{"gene":"ACVR2A","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2003,"finding":"Crystal structure of BMP7 in complex with the extracellular domain (ECD) of ACVR2A (activin type II receptor) revealed a four-receptor model in which type I and type II receptor ECDs make no direct contacts, yet truncated receptors lacking cytoplasmic domains retain cooperative assembly ability in the cell membrane; presence of the type II receptor ECD increases BMP7 affinity for its low-affinity type I receptor ECD 5-fold, demonstrating ligand-mediated cooperative receptor assembly.","method":"X-ray crystallography of BMP7/ActRII ECD complex; cell membrane assembly assays with truncated receptors; affinity binding measurements","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation of cooperative assembly mechanism, highly cited foundational study","pmids":["12667445"],"is_preprint":false},{"year":2003,"finding":"ACVR2A (ACVR2) gene contains two 8-bp polyadenine tracts that are targets for inactivating frameshift mutations in microsatellite-unstable (MSI) gastrointestinal cancers; biallelic mutations found in 25/28 MSI colorectal and pancreatic cancers, supporting ACVR2 as a tumor suppressor gene whose inactivation is selected for during tumorigenesis.","method":"Sequencing of tumor samples; loss-of-heterozygosity analysis; identification of biallelic frameshift mutations","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (sequencing, LOH), replicated across large tumor cohort, highly cited","pmids":["12615714"],"is_preprint":false},{"year":2004,"finding":"Restoration of wild-type ACVR2A in ACVR2-deficient MSI-H colon cancer cells decreased cell growth and increased phosphorylated SMAD2 levels, and induced expression of AP-1 complex genes (JUND, JUN, FOSB) and small GTPase family members (RHOB, ARHE, ARHGDIA), indicating ACVR2A signals through SMAD2 phosphorylation and activates TGF-β effector pathways.","method":"Wild-type ACVR2A transfection into mutant colon cancer cells; Western blotting for pSMAD2; microarray gene expression analysis; cell growth assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reconstitution of function with multiple readouts (growth, SMAD phosphorylation, transcriptomics)","pmids":["15520171"],"is_preprint":false},{"year":2005,"finding":"Truncating mutations in ACVR2A in prostate cancer cell lines result in significantly reduced activin-mediated cell signaling, as demonstrated by an activin response assay, establishing that ACVR2A kinase activity is required for activin signal transduction.","method":"Sequencing of prostate cancer cell lines for ACVR2 mutations; activin response assay to measure signaling output of truncated vs. wild-type ACVR2A","journal":"Cancer genetics and cytogenetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay linking truncation mutations to loss of signaling, single study","pmids":["16337854"],"is_preprint":false},{"year":2005,"finding":"In zebrafish, acvr2a morpholino knockdown causes defects in development of most cranial neural crest cell (NCC)-derived cartilage, bone, and pharyngeal tooth structures, while acvr2b morphants show distinct posterior arch defects, demonstrating distinct roles for acvr2a and acvr2b in hindbrain/NCC patterning and craniofacial development.","method":"Morpholino-based targeted protein depletion in zebrafish; phenotypic analysis of craniofacial structures","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function in vertebrate model with defined cellular phenotype, single study","pmids":["15977175"],"is_preprint":false},{"year":2015,"finding":"Activin A antagonizes BMP-6 and BMP-9 (but not BMP-2 or BMP-4) by binding to ACVR2A and ACVR2B, thereby competing with BMPs that signal through ACVR2A/ACVR2B in combination with ALK2, establishing that activin A regulates cell behavior by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.","method":"Receptor binding competition assays in myeloma cell lines with well-characterized BMP-receptor expression; BMP signaling inhibition assays","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 — functional competition assays with defined receptor expression, single lab","pmids":["26047946"],"is_preprint":false},{"year":2017,"finding":"Conditional deletion of ACVR2A (but not ACVR2B) in osteoblasts/osteocytes in mice leads to enhanced osteoblast differentiation in vitro (increased alkaline phosphatase activity, mineral deposition, osterix/osteocalcin expression) and significantly increased femoral trabecular bone volume in vivo, demonstrating that ACVR2A directly and negatively regulates bone mass in osteoblasts via activin/SMAD2/3 signaling.","method":"Conditional knockout mice (osteocalcin-Cre); primary osteoblast cultures; alkaline phosphatase activity assay; micro-CT; IHC localization of ACVR2A/ACVR2B to osteoblasts and osteocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — conditional knockout with multiple in vitro and in vivo phenotypic readouts, orthogonal methods","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 this pathway suppresses pentraxin 3 (PTX3) expression in human granulosa-lutein cells; knockdown of ACVR2A (or BMPR2) abolished BMP2-induced SMAD1/5/8 phosphorylation and restored PTX3 expression.","method":"siRNA knockdown of ACVR2A and other receptors in human granulosa-lutein cells; Western blotting for pSMAD1/5/8; PTX3 expression measurement; BMP type I receptor inhibitor assays","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with multiple receptor-specific readouts, single study","pmids":["28977600"],"is_preprint":false},{"year":2020,"finding":"Gonadotrope-specific conditional knockout of Acvr2a in mice causes marked decreases in serum FSH and subfertility/hypogonadism, and double knockout of Acvr2a and Acvr2b leads to profound FSH deficiency and sterility, demonstrating that ACVR2A is the primary type II receptor through which activins stimulate FSH production in pituitary gonadotropes.","method":"Cre-lox conditional knockout (gonadotrope-specific); serum FSH measurement; fertility and reproductive phenotype analysis","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — clean conditional knockout with defined endocrine phenotype, single and double knockout comparison","pmids":["32270195"],"is_preprint":false},{"year":2021,"finding":"Conditional deletion of ACVR2A (using PR-Cre) but not ACVR2B in the mouse uterus disrupts BMP-induced SMAD1/5 signaling, causing cystic endometrial glands, hyperproliferative endometrial epithelium during the implantation window, impaired apicobasal transformation, and infertility, establishing that BMP signals through an ACVR2A-SMAD1/5 axis to promote endometrial receptivity and embryo implantation.","method":"Conditional knockout mice (PR-Cre for ACVR2A and ACVR2B, single and double); SMAD1/5 deletion mice; histological analysis; implantation and fertility assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — conditional knockout with multiple orthogonal phenotypic and molecular readouts, strong genetic dissection of ACVR2A vs. ACVR2B","pmids":["34099644"],"is_preprint":false},{"year":2022,"finding":"ACVR2A forms stable heteromeric complexes at the plasma membrane with ALK4 (activin type I receptor) as well as with BMP type I receptors (ALK2/3/6); ALK4 and BMP type I receptors compete for binding to ACVR2A, and this competition balances signaling between the Smad2/3 and Smad1/5/8 branches.","method":"IgG-mediated patching-immobilization combined with FRAP measurements of lateral diffusion; ligand stimulation and type I receptor overexpression experiments; Smad pathway reporter assays in U2OS cells","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 1-2 — biophysical receptor interaction measurement (FRAP) combined with functional signaling readouts, multiple receptor pairs tested","pmids":["35177083"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of ACVR2A in complex with activin A (and of BMPR2 with activin B) showed that ACVR2A binds growth factors with a conserved hydrophobic hot spot using nearly identical geometry to BMPR2; high-affinity GFs for ACVR2A are activin A, activin B, and GDF11, distinct from BMPR2's preferred ligands (BMP15, BMP10, Nodal).","method":"X-ray crystallography; in vitro GF binding affinity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with in vitro binding validation, defines ligand specificity mechanistically","pmids":["35643319"],"is_preprint":false},{"year":2014,"finding":"miR-590 directly targets Acvr2a in mouse ESCs, reducing Activin signaling and upregulating Rad51b (a homologous recombination repair gene), thereby balancing DNA damage repair and rapid proliferation during self-renewal.","method":"miR-590 overexpression; Acvr2a knockdown/targeting validation; DNA damage repair assays (SSB, DSB); cell cycle analysis in mESCs","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct targeting validated with functional downstream readout (DNA repair), single study","pmids":["25458897"],"is_preprint":false},{"year":2015,"finding":"A promoter polymorphism (rs1424954) in ACVR2A reduces ACVR2A expression in trophoblast cells; knockdown of ACVR2A in trophoblasts causes reduced NODAL mRNA expression in response to physiologic Activin-A concentrations (suggesting increased trophoblast invasion capacity), but this protective effect is lost at pathologic Activin-A levels as seen in pre-eclampsia.","method":"Transfection of ACVR2A promoter constructs in SGHPL-5 extravillous trophoblasts; qRT-PCR; siRNA knockdown of ACVR2A","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, functional knockdown with NODAL as readout but limited mechanistic depth","pmids":["25659497"],"is_preprint":false},{"year":2023,"finding":"Activin A binding to ACVR2A activates SMAD2 (but not SMAD3) transcription and inhibits colon cancer cell migration, invasion, and epithelial-to-mesenchymal transition in vitro and in vivo; ACVR2A downregulation promotes colon cancer metastasis via loss of SMAD2 activation.","method":"In vitro migration/invasion assays; EMT marker analysis; in vivo animal experiments; mechanistic studies showing selective activin A/ACVR2A/SMAD2 activation; clinical sample analysis","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro and in vivo readouts with mechanistic pathway placement, single study","pmids":["37378449"],"is_preprint":false},{"year":2024,"finding":"ACVR2A impairment in hepatocellular carcinoma induces hyperglycolysis through inactivation of the SMAD signaling pathway, leading to upregulation of LDHA and MCT4, increased lactate secretion, and recruitment of regulatory T cells, causing resistance to immune checkpoint inhibitors.","method":"Syngeneic transplantation mouse models; genetic knockdown and pharmacological inhibition of MCT4; human clinical sample analysis; Western blotting for SMAD pathway components","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — syngeneic models plus pharmacological rescue with mechanistic pathway (SMAD→LDHA/MCT4→lactate→Treg), single study","pmids":["40139191"],"is_preprint":false},{"year":2024,"finding":"ACVR2A mediates TGF-β1/Smad signaling in hepatic stellate cells to regulate hepatic fibrosis; inhibition of ACVR2A reduces SMAD pathway activation and attenuates liver fibrosis in vivo and in vitro.","method":"Transcriptome analysis; siRNA inhibition and overexpression of ACVR2A in LX-2 hepatic stellate cells; in vivo high-fat diet mouse model; proliferation/migration assays","journal":"Molecular nutrition & food research","confidence":"Medium","confidence_rationale":"Tier 2 — gain and loss of function with pathway validation in vitro and in vivo, single study","pmids":["38366962"],"is_preprint":false},{"year":2024,"finding":"ACVR2A homo-dimerization is ligand (Activin A)-dependent, in contrast to ACVR2B which forms stable homomeric complexes without ligand; ACVR2B can activate the FOP-inducing ALK2-R206H mutant without ligand, while ACVR2A-mediated activation of ALK2-R206H requires Activin A, demonstrating that homo-oligomerization patterns of ACVR2A versus ACVR2B dictate their ability to recruit and activate ALK2-R206H.","method":"IgG-mediated receptor immobilization combined with FRAP lateral diffusion measurements; pSMAD1/5/8 Western blotting; BRE-Luc transcriptional reporter assays","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1-2 — biophysical measurement of oligomerization (FRAP) combined with functional signaling assays, multiple receptor variants tested","pmids":["38334613"],"is_preprint":false},{"year":2025,"finding":"CRISPR/Cas9 deletion of ACVR2A in trophoblast cell lines (HTR8/SVneo, JAR) inhibits trophoblast migration, proliferation, and invasion; RNA-seq revealed that ACVR2A knockout disrupts the TCF7/c-JUN pathway, which was validated by RT-PCR and immunohistochemistry.","method":"CRISPR/Cas9 knockout; functional migration/proliferation/invasion assays; RNA-seq; RT-PCR; immunohistochemistry","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with RNA-seq pathway mapping and functional validation, single study","pmids":["40444773"],"is_preprint":false},{"year":2018,"finding":"miR-590 targets Acvr2a in mouse pre-iPSCs; downregulation of Acvr2a promotes telomere elongation and pluripotency by reducing pSMAD2 binding to the Terf1 promoter, thereby increasing Terf1 expression; this defines a miR-590/Acvr2a/Terf1 signaling axis in iPSC reprogramming.","method":"miR-590 overexpression; Acvr2a shRNA knockdown; chromatin immunoprecipitation (ChIP) for pSMAD2 at Terf1 promoter; telomere length measurement; pluripotency assays in pre-iPSCs","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, KD, OE) linking Acvr2a to Terf1/telomere regulation, single lab","pmids":["29910124"],"is_preprint":false}],"current_model":"ACVR2A is a type II serine/threonine kinase receptor that, upon binding to high-affinity ligands (activin A/B, GDF11) via a conserved hydrophobic interface, cooperatively assembles heteromeric complexes with type I receptors (ALK4 for activin signaling to SMAD2/3; ALK2/3/6 for BMP signaling to SMAD1/5/8) in a ligand-mediated manner without direct type I–type II receptor contact; competition among type I receptors for ACVR2A binding fine-tunes the balance between these two SMAD branches, while ACVR2A-mediated SMAD signaling suppresses osteoblast activity, regulates FSH production in gonadotropes, promotes endometrial receptivity, inhibits EMT and hyperglycolysis in cancer, and controls trophoblast invasion, with its inactivation by frameshift mutations in MSI cancers abrogating tumor-suppressive SMAD2/3 signaling."},"narrative":{"teleology":[{"year":2003,"claim":"Structural determination of how ACVR2A assembles signaling complexes resolved the question of whether type I and type II receptor ectodomains directly contact each other, showing instead that BMP7/ACVR2A binding allosterically increases type I receptor affinity through a ligand-mediated cooperative mechanism.","evidence":"X-ray crystallography of BMP7/ActRII ECD complex with cell membrane assembly assays and affinity measurements","pmids":["12667445"],"confidence":"High","gaps":["Full-length receptor complex structure not resolved","Cooperative assembly mechanism for activin ligands not structurally characterized","Stoichiometry in native membrane not determined"]},{"year":2003,"claim":"The identification of recurrent biallelic frameshift mutations in ACVR2A poly(A) tracts in MSI cancers established it as a bona fide tumor suppressor gene under positive selection during tumorigenesis, raising the question of which downstream pathway mediates its growth-suppressive function.","evidence":"Sequencing and LOH analysis of MSI colorectal and pancreatic tumor cohorts (25/28 biallelic)","pmids":["12615714"],"confidence":"High","gaps":["Functional consequence of mutations not yet tested at time of discovery","Whether mutations drive tumorigenesis or are passenger events in MSI context"]},{"year":2004,"claim":"Reconstitution of wild-type ACVR2A in MSI colon cancer cells directly answered which signaling pathway is lost: SMAD2 phosphorylation was restored, growth was suppressed, and AP-1 and small GTPase effectors were induced, connecting ACVR2A loss to deregulation of the activin/SMAD2 axis.","evidence":"Wild-type ACVR2A transfection into mutant colon cancer cells with Western blot for pSMAD2, microarray, and growth assays","pmids":["15520171"],"confidence":"High","gaps":["Whether SMAD2 is the sole mediator or SMAD3 also contributes","In vivo tumor suppression not demonstrated"]},{"year":2005,"claim":"Morpholino knockdown in zebrafish established that ACVR2A has non-redundant developmental roles distinct from ACVR2B, specifically in cranial neural crest–derived craniofacial structures.","evidence":"Morpholino knockdown in zebrafish with craniofacial phenotypic analysis","pmids":["15977175"],"confidence":"Medium","gaps":["Morpholino off-target effects not ruled out by genetic mutant","Downstream signaling branch (SMAD2/3 vs SMAD1/5/8) in this context unknown","Mammalian craniofacial phenotype not tested"]},{"year":2015,"claim":"Activin A was shown to antagonize BMP-6/BMP-9 signaling by competing for ACVR2A/ACVR2B binding to ALK2, revealing that ACVR2A serves as a contested node where activin and BMP ligands compete for access to type I receptors.","evidence":"Receptor binding competition and BMP signaling inhibition assays in myeloma cells with defined receptor expression","pmids":["26047946"],"confidence":"Medium","gaps":["Competition dynamics not quantified at endogenous receptor levels","In vivo relevance of BMP antagonism through ACVR2A not tested"]},{"year":2017,"claim":"Conditional knockout of ACVR2A in osteoblasts/osteocytes demonstrated that ACVR2A directly and negatively regulates bone mass via activin/SMAD2/3, answering whether ACVR2A functions cell-autonomously in bone and distinguishing it from ACVR2B.","evidence":"Osteocalcin-Cre conditional knockout mice; primary osteoblast cultures; micro-CT; alkaline phosphatase activity","pmids":["28659341"],"confidence":"High","gaps":["Identity of the endogenous ligand (activin A vs. other) driving bone phenotype not resolved","Whether ACVR2A also signals through SMAD1/5/8 in osteoblasts not tested"]},{"year":2020,"claim":"Gonadotrope-specific knockout established ACVR2A as the dominant type II receptor for activin-stimulated FSH production, with ACVR2B playing an additive but secondary role, resolving receptor usage hierarchy in the reproductive endocrine axis.","evidence":"Cre-lox gonadotrope-specific single and double knockout mice; serum FSH measurement; fertility phenotyping","pmids":["32270195"],"confidence":"High","gaps":["Whether ACVR2A signals through ALK4 exclusively in gonadotropes not formally tested","Pulsatile regulation of FSH by ACVR2A not characterized"]},{"year":2021,"claim":"Uterine-specific deletion revealed that ACVR2A, but not ACVR2B, is essential for BMP-SMAD1/5 signaling in the endometrium and embryo implantation, establishing a tissue where ACVR2A preferentially engages the BMP/SMAD1/5 branch rather than the activin/SMAD2/3 branch.","evidence":"PR-Cre conditional knockout of ACVR2A and ACVR2B in mouse uterus; SMAD1/5 deletion phenocopy; histology and implantation assays","pmids":["34099644"],"confidence":"High","gaps":["Which BMP ligand acts through ACVR2A in the uterus not identified","Type I receptor partner (ALK2/3/6) in uterine signaling not defined"]},{"year":2022,"claim":"Biophysical and structural studies resolved how ACVR2A integrates two SMAD branches at the receptor level: ALK4 and BMP type I receptors form stable complexes with ACVR2A and compete for its binding, and a crystal structure of ACVR2A with activin A defined the conserved hydrophobic binding interface and ligand specificity (activin A/B, GDF11).","evidence":"IgG-patching/FRAP in U2OS cells; Smad reporter assays; X-ray crystallography of ACVR2A/activin A complex; in vitro binding affinity measurements","pmids":["35177083","35643319"],"confidence":"High","gaps":["Full heteromeric complex structure (type II + ligand + type I) not solved","Kinetic parameters of type I receptor competition at endogenous expression levels unknown"]},{"year":2024,"claim":"ACVR2A homo-dimerization was shown to be ligand-dependent (unlike ACVR2B), explaining why ACVR2A requires activin A to activate the FOP-causing ALK2-R206H mutant while ACVR2B can do so constitutively—resolving a mechanistic distinction between the two type II receptors relevant to fibrodysplasia ossificans progressiva.","evidence":"FRAP-based oligomerization measurements; pSMAD1/5/8 Western blotting; BRE-Luc reporter assays with wild-type and R206H ALK2","pmids":["38334613"],"confidence":"High","gaps":["Structural basis of ligand-dependent versus ligand-independent dimerization not resolved","In vivo relevance for FOP pathogenesis not tested"]},{"year":2024,"claim":"ACVR2A impairment in hepatocellular carcinoma was linked to immune evasion through a SMAD-inactivation/hyperglycolysis/lactate/Treg recruitment axis, and in hepatic stellate cells ACVR2A mediates TGF-β1/SMAD-driven fibrosis, broadening its tumor-suppressive and fibrogenic roles beyond colorectal cancer.","evidence":"Syngeneic mouse models with ACVR2A knockdown; pharmacological MCT4 inhibition; siRNA/overexpression in LX-2 cells; in vivo fibrosis models","pmids":["40139191","38366962"],"confidence":"Medium","gaps":["Mechanism by which SMAD inactivation upregulates LDHA/MCT4 not fully defined","Relative contribution of ACVR2A versus other TGF-β type II receptors in stellate cell fibrosis unclear","Single studies for each phenotype"]},{"year":2025,"claim":"CRISPR knockout of ACVR2A in trophoblast cell lines confirmed its requirement for trophoblast migration, proliferation, and invasion, and identified a TCF7/c-JUN downstream pathway, extending ACVR2A's role in placental development.","evidence":"CRISPR/Cas9 knockout in HTR8/SVneo and JAR cells; RNA-seq; functional migration/invasion assays; RT-PCR/IHC validation","pmids":["40444773"],"confidence":"Medium","gaps":["In vivo placental phenotype of ACVR2A loss not demonstrated","Whether TCF7/c-JUN pathway is SMAD-dependent or independent not established"]},{"year":null,"claim":"A full-length heteromeric signaling complex structure (type II receptor + ligand + type I receptor + SMAD) remains unsolved, and the tissue-specific rules determining whether ACVR2A engages the SMAD2/3 versus SMAD1/5/8 branch are incompletely understood.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full heteromeric complex crystal structure","Tissue-specific determinants of SMAD branch selection not systematically mapped","Relative contributions of ACVR2A versus ACVR2B in most tissues not genetically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,6,7,8,9,10,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,10,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5,7,10,11,14,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,14,15]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[8,9]}],"complexes":["Activin-ACVR2A-ALK4 complex","BMP-ACVR2A-ALK2/3/6 complex"],"partners":["ALK4","ALK2","ALK3","ALK6","SMAD2","SMAD1","ACVR2B"],"other_free_text":[]},"mechanistic_narrative":"ACVR2A is a type II serine/threonine kinase receptor that serves as a central signaling hub for activin, BMP, and GDF ligands, transducing signals through SMAD2/3 and SMAD1/5/8 pathways to regulate tissue development, endocrine function, and tumor suppression. ACVR2A binds activin A, activin B, and GDF11 with high affinity via a conserved hydrophobic interface and assembles ligand-mediated heteromeric complexes with type I receptors (ALK4 for SMAD2/3 signaling; ALK2/3/6 for SMAD1/5/8 signaling) without direct type I–type II receptor contact, where competition among type I receptors for ACVR2A binding balances the two SMAD branches [PMID:12667445, PMID:35177083, PMID:35643319]. ACVR2A-dependent activin/SMAD2/3 signaling is the primary pathway for FSH production in pituitary gonadotropes, negatively regulates osteoblast differentiation and bone mass, and suppresses epithelial-to-mesenchymal transition in colon cancer, while ACVR2A-dependent BMP/SMAD1/5 signaling is essential for endometrial receptivity and embryo implantation [PMID:32270195, PMID:28659341, PMID:37378449, PMID:34099644]. Biallelic frameshift mutations in poly(A) tracts of ACVR2A are recurrently selected in microsatellite-unstable colorectal and pancreatic cancers, establishing ACVR2A as a tumor suppressor whose loss abrogates SMAD2 signaling and promotes metastasis and immune evasion [PMID:12615714, PMID:15520171, PMID:40139191]."},"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 all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACVR2A"},"hgnc":{"alias_symbol":["ACTRII"],"prev_symbol":["ACVR2"]},"alphafold":{"accession":"P27037","domains":[{"cath_id":"2.10.60.10","chopping":"27-115","consensus_level":"high","plddt":87.1262,"start":27,"end":115},{"cath_id":"3.30.200.20","chopping":"191-267","consensus_level":"high","plddt":89.6288,"start":191,"end":267},{"cath_id":"1.10.510.10","chopping":"273-493","consensus_level":"high","plddt":94.361,"start":273,"end":493}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P27037","model_url":"https://alphafold.ebi.ac.uk/files/AF-P27037-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P27037-F1-predicted_aligned_error_v6.png","plddt_mean":83.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACVR2A","jax_strain_url":"https://www.jax.org/strain/search?query=ACVR2A"},"sequence":{"accession":"P27037","fasta_url":"https://rest.uniprot.org/uniprotkb/P27037.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P27037/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P27037"}},"corpus_meta":[{"pmid":"12667445","id":"PMC_12667445","title":"The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/12667445","citation_count":224,"is_preprint":false},{"pmid":"31101108","id":"PMC_31101108","title":"Circular RNA ACVR2A suppresses bladder cancer cells proliferation and metastasis through miR-626/EYA4 axis.","date":"2019","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31101108","citation_count":133,"is_preprint":false},{"pmid":"26047946","id":"PMC_26047946","title":"Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B.","date":"2015","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/26047946","citation_count":129,"is_preprint":false},{"pmid":"12615714","id":"PMC_12615714","title":"Evidence of selection for clones having genetic inactivation of the activin A type II receptor (ACVR2) gene in gastrointestinal 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type I receptor ECD 5-fold, demonstrating ligand-mediated cooperative receptor assembly.\",\n      \"method\": \"X-ray crystallography of BMP7/ActRII ECD complex; cell membrane assembly assays with truncated receptors; affinity binding measurements\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation of cooperative assembly mechanism, highly cited foundational study\",\n      \"pmids\": [\"12667445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ACVR2A (ACVR2) gene contains two 8-bp polyadenine tracts that are targets for inactivating frameshift mutations in microsatellite-unstable (MSI) gastrointestinal cancers; biallelic mutations found in 25/28 MSI colorectal and pancreatic cancers, supporting ACVR2 as a tumor suppressor gene whose inactivation is selected for during tumorigenesis.\",\n      \"method\": \"Sequencing of tumor samples; loss-of-heterozygosity analysis; identification of biallelic frameshift mutations\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (sequencing, LOH), replicated across large tumor cohort, highly cited\",\n      \"pmids\": [\"12615714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Restoration of wild-type ACVR2A in ACVR2-deficient MSI-H colon cancer cells decreased cell growth and increased phosphorylated SMAD2 levels, and induced expression of AP-1 complex genes (JUND, JUN, FOSB) and small GTPase family members (RHOB, ARHE, ARHGDIA), indicating ACVR2A signals through SMAD2 phosphorylation and activates TGF-β effector pathways.\",\n      \"method\": \"Wild-type ACVR2A transfection into mutant colon cancer cells; Western blotting for pSMAD2; microarray gene expression analysis; cell growth assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reconstitution of function with multiple readouts (growth, SMAD phosphorylation, transcriptomics)\",\n      \"pmids\": [\"15520171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Truncating mutations in ACVR2A in prostate cancer cell lines result in significantly reduced activin-mediated cell signaling, as demonstrated by an activin response assay, establishing that ACVR2A kinase activity is required for activin signal transduction.\",\n      \"method\": \"Sequencing of prostate cancer cell lines for ACVR2 mutations; activin response assay to measure signaling output of truncated vs. wild-type ACVR2A\",\n      \"journal\": \"Cancer genetics and cytogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay linking truncation mutations to loss of signaling, single study\",\n      \"pmids\": [\"16337854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In zebrafish, acvr2a morpholino knockdown causes defects in development of most cranial neural crest cell (NCC)-derived cartilage, bone, and pharyngeal tooth structures, while acvr2b morphants show distinct posterior arch defects, demonstrating distinct roles for acvr2a and acvr2b in hindbrain/NCC patterning and craniofacial development.\",\n      \"method\": \"Morpholino-based targeted protein depletion in zebrafish; phenotypic analysis of craniofacial structures\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function in vertebrate model with defined cellular phenotype, single study\",\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 binding to ACVR2A and ACVR2B, thereby competing with BMPs that signal through ACVR2A/ACVR2B in combination with ALK2, establishing that activin A regulates cell behavior by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.\",\n      \"method\": \"Receptor binding competition assays in myeloma cell lines with well-characterized BMP-receptor expression; BMP signaling inhibition assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional competition assays with defined receptor expression, single lab\",\n      \"pmids\": [\"26047946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Conditional deletion of ACVR2A (but not ACVR2B) in osteoblasts/osteocytes in mice leads to enhanced osteoblast differentiation in vitro (increased alkaline phosphatase activity, mineral deposition, osterix/osteocalcin expression) and significantly increased femoral trabecular bone volume in vivo, demonstrating that ACVR2A directly and negatively regulates bone mass in osteoblasts via activin/SMAD2/3 signaling.\",\n      \"method\": \"Conditional knockout mice (osteocalcin-Cre); primary osteoblast cultures; alkaline phosphatase activity assay; micro-CT; IHC localization of ACVR2A/ACVR2B to osteoblasts and osteocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout with multiple in vitro and in vivo phenotypic readouts, orthogonal methods\",\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 this pathway suppresses pentraxin 3 (PTX3) expression in human granulosa-lutein cells; knockdown of ACVR2A (or BMPR2) abolished BMP2-induced SMAD1/5/8 phosphorylation and restored PTX3 expression.\",\n      \"method\": \"siRNA knockdown of ACVR2A and other receptors in human granulosa-lutein cells; Western blotting for pSMAD1/5/8; PTX3 expression measurement; BMP type I receptor inhibitor assays\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with multiple receptor-specific readouts, single study\",\n      \"pmids\": [\"28977600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Gonadotrope-specific conditional knockout of Acvr2a in mice causes marked decreases in serum FSH and subfertility/hypogonadism, and double knockout of Acvr2a and Acvr2b leads to profound FSH deficiency and sterility, demonstrating that ACVR2A is the primary type II receptor through which activins stimulate FSH production in pituitary gonadotropes.\",\n      \"method\": \"Cre-lox conditional knockout (gonadotrope-specific); serum FSH measurement; fertility and reproductive phenotype analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional knockout with defined endocrine phenotype, single and double knockout comparison\",\n      \"pmids\": [\"32270195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional deletion of ACVR2A (using PR-Cre) but not ACVR2B in the mouse uterus disrupts BMP-induced SMAD1/5 signaling, causing cystic endometrial glands, hyperproliferative endometrial epithelium during the implantation window, impaired apicobasal transformation, and infertility, establishing that BMP signals through an ACVR2A-SMAD1/5 axis to promote endometrial receptivity and embryo implantation.\",\n      \"method\": \"Conditional knockout mice (PR-Cre for ACVR2A and ACVR2B, single and double); SMAD1/5 deletion mice; histological analysis; implantation and fertility assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout with multiple orthogonal phenotypic and molecular readouts, strong genetic dissection of ACVR2A vs. ACVR2B\",\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) as well as with BMP type I receptors (ALK2/3/6); ALK4 and BMP type I receptors compete for binding to ACVR2A, and this competition balances signaling between the Smad2/3 and Smad1/5/8 branches.\",\n      \"method\": \"IgG-mediated patching-immobilization combined with FRAP measurements of lateral diffusion; ligand stimulation and type I receptor overexpression experiments; Smad pathway reporter assays in U2OS cells\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biophysical receptor interaction measurement (FRAP) combined with functional signaling readouts, multiple receptor pairs tested\",\n      \"pmids\": [\"35177083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of ACVR2A in complex with activin A (and of BMPR2 with activin B) showed that ACVR2A binds growth factors with a conserved hydrophobic hot spot using nearly identical geometry to BMPR2; high-affinity GFs for ACVR2A are activin A, activin B, and GDF11, distinct from BMPR2's preferred ligands (BMP15, BMP10, Nodal).\",\n      \"method\": \"X-ray crystallography; in vitro GF binding affinity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with in vitro binding validation, defines ligand specificity mechanistically\",\n      \"pmids\": [\"35643319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-590 directly targets Acvr2a in mouse ESCs, reducing Activin signaling and upregulating Rad51b (a homologous recombination repair gene), thereby balancing DNA damage repair and rapid proliferation during self-renewal.\",\n      \"method\": \"miR-590 overexpression; Acvr2a knockdown/targeting validation; DNA damage repair assays (SSB, DSB); cell cycle analysis in mESCs\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct targeting validated with functional downstream readout (DNA repair), single study\",\n      \"pmids\": [\"25458897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A promoter polymorphism (rs1424954) in ACVR2A reduces ACVR2A expression in trophoblast cells; knockdown of ACVR2A in trophoblasts causes reduced NODAL mRNA expression in response to physiologic Activin-A concentrations (suggesting increased trophoblast invasion capacity), but this protective effect is lost at pathologic Activin-A levels as seen in pre-eclampsia.\",\n      \"method\": \"Transfection of ACVR2A promoter constructs in SGHPL-5 extravillous trophoblasts; qRT-PCR; siRNA knockdown of ACVR2A\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional knockdown with NODAL as readout but limited mechanistic depth\",\n      \"pmids\": [\"25659497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Activin A binding to ACVR2A activates SMAD2 (but not SMAD3) transcription and inhibits colon cancer cell migration, invasion, and epithelial-to-mesenchymal transition in vitro and in vivo; ACVR2A downregulation promotes colon cancer metastasis via loss of SMAD2 activation.\",\n      \"method\": \"In vitro migration/invasion assays; EMT marker analysis; in vivo animal experiments; mechanistic studies showing selective activin A/ACVR2A/SMAD2 activation; clinical sample analysis\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo readouts with mechanistic pathway placement, single study\",\n      \"pmids\": [\"37378449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2A impairment in hepatocellular carcinoma induces hyperglycolysis through inactivation of the SMAD signaling pathway, leading to upregulation of LDHA and MCT4, increased lactate secretion, and recruitment of regulatory T cells, causing resistance to immune checkpoint inhibitors.\",\n      \"method\": \"Syngeneic transplantation mouse models; genetic knockdown and pharmacological inhibition of MCT4; human clinical sample analysis; Western blotting for SMAD pathway components\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — syngeneic models plus pharmacological rescue with mechanistic pathway (SMAD→LDHA/MCT4→lactate→Treg), single study\",\n      \"pmids\": [\"40139191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2A mediates TGF-β1/Smad signaling in hepatic stellate cells to regulate hepatic fibrosis; inhibition of ACVR2A reduces SMAD pathway activation and attenuates liver fibrosis in vivo and in vitro.\",\n      \"method\": \"Transcriptome analysis; siRNA inhibition and overexpression of ACVR2A in LX-2 hepatic stellate cells; in vivo high-fat diet mouse model; proliferation/migration assays\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss of function with pathway validation in vitro and in vivo, single study\",\n      \"pmids\": [\"38366962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACVR2A homo-dimerization is ligand (Activin A)-dependent, in contrast to ACVR2B which forms stable homomeric complexes without ligand; ACVR2B can activate the FOP-inducing ALK2-R206H mutant without ligand, while ACVR2A-mediated activation of ALK2-R206H requires Activin A, demonstrating that homo-oligomerization patterns of ACVR2A versus ACVR2B dictate their ability to recruit and activate ALK2-R206H.\",\n      \"method\": \"IgG-mediated receptor immobilization combined with FRAP lateral diffusion measurements; pSMAD1/5/8 Western blotting; BRE-Luc transcriptional reporter assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biophysical measurement of oligomerization (FRAP) combined with functional signaling assays, multiple receptor variants tested\",\n      \"pmids\": [\"38334613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPR/Cas9 deletion of ACVR2A in trophoblast cell lines (HTR8/SVneo, JAR) inhibits trophoblast migration, proliferation, and invasion; RNA-seq revealed that ACVR2A knockout disrupts the TCF7/c-JUN pathway, which was validated by RT-PCR and immunohistochemistry.\",\n      \"method\": \"CRISPR/Cas9 knockout; functional migration/proliferation/invasion assays; RNA-seq; RT-PCR; immunohistochemistry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with RNA-seq pathway mapping and functional validation, single study\",\n      \"pmids\": [\"40444773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-590 targets Acvr2a in mouse pre-iPSCs; downregulation of Acvr2a promotes telomere elongation and pluripotency by reducing pSMAD2 binding to the Terf1 promoter, thereby increasing Terf1 expression; this defines a miR-590/Acvr2a/Terf1 signaling axis in iPSC reprogramming.\",\n      \"method\": \"miR-590 overexpression; Acvr2a shRNA knockdown; chromatin immunoprecipitation (ChIP) for pSMAD2 at Terf1 promoter; telomere length measurement; pluripotency assays in pre-iPSCs\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, KD, OE) linking Acvr2a to Terf1/telomere regulation, single lab\",\n      \"pmids\": [\"29910124\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACVR2A is a type II serine/threonine kinase receptor that, upon binding to high-affinity ligands (activin A/B, GDF11) via a conserved hydrophobic interface, cooperatively assembles heteromeric complexes with type I receptors (ALK4 for activin signaling to SMAD2/3; ALK2/3/6 for BMP signaling to SMAD1/5/8) in a ligand-mediated manner without direct type I–type II receptor contact; competition among type I receptors for ACVR2A binding fine-tunes the balance between these two SMAD branches, while ACVR2A-mediated SMAD signaling suppresses osteoblast activity, regulates FSH production in gonadotropes, promotes endometrial receptivity, inhibits EMT and hyperglycolysis in cancer, and controls trophoblast invasion, with its inactivation by frameshift mutations in MSI cancers abrogating tumor-suppressive SMAD2/3 signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ACVR2A is a type II serine/threonine kinase receptor that serves as a central signaling hub for activin, BMP, and GDF ligands, transducing signals through SMAD2/3 and SMAD1/5/8 pathways to regulate tissue development, endocrine function, and tumor suppression. ACVR2A binds activin A, activin B, and GDF11 with high affinity via a conserved hydrophobic interface and assembles ligand-mediated heteromeric complexes with type I receptors (ALK4 for SMAD2/3 signaling; ALK2/3/6 for SMAD1/5/8 signaling) without direct type I–type II receptor contact, where competition among type I receptors for ACVR2A binding balances the two SMAD branches [PMID:12667445, PMID:35177083, PMID:35643319]. ACVR2A-dependent activin/SMAD2/3 signaling is the primary pathway for FSH production in pituitary gonadotropes, negatively regulates osteoblast differentiation and bone mass, and suppresses epithelial-to-mesenchymal transition in colon cancer, while ACVR2A-dependent BMP/SMAD1/5 signaling is essential for endometrial receptivity and embryo implantation [PMID:32270195, PMID:28659341, PMID:37378449, PMID:34099644]. Biallelic frameshift mutations in poly(A) tracts of ACVR2A are recurrently selected in microsatellite-unstable colorectal and pancreatic cancers, establishing ACVR2A as a tumor suppressor whose loss abrogates SMAD2 signaling and promotes metastasis and immune evasion [PMID:12615714, PMID:15520171, PMID:40139191].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Structural determination of how ACVR2A assembles signaling complexes resolved the question of whether type I and type II receptor ectodomains directly contact each other, showing instead that BMP7/ACVR2A binding allosterically increases type I receptor affinity through a ligand-mediated cooperative mechanism.\",\n      \"evidence\": \"X-ray crystallography of BMP7/ActRII ECD complex with cell membrane assembly assays and affinity measurements\",\n      \"pmids\": [\"12667445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor complex structure not resolved\", \"Cooperative assembly mechanism for activin ligands not structurally characterized\", \"Stoichiometry in native membrane not determined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The identification of recurrent biallelic frameshift mutations in ACVR2A poly(A) tracts in MSI cancers established it as a bona fide tumor suppressor gene under positive selection during tumorigenesis, raising the question of which downstream pathway mediates its growth-suppressive function.\",\n      \"evidence\": \"Sequencing and LOH analysis of MSI colorectal and pancreatic tumor cohorts (25/28 biallelic)\",\n      \"pmids\": [\"12615714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of mutations not yet tested at time of discovery\", \"Whether mutations drive tumorigenesis or are passenger events in MSI context\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Reconstitution of wild-type ACVR2A in MSI colon cancer cells directly answered which signaling pathway is lost: SMAD2 phosphorylation was restored, growth was suppressed, and AP-1 and small GTPase effectors were induced, connecting ACVR2A loss to deregulation of the activin/SMAD2 axis.\",\n      \"evidence\": \"Wild-type ACVR2A transfection into mutant colon cancer cells with Western blot for pSMAD2, microarray, and growth assays\",\n      \"pmids\": [\"15520171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SMAD2 is the sole mediator or SMAD3 also contributes\", \"In vivo tumor suppression not demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Morpholino knockdown in zebrafish established that ACVR2A has non-redundant developmental roles distinct from ACVR2B, specifically in cranial neural crest–derived craniofacial structures.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with craniofacial phenotypic analysis\",\n      \"pmids\": [\"15977175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino off-target effects not ruled out by genetic mutant\", \"Downstream signaling branch (SMAD2/3 vs SMAD1/5/8) in this context unknown\", \"Mammalian craniofacial phenotype not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Activin A was shown to antagonize BMP-6/BMP-9 signaling by competing for ACVR2A/ACVR2B binding to ALK2, revealing that ACVR2A serves as a contested node where activin and BMP ligands compete for access to type I receptors.\",\n      \"evidence\": \"Receptor binding competition and BMP signaling inhibition assays in myeloma cells with defined receptor expression\",\n      \"pmids\": [\"26047946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competition dynamics not quantified at endogenous receptor levels\", \"In vivo relevance of BMP antagonism through ACVR2A not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional knockout of ACVR2A in osteoblasts/osteocytes demonstrated that ACVR2A directly and negatively regulates bone mass via activin/SMAD2/3, answering whether ACVR2A functions cell-autonomously in bone and distinguishing it from ACVR2B.\",\n      \"evidence\": \"Osteocalcin-Cre conditional knockout mice; primary osteoblast cultures; micro-CT; alkaline phosphatase activity\",\n      \"pmids\": [\"28659341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the endogenous ligand (activin A vs. other) driving bone phenotype not resolved\", \"Whether ACVR2A also signals through SMAD1/5/8 in osteoblasts not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Gonadotrope-specific knockout established ACVR2A as the dominant type II receptor for activin-stimulated FSH production, with ACVR2B playing an additive but secondary role, resolving receptor usage hierarchy in the reproductive endocrine axis.\",\n      \"evidence\": \"Cre-lox gonadotrope-specific single and double knockout mice; serum FSH measurement; fertility phenotyping\",\n      \"pmids\": [\"32270195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ACVR2A signals through ALK4 exclusively in gonadotropes not formally tested\", \"Pulsatile regulation of FSH by ACVR2A not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uterine-specific deletion revealed that ACVR2A, but not ACVR2B, is essential for BMP-SMAD1/5 signaling in the endometrium and embryo implantation, establishing a tissue where ACVR2A preferentially engages the BMP/SMAD1/5 branch rather than the activin/SMAD2/3 branch.\",\n      \"evidence\": \"PR-Cre conditional knockout of ACVR2A and ACVR2B in mouse uterus; SMAD1/5 deletion phenocopy; histology and implantation assays\",\n      \"pmids\": [\"34099644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which BMP ligand acts through ACVR2A in the uterus not identified\", \"Type I receptor partner (ALK2/3/6) in uterine signaling not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Biophysical and structural studies resolved how ACVR2A integrates two SMAD branches at the receptor level: ALK4 and BMP type I receptors form stable complexes with ACVR2A and compete for its binding, and a crystal structure of ACVR2A with activin A defined the conserved hydrophobic binding interface and ligand specificity (activin A/B, GDF11).\",\n      \"evidence\": \"IgG-patching/FRAP in U2OS cells; Smad reporter assays; X-ray crystallography of ACVR2A/activin A complex; in vitro binding affinity measurements\",\n      \"pmids\": [\"35177083\", \"35643319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full heteromeric complex structure (type II + ligand + type I) not solved\", \"Kinetic parameters of type I receptor competition at endogenous expression levels unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ACVR2A homo-dimerization was shown to be ligand-dependent (unlike ACVR2B), explaining why ACVR2A requires activin A to activate the FOP-causing ALK2-R206H mutant while ACVR2B can do so constitutively—resolving a mechanistic distinction between the two type II receptors relevant to fibrodysplasia ossificans progressiva.\",\n      \"evidence\": \"FRAP-based oligomerization measurements; pSMAD1/5/8 Western blotting; BRE-Luc reporter assays with wild-type and R206H ALK2\",\n      \"pmids\": [\"38334613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ligand-dependent versus ligand-independent dimerization not resolved\", \"In vivo relevance for FOP pathogenesis not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ACVR2A impairment in hepatocellular carcinoma was linked to immune evasion through a SMAD-inactivation/hyperglycolysis/lactate/Treg recruitment axis, and in hepatic stellate cells ACVR2A mediates TGF-β1/SMAD-driven fibrosis, broadening its tumor-suppressive and fibrogenic roles beyond colorectal cancer.\",\n      \"evidence\": \"Syngeneic mouse models with ACVR2A knockdown; pharmacological MCT4 inhibition; siRNA/overexpression in LX-2 cells; in vivo fibrosis models\",\n      \"pmids\": [\"40139191\", \"38366962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SMAD inactivation upregulates LDHA/MCT4 not fully defined\", \"Relative contribution of ACVR2A versus other TGF-β type II receptors in stellate cell fibrosis unclear\", \"Single studies for each phenotype\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CRISPR knockout of ACVR2A in trophoblast cell lines confirmed its requirement for trophoblast migration, proliferation, and invasion, and identified a TCF7/c-JUN downstream pathway, extending ACVR2A's role in placental development.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in HTR8/SVneo and JAR cells; RNA-seq; functional migration/invasion assays; RT-PCR/IHC validation\",\n      \"pmids\": [\"40444773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo placental phenotype of ACVR2A loss not demonstrated\", \"Whether TCF7/c-JUN pathway is SMAD-dependent or independent not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length heteromeric signaling complex structure (type II receptor + ligand + type I receptor + SMAD) remains unsolved, and the tissue-specific rules determining whether ACVR2A engages the SMAD2/3 versus SMAD1/5/8 branch are incompletely understood.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full heteromeric complex crystal structure\", \"Tissue-specific determinants of SMAD branch selection not systematically mapped\", \"Relative contributions of ACVR2A versus ACVR2B in most tissues not genetically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 6, 7, 8, 9, 10, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 10, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5, 7, 10, 11, 14, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 14, 15]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [\n      \"Activin-ACVR2A-ALK4 complex\",\n      \"BMP-ACVR2A-ALK2/3/6 complex\"\n    ],\n    \"partners\": [\n      \"ALK4\",\n      \"ALK2\",\n      \"ALK3\",\n      \"ALK6\",\n      \"SMAD2\",\n      \"SMAD1\",\n      \"ACVR2B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}