MSI colon cancer cells decreased cell growth, increased phosphorylated SMAD2, and induced overexpression of TGF-β effector pathway genes including JUND, JUN, FOSB, RHOB, ARHE, and ARHGDIA, demonstrating that ACVR2A signals through SMAD2 phosphorylation and activates AP-1 and small GTPase signaling pathways.\",\n      \"method\": \"Wild-type ACVR2A transfection; Western blot for pSMAD2; microarray gene expression analysis; cell growth assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function rescue experiment with multiple orthogonal readouts (growth, Western blot, microarray), single lab\",\n      \"pmids\": [\"15520171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Truncating mutations in ACVR2A found in prostate cancer cell lines result in significantly reduced activin-mediated cell signaling, as measured by an activin response assay, demonstrating that the kinase domain integrity is required for ACVR2A signal transduction.\",\n      \"method\": \"Sequencing of ACVR2A in prostate cancer lines; activin response functional assay\",\n      \"journal\": \"Cancer genetics and cytogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional activin response assay directly linking truncating mutations to signaling loss, single lab\",\n      \"pmids\": [\"16337854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In zebrafish, acvr2a and acvr2b exhibit distinct roles in craniofacial development: acvr2a morphants display defects in most cranial neural crest cell-derived cartilage, bone, and pharyngeal tooth structures, while acvr2b morphants show primarily posterior arch defects, establishing non-redundant functions for the two receptors.\",\n      \"method\": \"Morpholino-based protein depletion in zebrafish; phenotypic analysis of craniofacial structures\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in a model organism with defined cellular phenotype, single lab\",\n      \"pmids\": [\"15977175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Activin A antagonizes BMP-6 and BMP-9 (but not BMP-2 or BMP-4) by competing for binding to ACVR2A and ACVR2B, thereby inhibiting BMP signaling through ALK2-coupled receptor complexes but not through BMPR2/ALK3/ALK6 complexes.\",\n      \"method\": \"Cell-based signaling assays with activin A and BMP ligands; receptor expression characterization in myeloma cell lines\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based competition assay with defined receptor specificity mapping, single lab\",\n      \"pmids\": [\"26047946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Conditional deletion of ACVR2A in osteoblasts (using osteocalcin-Cre) results in significantly increased femoral trabecular bone volume and enhanced osteoblast differentiation in vitro (alkaline phosphatase activity, mineral deposition, osterix/osteocalcin/DMP1 expression), while ACVR2B deletion has no significant effect, establishing ACVR2A as the dominant negative regulator of bone mass in osteoblasts via activin/SMAD2/3 signaling.\",\n      \"method\": \"Conditional knockout mice (osteocalcin-Cre); microCT bone analysis; primary osteoblast culture; in vitro differentiation assays; immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with multiple orthogonal in vivo and in vitro readouts; ACVR2B conditional knockout served as internal control confirming specificity\",\n      \"pmids\": [\"28659341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BMP2 signals through ALK2/ALK3 type I receptors and BMPR2/ACVR2A type II receptors to phosphorylate SMAD1/5/8 and suppress PTX3 expression in human granulosa-lutein cells; knockdown of ACVR2A completely reverses BMP2-induced SMAD1/5/8 phosphorylation and restores PTX3 expression.\",\n      \"method\": \"siRNA knockdown of ACVR2A and other receptors; Western blot for pSMAD1/5/8; qRT-PCR for PTX3; pharmacological receptor inhibition\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with phospho-signaling readout and rescue experiment, single lab\",\n      \"pmids\": [\"28977600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Gonadotrope-specific conditional deletion of Acvr2a in mice causes marked decreases in serum FSH, subfertility in females, and hypogonadism in males; simultaneous deletion of Acvr2a and Acvr2b causes profound FSH deficiency and sterility, establishing ACVR2A as the primary type II receptor mediating activin-stimulated FSH production in pituitary gonadotropes in vivo.\",\n      \"method\": \"Cre-lox conditional knockout (Acvr2a and/or Acvr2b in gonadotropes); serum FSH measurement; fertility assessment; testicular weight analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with double KO control establishing specificity; replicated across both sexes with multiple phenotypic readouts\",\n      \"pmids\": [\"32270195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BMP signaling controls endometrial receptivity via a conserved ACVR2A/SMAD1/5 signaling pathway; conditional deletion of Acvr2a in uterine cells (PR-Cre) impairs BMP signaling and leads to defective implantation, while ACVR2B deletion does not affect implantation, establishing ACVR2A as the requisite type II receptor for endometrial BMP-SMAD1/5 signaling during embryo implantation.\",\n      \"method\": \"Conditional knockout mice (PR-Cre for Acvr2a, Acvr2b, Smad1/5); fertility/implantation phenotyping; histological analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with receptor-specific controls (ACVR2B KO as comparator) and multiple phenotypic readouts\",\n      \"pmids\": [\"34099644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACVR2A forms stable heteromeric complexes at the plasma membrane with ALK4 (activin type I receptor) and with BMP type I receptors ALK2, ALK3, and ALK6; ALK4 and BMP type I receptors compete for binding to ACVR2A, and differential complex formation of distinct type I receptors with ACVR2A balances signaling between SMAD2/3 (via ACVR2A/ALK4 in activin A signaling) and SMAD1/5/8 (via ACVR2A/ALK2 or ALK3 in BMP9 signaling).\",\n      \"method\": \"IgG-mediated patching-immobilization combined with FRAP measurements of lateral diffusion; receptor overexpression competition; downstream signaling readouts (pSMAD2/3 and pSMAD1/5/8)\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biophysical FRAP membrane diffusion assays plus functional signaling outputs, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35177083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of ACVR2A in complex with activin A shows that ACVR2A binds activin A (and activin B) with high affinity using a conserved hydrophobic hot spot geometry nearly identical to BMPR2; high-affinity ligands for ACVR2A are activin A, activin B, and GDF11, whereas those for BMPR2 are BMP15, BMP10, and Nodal.\",\n      \"method\": \"X-ray crystallography of ACVR2A-activin A complex; in vitro binding affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with ligand-binding specificity profiling, single lab but rigorous structural and biochemical methods\",\n      \"pmids\": [\"35643319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Activin A binding to ACVR2A selectively activates SMAD2 (but not SMAD3) transcription to inhibit colon cancer cell migration, invasion, and epithelial-to-mesenchymal transition; ACVR2A downregulation is associated with loss of this suppressive signaling in colorectal cancer metastasis.\",\n      \"method\": \"Loss-of-function and gain-of-function experiments in colon cancer cells; in vivo animal experiments; Western blot for pSMAD2/3; migration/invasion assays; paired clinical sample analysis\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell-based and in vivo readouts establishing SMAD2 selectivity, single lab\",\n      \"pmids\": [\"37378449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2A impairment induces hyperglycolysis through inactivation of the SMAD signaling pathway, causing upregulation of LDHA and MCT4 expression, increased lactate secretion, and Treg cell accumulation in the tumor microenvironment, leading to resistance to immune checkpoint inhibitors; MCT4 inhibition restores anti-tumor immunity in ACVR2A-deficient HCC.\",\n      \"method\": \"Genetic knockdown and syngeneic transplantation mouse models; pharmacological MCT4 inhibition; human clinical sample analysis; Western blot for SMAD signaling\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined in vivo and in vitro functional experiments with pharmacological validation, single lab\",\n      \"pmids\": [\"40139191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2A forms homodimers only in the presence of activin A (ActA), while ACVR2B forms stable homodimers without ligand; this distinction dictates their ability to activate the FOP-inducing ALK2-R206H mutant — ACVR2B activates ALK2-R206H without ligand, whereas ACVR2A activation of ALK2-R206H requires ActA. Both receptors form heteromeric complexes with ALK2-R206H, with ACVR2B being more efficient.\",\n      \"method\": \"IgG-mediated receptor immobilization + FRAP lateral diffusion measurements; BRE-Luc reporter transcriptional assays; pSMAD1/5/8 Western blotting\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biophysical FRAP plus orthogonal signaling assays (reporter gene + Western blot) dissecting mechanism, single lab with rigorous controls\",\n      \"pmids\": [\"38334613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPR/Cas9-mediated deletion of ACVR2A in trophoblast cell lines (HTR8/SVneo and JAR) inhibits trophoblast migration, proliferation, and invasion; RNA-seq analysis reveals that ACVR2A signals through the TCF7/c-JUN pathway to regulate these trophoblast functions.\",\n      \"method\": \"CRISPR/Cas9 knockout; RNA-seq; RT-PCR; immunohistochemistry; functional migration/invasion/proliferation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR knockout with transcriptome-level pathway identification and functional validation, single lab\",\n      \"pmids\": [\"40444773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A susceptibility variant in the ACVR2A promoter (rs1424954 A>G) causes downregulation of ACVR2A expression in trophoblasts; ACVR2A knockdown in SGHPL-5 trophoblasts leads to reduced NODAL mRNA expression upon physiologic activin A stimulation (suggesting increased trophoblast invasion potential), but this protective effect is lost at pathologic activin A concentrations seen in pre-eclampsia.\",\n      \"method\": \"Promoter-reporter transfections in SGHPL-5 trophoblasts; siRNA knockdown of ACVR2A; qRT-PCR for NODAL\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transfection and siRNA experiments linking promoter variant to downstream signaling in trophoblasts, single lab with multiple complementary approaches\",\n      \"pmids\": [\"25659497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-590 directly targets Acvr2a to suppress activin signaling in mouse ESCs; downregulation of Acvr2a by miR-590 promotes Rad51b-mediated homologous recombination repair of single-strand and double-strand breaks, balancing DNA damage repair with rapid proliferation during self-renewal.\",\n      \"method\": \"miRNA target validation; Acvr2a knockdown; DNA damage repair assays; cell cycle analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation combined with functional DNA repair assays establishing pathway position, single lab\",\n      \"pmids\": [\"25458897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Downregulation of Acvr2a in pre-iPSCs (via miR-590 overexpression or shRNA) promotes telomere elongation and pluripotency acquisition; mechanistically, p-SMAD2 binds the Terf1 promoter in pre-iPSCs, and inhibition of Acvr2a/Activin signaling increases Terf1 expression, which mediates telomere re-elongation.\",\n      \"method\": \"miR-590 overexpression; shRNA knockdown of Acvr2a; ChIP for pSMAD2 at Terf1 promoter; telomere length assays; pluripotency assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin immunoprecipitation plus functional telomere and pluripotency readouts, single lab\",\n      \"pmids\": [\"29910124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Decidual ACVR2A activity, as modeled in St-T1b cells, regulates trophoblast adhesion, proliferation, migration, and invasion in vitro via paracrine signaling; siRNA knockdown of ACVR2A in decidual cells attenuated the inhibitory effects of conditioned medium on all four trophoblast functions.\",\n      \"method\": \"siRNA knockdown of ACVR2A in decidual stromal cell line; conditioned medium transfer; functional trophoblast assays\",\n      \"journal\": \"Pregnancy hypertension\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect conditioned-medium approach, limited mechanistic resolution\",\n      \"pmids\": [\"29203340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2A mediates TGF-β1/Smad signaling in hepatic stellate cells; Echinacoside exerts antifibrotic effects by modulating ACVR2A expression, and both inhibition and induction of ACVR2A in LX-2 cells confirmed it as a regulator of the TGF-β1/Smad fibrotic axis.\",\n      \"method\": \"Transcriptome analysis; ACVR2A knockdown and induction in LX-2 cells; in vivo high-fat diet mouse model; functional cell proliferation and migration assays\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological agent as primary tool with ACVR2A modulation as secondary validation\",\n      \"pmids\": [\"38366962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2A suppression in colorectal cancer cells under hypoxia activates the PI3K/AKT/mTOR pathway, upregulates MMP3, CyclinA, CyclinD1, and HIF1α, and promotes angiogenesis; in vitro experiments confirmed ACVR2A suppresses CRC proliferation, migration, and invasion.\",\n      \"method\": \"In vitro transwell migration/invasion assays; colony formation; Western blot for PI3K/AKT/mTOR pathway proteins; angiogenesis assay; in vivo tumor experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily knockdown phenotyping with signaling pathway inference\",\n      \"pmids\": [\"38898042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Acvr2a is specifically induced during Th17 cell differentiation and requires both TGF-β and IL-6 for its induction; its expression is not seen in Th1 or Th2 cells and is inhibited when Th17 differentiation is blocked by ATRA.\",\n      \"method\": \"Gene expression analysis during T helper cell differentiation; cytokine dependency experiments; ATRA inhibition of Th17 differentiation\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression-based findings with limited direct mechanistic follow-up, single lab\",\n      \"pmids\": [\"22056434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel ACVR2A::RAF1 fusion protein (comprising the first four exons of ACVR2A and the last nine exons of RAF1, retaining ACVR2A extracellular and transmembrane domains fused to the RAF1 kinase domain) drives spindle cell sarcoma tumorigenesis and responds to MEK inhibitor trametinib treatment.\",\n      \"method\": \"Next-generation sequencing identifying fusion; clinical response to trametinib as functional validation\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single case report with clinical response as only functional evidence, no in vitro mechanistic validation\",\n      \"pmids\": [\"39950347\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACVR2A is a type II serine/threonine kinase receptor of the TGF-β superfamily that assembles ligand-induced heteromeric receptor complexes with type I receptors (ALK4 for activin/SMAD2/3 signaling; ALK2/3/6 for BMP/SMAD1/5/8 signaling) without direct type I–type II receptor contact, using a conserved hydrophobic interface to bind high-affinity ligands (activin A/B, GDF11) and transduce signals preferentially through SMAD2/3; competition between ALK4 and BMP type I receptors for ACVR2A binding balances the two Smad branches, while ACVR2A homodimerization requires activin A (unlike constitutively dimeric ACVR2B), regulating its activation of downstream effectors including ALK2-R206H in FOP; physiologically, ACVR2A functions as the dominant activin type II receptor for FSH production in pituitary gonadotropes, endometrial BMP-SMAD1/5 signaling required for embryo implantation, and as a negative regulator of osteoblast bone formation, and is frequently inactivated by frameshift mutations in MSI gastrointestinal cancers where it acts as a tumor suppressor through SMAD2 activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACVR2A is a type II receptor of the TGF-β superfamily that nucleates ligand-induced heteromeric receptor complexes to transduce activin and BMP signals into the cell [#10, #11]. Structurally, ACVR2A binds high-affinity ligands — activin A, activin B, and GDF11 — through a conserved hydrophobic hot spot, and its extracellular domain cooperatively assembles four-receptor complexes with type I receptors despite making no direct type I–type II contacts, increasing ligand affinity for the type I receptor ECD [#0, #11]. At the plasma membrane ACVR2A forms stable heteromeric complexes with the activin type I receptor ALK4 and with BMP type I receptors ALK2, ALK3, and ALK6; ALK4 and the BMP type I receptors compete for ACVR2A, so differential complex formation balances signaling between the SMAD2/3 branch (ACVR2A/ALK4) and the SMAD1/5/8 branch (ACVR2A/ALK2 or ALK3) [#10]. Unlike the constitutively dimeric ACVR2B, ACVR2A homodimerizes only in the presence of activin A, a distinction that governs its ligand-dependent activation of the FOP-associated ALK2-R206H mutant [#14]. Physiologically, ACVR2A is the dominant type II receptor for activin-stimulated FSH production in pituitary gonadotropes, for endometrial BMP-SMAD1/5 signaling required for embryo implantation, and is a negative regulator of osteoblast bone formation acting through activin/SMAD2/3, with ACVR2B unable to substitute in these contexts [#6, #8, #9]. ACVR2A functions as a tumor suppressor in microsatellite-unstable gastrointestinal cancers, where it is biallelically inactivated by frameshift mutations in a polyadenine tract; restoration of wild-type receptor restores SMAD2 phosphorylation and suppresses growth, and activin-driven SMAD2 activation inhibits colon cancer migration, invasion, and epithelial-to-mesenchymal transition [#1, #2, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing how ACVR2A assembles signaling complexes resolved whether type I and type II receptors contact each other directly, defining the architecture of superfamily signal transduction.\",\n      \"evidence\": \"X-ray crystallography of the BMP7–ACVR2A ECD complex with receptor truncation and membrane assembly binding assays\",\n      \"pmids\": [\"12667445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the full-length cytoplasmic kinase architecture\", \"Cooperativity quantified for BMP7 but not other ligands\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery of recurrent biallelic frameshift inactivation in MSI gastrointestinal cancers reframed ACVR2A from a signaling receptor to a candidate tumor suppressor under selective pressure.\",\n      \"evidence\": \"Mutational sequencing and LOH analysis of 28 MSI colorectal and pancreatic tumors\",\n      \"pmids\": [\"12615714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not demonstrate the downstream signaling consequence of inactivation\", \"Causal contribution to tumorigenesis not tested functionally\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Re-expression rescue established the mechanistic link between ACVR2A loss and tumor phenotype by identifying SMAD2 phosphorylation and downstream AP-1/small GTPase programs as the effector output.\",\n      \"evidence\": \"Wild-type ACVR2A transfection into deficient MSI colon cancer cells with pSMAD2 Western blot, microarray, and growth assays\",\n      \"pmids\": [\"15520171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"AP-1 and GTPase gene induction correlative, not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Functional assays in prostate cancer lines and morphant zebrafish established that kinase-domain integrity is required for signaling and that ACVR2A has non-redundant developmental roles distinct from ACVR2B.\",\n      \"evidence\": \"Sequencing plus activin response assays in prostate lines; morpholino depletion and craniofacial phenotyping in zebrafish\",\n      \"pmids\": [\"16337854\", \"15977175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino phenotypes lack genetic confirmation\", \"Distinct ligand basis for ACVR2A/ACVR2B divergence not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that activin A competes for type II receptor occupancy revealed ACVR2A as a node where ligands antagonize each other to redirect BMP signaling through specific type I receptor complexes.\",\n      \"evidence\": \"Cell-based signaling competition assays with activin A and BMP ligands in myeloma lines\",\n      \"pmids\": [\"26047946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity mapped functionally but not structurally\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional knockouts and granulosa-cell knockdown established ACVR2A as the dominant, ACVR2B-non-redundant type II receptor for both activin/SMAD2/3-mediated bone repression and BMP2/SMAD1/5/8 signaling.\",\n      \"evidence\": \"Osteoblast and granulosa-cell loss-of-function (osteocalcin-Cre KO; siRNA) with microCT, differentiation, and phospho-SMAD readouts\",\n      \"pmids\": [\"28659341\", \"28977600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand identity driving osteoblast repression not fully resolved\", \"Granulosa findings from a single cell context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Gonadotrope-specific deletion with double-knockout controls established ACVR2A as the primary in vivo type II receptor for activin-stimulated FSH production and fertility.\",\n      \"evidence\": \"Cre-lox conditional KO of Acvr2a and/or Acvr2b in gonadotropes; serum FSH and fertility phenotyping\",\n      \"pmids\": [\"32270195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partial redundancy with ACVR2B revealed only in double KO\", \"Type I receptor partner in gonadotropes not defined here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uterine conditional deletion identified an ACVR2A/SMAD1/5 BMP pathway as required for endometrial receptivity and implantation, with ACVR2B unable to substitute.\",\n      \"evidence\": \"PR-Cre conditional KO of Acvr2a, Acvr2b, and Smad1/5 with implantation and histological phenotyping\",\n      \"pmids\": [\"34099644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BMP ligand driving endometrial signaling not specified\", \"Type I receptor partner in uterus not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Biophysical membrane diffusion and structural studies defined the molecular logic of branch selection: ALK4 versus BMP type I receptors compete for ACVR2A, and a conserved hydrophobic interface sets ligand specificity.\",\n      \"evidence\": \"FRAP lateral diffusion of immobilized receptors with signaling readouts; crystal structure of ACVR2A–activin A with binding-affinity profiling\",\n      \"pmids\": [\"35177083\", \"35643319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relied partly on receptor overexpression\", \"Endogenous stoichiometry of competing complexes not measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Selective SMAD2 (not SMAD3) activation downstream of ACVR2A was shown to mediate suppression of colon cancer migration, invasion, and EMT, sharpening the tumor-suppressor mechanism.\",\n      \"evidence\": \"Loss- and gain-of-function in colon cancer cells, in vivo experiments, phospho-SMAD blotting, and paired clinical samples\",\n      \"pmids\": [\"37378449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Basis for SMAD2-over-SMAD3 selectivity unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mechanistic dissection of homodimerization explained the FOP-relevant divergence from ACVR2B: ACVR2A homodimerizes and activates ALK2-R206H only with activin A, whereas ACVR2B does so constitutively.\",\n      \"evidence\": \"FRAP immobilization diffusion measurements, BRE-Luc reporter, and pSMAD1/5/8 blotting comparing ACVR2A and ACVR2B\",\n      \"pmids\": [\"38334613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In cell-line overexpression context\", \"Structural basis of ligand-dependent homodimerization not solved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tumor-microenvironment studies extended ACVR2A loss-of-function to metabolic reprogramming, where SMAD-pathway inactivation drives hyperglycolysis, Treg accumulation, and immune-checkpoint resistance.\",\n      \"evidence\": \"Genetic knockdown and syngeneic mouse models, MCT4 pharmacological inhibition, and human HCC samples\",\n      \"pmids\": [\"40139191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct mechanistic link from SMAD inactivation to LDHA/MCT4 not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CRISPR knockout placed ACVR2A in control of trophoblast migration, proliferation, and invasion via a TCF7/c-JUN transcriptional program, complementing earlier trophoblast and decidual findings.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in HTR8/SVneo and JAR trophoblast lines with RNA-seq and functional assays\",\n      \"pmids\": [\"40444773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection between canonical SMAD output and TCF7/c-JUN not delineated\", \"In vitro cell lines only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ACVR2A complex stoichiometry and type I receptor competition are regulated at endogenous expression to set SMAD2/3-versus-SMAD1/5/8 output across distinct physiological tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous-level structural/stoichiometric measurement of competing complexes\", \"Tissue-specific ligand and type I partner combinations incompletely mapped\", \"Mechanism converting receptor loss into specific transcriptional/metabolic reprogramming not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 10, 11]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 10, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 10, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 12, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 9, 15]}\n    ],\n    \"complexes\": [\n      \"ACVR2A/ALK4 activin receptor complex\",\n      \"ACVR2A/ALK2 BMP receptor complex\",\n      \"ACVR2A/ALK3 BMP receptor complex\"\n    ],\n    \"partners\": [\n      \"ALK4\",\n      \"ALK2\",\n      \"ALK3\",\n      \"ALK6\",\n      \"BMPR2\",\n      \"SMAD2\",\n      \"SMAD1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}