Affinage

BMPR2

Bone morphogenetic protein receptor type-2 · UniProt Q13873

Length
1038 aa
Mass
115.2 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BMPR2 is a TGF-β superfamily type II serine/threonine kinase receptor that orchestrates BMP signaling to control vascular, skeletal, metabolic, and reproductive homeostasis. Upon BMP ligand binding (with BMP9 as a preferred endothelial ligand), BMPR2 forms a tetrameric complex with type I receptors (ALK1/2/3) through a kinase-domain C-lobe heterodimer interface, phosphorylates type I receptor GS domains, and activates canonical SMAD1/5/8 signaling as well as non-canonical pathways including MAPK, PI3K, JNK, and RhoA-ROCK-LIMK2; it also stabilizes XIAP to suppress caspase-mediated apoptosis independently of SMADs (PMID:34400635, PMID:19782107, PMID:26076038, PMID:28938584). BMPR2 functions as a signaling gatekeeper: its loss permits formation of promiscuous BMPR1/TGFβR heteromeric complexes that amplify TGFβ-SMAD2/3 and TAK1-MAPK signaling, elevates β-arrestin2/β-catenin, activates Ras/Raf/ERK, and upregulates inflammatory chemokines (CXCR2/KC), collectively driving the hyperproliferative, apoptosis-resistant, and inflammatory vascular remodeling characteristic of pulmonary arterial hypertension (PAH) (PMID:31826007, PMID:22388934, PMID:36744494, PMID:21900197). Heterozygous loss-of-function mutations in BMPR2—predominantly causing haploinsufficiency through nonsense-mediated mRNA decay—are the major genetic cause of familial and idiopathic PAH, with disease penetrance modulated by alternative splicing of exon 12 regulated by SRSF2 (PMID:16429395, PMID:22923426).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Defining how BMP ligands physically engage BMPR2 established the structural basis for type II receptor recognition: BMP-2 contacts BMPR-II via a low-affinity epitope assembled by a single monomer, and disruption of this interface produces dominant-negative antagonists.

    Evidence BMP-2 mutagenesis with ectodomain binding assays and C2C12 bioassay

    PMID:10880444

    Open questions at the time
    • No crystal structure of the full BMP-BMPR2 complex at atomic resolution
    • Binding mode for other BMP ligands (BMP9, GDF5) to BMPR2 not resolved
  2. 2006 High

    Establishing haploinsufficiency via NMD as the predominant disease mechanism resolved how heterogeneous BMPR2 mutations converge on a common pathogenic principle in PAH.

    Evidence Compilation of 144 mutations across 210 PAH subjects with in vitro signaling assays

    PMID:16429395

    Open questions at the time
    • Why only ~20% of BMPR2 mutation carriers develop clinical PAH (incomplete penetrance) was not explained
    • Contribution of missense mutations acting through dominant-negative mechanisms vs. loss-of-function not fully delineated
  3. 2008 High

    Demonstrating that PAH mutations cause heterogeneous receptor-level defects—impaired type I receptor phosphorylation and altered complex stoichiometry—showed that BMPR2 dysfunction is not limited to ligand binding but extends to intracellular signaling assembly.

    Evidence Enzymatic activity assays, NMD analysis, receptor stoichiometry assays, and translational readthrough experiments

    PMID:18321866

    Open questions at the time
    • Structural basis for stoichiometric disruption not resolved
    • How different mutation classes quantitatively impair type I receptor activation remained unclear
  4. 2009 High

    Identifying a SMAD/MAPK-independent anti-apoptotic mechanism through direct BMPR2–XIAP interaction revealed a non-canonical survival pathway: BMP stimulation stabilizes XIAP by reducing its ubiquitination, suppressing caspase activation.

    Evidence Co-immunoprecipitation of BMPR2 with XIAP, ubiquitination assays, and caspase activity measurements in mouse embryonic fibroblasts

    PMID:19782107

    Open questions at the time
    • Identity of the E3 ligase targeting XIAP in BMPR2-deficient cells not determined
    • Whether BMPR2-XIAP interaction is direct or complex-mediated not distinguished
  5. 2011 High

    Two studies revealed that BMPR2 loss causes both cytoskeletal defects via Rac1 activation and inflammatory vascular remodeling via CXCR2/KC upregulation, broadening the downstream consequences of BMPR2 deficiency beyond SMAD signaling.

    Evidence Cytoskeletal assays with stable transfection and transgenic mice rescued by rhACE2; endothelial-specific Bmpr2 KO mice with CXCR1/2 antagonist reversal of PH

    PMID:21900197 PMID:22180660

    Open questions at the time
    • Whether Rac1 and CXCR2 pathways are mechanistically linked or independent was not tested
    • Upstream mechanism connecting BMPR2 loss to CXCR2 transcriptional induction not defined
  6. 2012 High

    Three concurrent advances established that BMPR2 deficiency activates TAK1-MAPK signaling in smooth muscle cells, that alternative splicing of exon 12 (regulated by SRSF2) modulates PAH penetrance, and that estrogen receptor alpha directly represses BMPR2 transcription—together explaining cell-type-specific and sex-biased disease susceptibility.

    Evidence Co-IP of TAK1–BMPR2 in primary PASMCs from knock-in mice with kinase inhibition; RT-PCR isoform analysis and SRSF2 siRNA in patient lymphocytes; gel mobility shift assay showing ERα binding to BMPR2 promoter

    PMID:22348410 PMID:22388934 PMID:22923426

    Open questions at the time
    • How isoform-B (lacking exon 12) mechanistically differs in cytoskeletal signaling (cofilin phosphorylation) not fully explained
    • Quantitative threshold of BMPR2 reduction required for disease onset undefined
  7. 2013 High

    Identification of FK506 as a dual activator of BMP signaling (calcineurin inhibition plus FKBP12 release from ALK1/2/3) and ataluren as a readthrough agent for BMPR2 nonsense mutations provided pharmacologic proof-of-concept for restoring BMPR2 pathway function.

    Evidence High-throughput BMP reporter screen, conditional Bmpr2 KO mice, and rat PAH models for FK506; patient-derived cells with nonsense BMPR2 mutations treated with ataluren showing restored BMPR-II protein and SMAD phosphorylation

    PMID:23590310 PMID:23867624

    Open questions at the time
    • Clinical efficacy of FK506 in PAH patients not established
    • Ataluren readthrough efficiency across different premature stop codon contexts not systematically quantified
  8. 2013 High

    Conditional uterine Bmpr2 deletion established an essential reproductive role: BMPR2 is required for decidual IL-15, VEGF, angiopoietin, and corin signaling, uterine NK cell development, and placental vascularization.

    Evidence Uterine-specific Bmpr2 conditional KO mice with histology, immunohistochemistry, and molecular pathway analysis

    PMID:23676498

    Open questions at the time
    • Whether BMPR2 acts through SMAD or non-SMAD pathways in decidual cells not dissected
    • Relevance to human pregnancy complications not directly tested
  9. 2015 High

    Two discoveries showed that BMPR2 modulates receptor-level competition: in bone, Bmpr2 deletion impairs activin (not BMP) signaling by freeing ACVR2A/B for BMPs, increasing bone mass; in endothelium, BMP9 selectively enhances BMPR-II function to reverse established PAH.

    Evidence Skeletal progenitor-specific Bmpr2 KO with activin sequestration experiments; BMP9 administration reversing PAH in three independent mouse/rat models

    PMID:25663702 PMID:26076038

    Open questions at the time
    • Structural basis for BMPR2's competitive exclusion of activins from ACVR2A/B not determined
    • Long-term safety of BMP9 supplementation unknown
  10. 2015 Medium

    BMPR2 silencing in pulmonary endothelial cells constitutively activates Ras/Raf/ERK signaling, and Raf inhibitors reverse the resulting hyperproliferation, identifying an actionable non-SMAD effector pathway.

    Evidence siRNA BMPR2 knockdown in human PAECs with expression profiling, ERK phosphorylation assays, and Raf inhibitor treatment

    PMID:26589479

    Open questions at the time
    • Single-lab study
    • Whether Raf activation is direct or indirect (e.g., via receptor cross-talk) not resolved
  11. 2017 Medium

    BMPR2 directly interacts with LIMK2 and activates the RhoA-ROCK-LIMK2 pathway to promote actin-based invasion, establishing a non-canonical cytoskeletal signaling route relevant to metastasis.

    Evidence Co-immunoprecipitation of BMPR2-LIMK2, iTRAQ phosphoproteomics, and orthotopic osteosarcoma xenograft model

    PMID:28938584

    Open questions at the time
    • Whether BMPR2-LIMK2 interaction requires kinase activity of BMPR2 not tested
    • Relevance to non-cancer cell types not established
  12. 2018 High

    BMPR2 was shown to sequester ALK2 away from ACVR2A/B, preventing activin- and BMP6/7/9-mediated SMAD1/5/8 activation; BMPR2 knockdown potentiates these signals and cell death in myeloma, refining the receptor competition model.

    Evidence BMPR2 siRNA with receptor interaction analysis and SMAD phosphorylation assays across multiple ligand/receptor combinations in myeloma and HepG2 cells

    PMID:29739878

    Open questions at the time
    • Whether BMPR2-ALK2 sequestration is constitutive or ligand-regulated not resolved
    • Structural basis for preferential BMPR2-ALK2 vs. ACVR2-ALK2 interaction unknown
  13. 2019 High

    Multiple studies in 2019 established the gatekeeper model: BMPR2 loss permits formation of mixed BMPR1/TGFβR complexes amplifying TGFβ-SMAD2/3 signaling, promotes fibrillin-1/integrin mechano-signaling, activates β-arrestin2/β-catenin to reduce PASMC contractility, and decreases JNK signaling to promote osteogenic EndMT—unifying vascular remodeling phenotypes.

    Evidence BMPR2 siRNA in ECs with receptor complex analysis and ECM/integrin assays; SMC-specific Bmpr2 KO mice with ARRB2 reduction rescue; EC cytokine stimulation with JNK pathway analysis and patient tissue

    PMID:30430573 PMID:31826007 PMID:36744494

    Open questions at the time
    • Quantitative stoichiometry of mixed receptor complexes not determined
    • Whether β-arrestin2 elevation is a direct or indirect consequence of BMPR2 loss not fully defined
  14. 2019 High

    BMPR2 in both smooth muscle and endothelial cells was shown to be required for collagen IV production that activates ILK→JNK→Notch1 signaling for endothelial regeneration, revealing a paracrine mechanism for BMPR2 in vascular repair.

    Evidence SMC-EC coculture, conditional Bmpr2 KO mice, carotid injury model, Notch1 EC-specific deletion, and ChIP-seq

    PMID:30582451

    Open questions at the time
    • Whether this collagen IV-ILK-Notch pathway operates in pulmonary vessels not tested
    • Direct connection between BMPR2 kinase activity and collagen IV transcription not established
  15. 2020 High

    BMPR2 loss converts BMP9 from an antiproliferative to a pro-proliferative signal in endothelial cells via prolonged ID1 induction and excessive angiogenesis, while 4PBA rescues ER-retained BMPR2 C118W mutant protein to normalize signaling, and BMPR2 was identified as a direct GATA-6 transcriptional target repressed by TWIST1—together clarifying how BMPR2 expression and function are contextually regulated.

    Evidence Patient BOECs and EC-specific Bmpr2 KO mice with BMP9 treatment; dermal fibroblasts from C118W patients and knock-in mice with 4PBA rescue; ChIP showing GATA-6 binding to BMPR2 promoter with TWIST1 KO/silencing

    PMID:32255665 PMID:32692930 PMID:32998516

    Open questions at the time
    • Mechanism by which BMPR2 loss prolongs ID1 induction (e.g., receptor recycling, phosphatase access) not identified
    • Whether 4PBA rescues other misfolding BMPR2 mutations beyond C118W not tested
  16. 2020 Medium

    BMPR2 was linked to metabolic regulation: in adipocytes, BMPR2 is required for perilipin phosphorylation, lipolysis, and mitochondrial oxidative phosphorylation; in cardiomyocytes, BMPR2 mutations cause mitochondrial dysfunction, insulin resistance, and constitutive Akt/AMPK activation.

    Evidence Adipocyte-specific BMPR2 KO with lipolysis and mitochondrial assays; H9c2 cardiomyocytes with patient-derived BMPR2 mutations analyzed by Seahorse and Western blot

    PMID:31850803 PMID:32350411

    Open questions at the time
    • Direct kinase substrate linking BMPR2 to perilipin phosphorylation not identified
    • Whether metabolic defects contribute to PAH pathogenesis in vivo not established
    • Single-lab studies for each tissue context
  17. 2021 High

    Structural resolution of the ALK2-BMPR2 kinase-domain heterodimer via C-lobe interaction established the molecular architecture of the active tetrameric receptor complex, explaining how PAH-associated BMPR2 mutations disrupt type I receptor GS-domain phosphorylation.

    Evidence HDX-MS, SAXS, molecular dynamics simulations, and SMAD signaling assays with interface mutants

    PMID:34400635

    Open questions at the time
    • Full-length receptor complex structure not yet available
    • Whether all type I receptors (ALK1, ALK3) use the same C-lobe interface not confirmed
  18. 2022 Medium

    SMOC1 was identified as a calcium-sensitive extracellular modulator that binds BMPR-II and inhibits BMP2-induced p38 phosphorylation; high calcium dissociates this interaction, linking vascular calcification to loss of BMPR2 pathway restraint.

    Evidence Co-IP of SMOC1–BMPR2 with domain mapping, p38 inhibitor experiments, and in vivo calcification models

    PMID:33757126

    Open questions at the time
    • Whether SMOC1–BMPR2 interaction is direct or requires co-receptors not resolved
    • Single-lab finding without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full-length structure of the active BMPR2 tetrameric complex, the mechanism by which BMPR2 loss causes prolonged ID1 induction and paradoxical BMP9-driven proliferation, the direct kinase substrates linking BMPR2 to perilipin and metabolic regulation, and the determinants of incomplete penetrance in BMPR2 mutation carriers.
  • Full-length heterotetrameric receptor complex structure not resolved
  • Molecular basis of incomplete penetrance in BMPR2 mutation carriers remains unknown
  • Direct BMPR2 kinase substrates beyond type I receptors not systematically identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ALK2CAV1LIMK2SMOC1SRSF2TAK1XIAP
Complex memberships
BMP type I/type II receptor tetramer (ALK1/ALK2/ALK3–BMPR2)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 BMP-2 binds BMPR-II via a low-affinity epitope (epitope 2) assembled by determinants of a single BMP-2 monomer; mutations in this epitope produce BMP-2 antagonists that partially or completely inhibit BMP-2 activity, defining the receptor-recognition mechanism for type II receptor engagement. BMP-2 mutant proteins analyzed by receptor ectodomain binding assays and C2C12 cell bioassay (in vitro mutagenesis + binding + functional assay) The EMBO journal High 10880444
2006 Haploinsufficiency is the predominant molecular mechanism of BMPR2-related PAH: the majority of FPAH/IPAH mutations (nonsense, frameshift, splice-site, gene rearrangements) lead to premature transcript termination and likely loss through nonsense-mediated decay (NMD), reducing functional receptor below a critical threshold. Compilation of 144 mutations in 210 PAH subjects; in vitro cell-based signaling assays for missense mutations; mechanistic inference from NMD pathway analysis Human mutation High 16429395
2008 PAH-causing mutations cause heterogeneous functional defects in BMPR-II including impaired type I receptor phosphorylation, altered receptor complex interactions, and stoichiometric imbalance in the receptor complex; the intracellular domain of BMPR-II is both necessary and sufficient for receptor complex interaction. Enzymatic and fluorescence activity-based assays; nonsense-mediated decay analysis; receptor complex stoichiometry assays; translational readthrough experiments Human molecular genetics High 18321866
2012 BMPR-II deficiency in pulmonary artery smooth muscle cells promotes activation of SMAD-independent MAPK pathways via TGFβ-associated kinase 1 (TAK1), resulting in pro-proliferative and anti-apoptotic responses; TAK1 interacts directly with BMPR-II, and this interaction is greatly reduced in the presence of pathogenic BMPR2 mutations. Primary PASMCs from knock-in mice; siRNA knockdown; kinase inhibition; ex vivo reporter assays; co-immunoprecipitation of TAK1 with BMPR-II Human molecular genetics High 22388934
2013 FK506 (tacrolimus) activates BMPR2 signaling via a dual mechanism: as a calcineurin inhibitor and by releasing the BMP signaling repressor FKBP12 from type I receptors ALK1, ALK2, and ALK3, thereby activating downstream SMAD1/5 and MAPK signaling and ID1 gene regulation. High-throughput luciferase reporter screen; mechanistic cell assays; conditional Bmpr2 knockout mice; rat PAH models The Journal of clinical investigation High 23867624
2013 BMPR2 is essential for postimplantation uterine decidual function: deletion of Bmpr2 in uterine deciduae suppresses IL-15, VEGF, angiopoietin, and corin signaling, leading to abnormal vascular development, trophoblast defects, and deficiency of uterine natural killer cells, causing placental abruption and fetal demise. Conditional uterine-specific Bmpr2 knockout mice; histology; immunohistochemistry; molecular pathway analysis The Journal of clinical investigation High 23676498
2011 BMPR2 mutations cause cytoskeletal defects in pulmonary microvascular endothelial cells through activation of the Rho GTPase Rac1; these defects are common across multiple BMPR2 mutation types and can be corrected by recombinant human angiotensin-converting enzyme 2 (rhACE2) in vitro and in vivo. Expression arrays; stable transfection; histological and functional cytoskeletal assays; transgenic mice; in vivo drug treatment American journal of physiology. Lung cellular and molecular physiology High 22180660
2012 BMPR2 alternative splicing affects BMP signaling: a higher ratio of isoform-B (missing exon 12) to isoform-A (full length) is associated with disease penetrance; exon 12 contains an exonic splice enhancer that binds SRSF2, and reduced SRSF2 promotes isoform-B formation and lower unphosphorylated cofilin after BMP stimulation. RT-PCR isoform analysis in patient lymphocytes; Western blot; siRNA knockdown of SRSF2; BMP stimulation assays Circulation High 22923426
2015 BMP9 is the preferred BMPR2 ligand for preventing apoptosis and enhancing monolayer integrity in pulmonary arterial endothelial cells; selective enhancement of endothelial BMPR-II with BMP9 reverses established PAH in BMPR2 R899X knock-in mice, monocrotaline, and VEGFR inhibition/hypoxia models. Cell-based apoptosis/integrity assays with patient cells; heterozygous knock-in mouse model generation; in vivo BMP9 administration and hemodynamic measurements Nature medicine High 26076038
2019 BMPR2 acts as a gatekeeper: BMPR2 deficiency in endothelial cells does not abolish BMP-SMAD1/5 responses but promotes formation of mixed heteromeric receptor complexes (BMPR1/TGFβR1/TGFβR2) that enable enhanced TGFβ canonical SMAD2/3 and lateral SMAD1/5 signaling, as well as mixed SMAD complexes. Loss of BMPR2 also causes accumulation of fibrillin-1 (FBN1) at junctions, enhanced β1-integrin/ILK mechano-complexes, and increased retrieval of active TGFβ from latent fibrillin-bound depots. BMPR2 siRNA knockdown in ECs; receptor complex analysis; signaling assays; ECM immunostaining; integrin adhesion assays; patient tissue immunohistochemistry PLoS biology High 31826007
2019 In smooth muscle cell-endothelial cell contact cocultures, BMPR2 is required by both cell types to produce collagen IV, which activates integrin-linked kinase (ILK); ILK directs phospho-JNK to the EC membrane, stabilizes presenilin1, and releases Notch1 intracellular domain (N1ICD) to promote EC proliferation and regeneration after arterial injury. SMC-EC coculture systems; conditional Bmpr2 knockout mice; carotid injury model; Notch1 EC-specific deletion; chromatin immunoprecipitation sequencing; metabolic assays Circulation research High 30582451
2015 Deletion of Bmpr2 in mouse skeletal progenitor cells selectively impairs activin signaling (not BMP signaling), resulting in increased bone formation rate and high bone mass; BMPR2 availability alleviates receptor-level competition between BMPs and activins for ACVR2A/ACVR2B. Conditional Bmpr2 knockout in skeletal progenitors; bone mass measurements; activin sequestration experiments; signaling pathway analysis Journal of cell science High 25663702
2009 GDF5 and BMP2 prevent apoptosis via BMPR2 by stimulating direct interaction of BMPR2 with XIAP, thereby reducing ubiquitination and increasing XIAP protein stability, which inactivates caspases; this anti-apoptotic mechanism is independent of Smad and MAPK signaling. Apoptosis assays in mouse embryonic fibroblasts; co-immunoprecipitation of BMPR2 with XIAP; ubiquitination assays; caspase activity measurements Biochimica et biophysica acta High 19782107
2018 BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with type 2 receptors ACVR2A and ACVR2B, which are necessary for ALK2 activation by activins and several BMPs; BMPR2 knockdown potentiates activin A/B- and BMP6/7/9-induced SMAD1/5/8 activation and cell death in myeloma cells. BMPR2 siRNA knockdown; receptor interaction analysis; SMAD1/5/8 phosphorylation assays in myeloma and HepG2 cells Journal of cell science High 29739878
2021 The kinase domain of type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes; this heterodimer is essential for ligand-induced receptor signaling and serves as the scaffold for assembly of the active tetrameric receptor complex enabling GS domain phosphorylation and SMAD activation; PAH-associated BMPR2 mutations target this interface. Hydrogen deuterium exchange mass spectrometry (HDX-MS); small angle X-ray scattering (SAXS); molecular dynamics simulations; SMAD signaling assays with mutants Nature communications High 34400635
2012 BMPR2 expression is suppressed by estrogen receptor alpha: estrogen receptor alpha binds directly to an evolutionarily conserved site in the BMPR2 promoter (shown by gel mobility shift assay), and increasing estrogen receptor alpha expression correlates strongly with decreasing BMPR2 expression in cell culture. Quantitative RT-PCR; gel mobility shift assay; luciferase activity assays; estrogen receptor alpha transfection experiments in cell culture; measurement in human lymphocytes and mouse lungs Biology of sex differences High 22348410
2016 BMPR2 gene delivery increases BMPR2 protein expression in pulmonary endothelial cells and in vivo, associated with increased Smad1/5/8 signaling, reduced Smad2/3 signaling, and non-Smad effects including increased PI3K and decreased p-p38-MAPK signaling, collectively ameliorating PAH. Adenoviral gene delivery to human pulmonary endothelial cells; in vivo monocrotaline rat model; Western blot signaling analysis Respirology (Carlton, Vic.) Medium 26809239
2011 Loss of endothelial BMPR-II leads to increased CXCR2 expression on endothelial cells and elevated KC (CXCR1/2 ligand) plasma levels, causing enhanced leukocyte recruitment into pulmonary vessels and pulmonary hypertension; CXCR1/2 antagonism reverses this pulmonary hypertension in endothelial-specific Bmpr2 knockout mice. Endothelial-specific conditional Bmpr2 knockout mice (L1Cre+;Bmpr2f/f); cytokine measurement; CXCR1/2 antagonist treatment; in vivo hemodynamic measurements Blood High 21900197
2019 Loss of BMPR2 in pulmonary artery smooth muscle cells (PASMC) elevates pERK1/2-pP38-pSMAD2/3, which increases ARRB2 (β-arrestin2), inactivates GSK3-beta via pAKT, causes CTNNB1 (β-catenin) nuclear translocation, and reduces RHOA and RAC1, resulting in reduced contractility and increased proliferation; decreasing ARRB2 normalizes this signaling and prevents/reverses PAH. SMC-specific Bmpr2 knockout mice; siRNA in human PASMC; PASMC from PAH patients with BMPR2 mutations; echocardiography; contractility assays; inducible SMC-specific ARRB2 reduction in mice Circulation research High 36744494
2020 Loss of BMPR2 in endothelial cells reverses the antiproliferative response to BMP9, causing enhanced EC proliferation linked to prolonged induction of the canonical BMP target ID1; in vivo, BMPR2 loss causes excessive angiogenesis in response to BMP9 in retinal and lung vascular beds. Blood outgrowth ECs from PAH patients with BMPR2 mutations; siRNA-mediated BMPR2 silencing; endothelial conditional Bmpr2 knockout mice; proliferation assays; in vivo BMP9 administration with vascular phenotyping Arteriosclerosis, thrombosis, and vascular biology High 32998516
2019 Inflammation (TNF-α and IL-1β) downregulates BMPR2 in endothelial cells; loss of BMPR2 decreases JNK signaling (rather than canonical BMP SMAD1/5 signaling) in ECs, enhancing BMP-9-induced osteogenic differentiation/mineralization, identifying BMPR2-JNK as a key axis in inflammation-induced EndMT and vascular calcification. In vitro endothelial cell experiments with cytokine stimulation; ex vivo animal tissue analysis; patient-derived tissue; BMPR2 knockdown; JNK pathway analysis The Journal of pathology High 30430573
2013 Smad3 upregulation in carotid restenosis transcriptionally activates the miR-17-92 cluster, which then targets and downregulates BMPR2, promoting VSMC proliferation; this constitutes a functional crosstalk between TGFβ/Smad3 and BMP/BMPR2 signaling pathways. Carotid artery restenosis model; VSMC cell culture; miR-17-92 target validation; Western blot; functional proliferation assays Molecular and cellular biochemistry Medium 24378993
2017 BMPR2 promotes invasion and metastasis in osteosarcoma cells via the RhoA-ROCK-LIMK2 pathway; BMPR2 directly interacts with LIMK2 (shown by co-IP) and activates it through RhoA/ROCK, promoting actin cytoskeletal changes that drive invasion and metastasis in vitro and in vivo. Co-immunoprecipitation; iTRAQ-based phosphoproteomic analysis; wound healing and transwell invasion assays; orthotopic mouse xenograft model Oncotarget Medium 28938584
2015 BMPR2 silencing in pulmonary artery endothelial cells constitutively activates Raf family members and ERK1/2 (Ras/Raf/ERK signaling), driving a proliferative and pro-migratory phenotype with cytoskeletal disruption; Raf inhibitors reverse the abnormal proliferation and hypermotility caused by BMPR2 deficiency. siRNA BMPR2 silencing in human pulmonary artery endothelial cells; gene set enrichment analysis; expression profiling; Raf/ERK phosphorylation assays; Raf inhibitor treatment American journal of physiology. Lung cellular and molecular physiology Medium 26589479
2020 BMPR2 knockout adipocytes are prone to both apoptosis and pyroptosis because BMPR2 deficiency inhibits phosphorylation of perilipin (a lipid-droplet-coating protein), impairing TNFα-stimulated lipolysis and subsequent fatty acid oxidation and oxidative phosphorylation, leading to mitochondria-mediated cell death. Adipocyte-specific BMPR2 knockout; lipolysis assays; perilipin phosphorylation analysis; mitochondrial function assays; apoptosis/pyroptosis measurements Communications biology Medium 32350411
2020 BMPR2 in cardiomyocytes is required for metabolic plasticity: BMPR2 mutant cardiomyocytes have reduced mitochondrial respiration, increased mitochondrial superoxide, enhanced baseline phosphorylation of Akt/AMPK/ACC (constitutive insulin-signaling pattern), and are insulin insensitive; the MFGE8-driven AktSer473 phosphorylation via PI3K/mTOR pathway may underlie the insulin resistance. H9c2 cardiomyocyte cell lines with patient-derived BMPR2 mutations; metabolic assays (Seahorse); immunofluorescence; Western analysis; radioactive isotope uptake studies American journal of physiology. Lung cellular and molecular physiology Medium 31850803
2020 TWIST1 in smooth muscle cells promotes pulmonary hypertension via GATA-6 degradation; BMPR2 is a direct transcriptional target of GATA-6 that binds to the BMPR2 promoter; TWIST1 inhibition restores GATA-6 recruitment to the BMPR2 promoter and BMPR2 expression. SMC-specific TWIST1 knockout/silencing mice and rats; chromatin immunoprecipitation; immunoprecipitation; mass spectrometry; in vitro proliferation/migration assays American journal of respiratory and critical care medicine High 32692930
2020 4-phenylbutyrate (4PBA), a chemical chaperone, rescues the BMPR2 C118W cysteine-substituted mutation (which causes ER retention and protein misfolding) in primary patient-derived cells: restoring BMPR2 expression, Smad1/5, ID1 and ID2 induction, and reducing hyperproliferation of PASMCs from knockin mice in vivo. Dermal fibroblasts from PAH patients; Bmpr2 C118W knockin mice; PASMC isolation; BMP4 stimulation; Western blot; in vivo 4PBA treatment with vascular morphometry American journal of respiratory cell and molecular biology High 32255665
2022 SMOC1 binds directly to BMPR-II (shown by co-immunoprecipitation) via amino acids 372-383 of its EF-hand calcium-binding domain and inhibits BMP2-induced phosphorylation of p38 via BMPR-II; under high calcium conditions, SMOC1 loses its ability to bind BMPR-II, enabling enhanced p38 activation and cell apoptosis. Co-immunoprecipitation; SMOC1 overexpression; p38 inhibitor experiments; in vitro and in vivo calcification models; immunostaining of patient tissue Cardiovascular research Medium 33757126
2022 In a PAH organ-on-chip model, BMPR2 dysfunction is linked to reduced SOX17 expression and decreased prostacyclin signaling, identifying a BMPR2-SOX17-prostacyclin signaling axis in the pulmonary endothelium that controls smooth muscle activation and proliferation. Biomimetic organ-on-chip coculture of pulmonary endothelial and smooth muscle cells; BMPR2 siRNA; hypoxia; gene expression profiling; drug treatment experiments Communications biology Medium 36344664
2018 CCL5 deficiency restores BMPR2 signaling in PAH endothelial cells by enhancing interaction of BMPR2 with caveolin-1, stabilizing endothelial surface caveolin-1 and amplifying both pSMAD-dependent and -independent BMPR2 signaling. CCL5 silencing in PAECs; co-immunoprecipitation of BMPR2 with caveolin-1; SMAD phosphorylation assays; Sugen5416/hypoxia mouse model Journal of molecular and cellular cardiology Medium 29374556
2017 BMPR2 loss of function in primary pulmonary arterial endothelial cells impairs BMP-mediated microRNA processing (a noncanonical BMP function); ataluren (PTC124) suppresses nonsense BMPR2 mutations via ribosomal readthrough, normalizing BMPR-II protein levels and ligand-dependent SMAD phosphorylation, and reversing the hyperproliferative phenotype of PASMCs and PAECs. Patient-derived lung/blood cells with BMPR2 nonsense mutations; microRNA processing assays; Western blot for BMPR-II; SMAD phosphorylation assays; proliferation assays after ataluren treatment American journal of respiratory cell and molecular biology High 23590310

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nature medicine 405 26076038
2013 FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. The Journal of clinical investigation 354 23867624
2006 Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Human mutation 299 16429395
2010 The PPH1 phosphatase is specifically involved in LHCII dephosphorylation and state transitions in Arabidopsis. Proceedings of the National Academy of Sciences of the United States of America 224 20176943
2000 BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II. The EMBO journal 212 10880444
2006 Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circulation research 189 16497988
2016 Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers. Cell stem cell 177 28017794
2005 Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation 166 16027259
2021 Optimized BMSC-derived osteoinductive exosomes immobilized in hierarchical scaffold via lyophilization for bone repair through Bmpr2/Acvr2b competitive receptor-activated Smad pathway. Biomaterials 161 33838528
2019 Inflammation induces endothelial-to-mesenchymal transition and promotes vascular calcification through downregulation of BMPR2. The Journal of pathology 156 30430573
2011 Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. The European respiratory journal 152 21737550
2006 BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Human mutation 151 16429403
2004 BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. American journal of physiology. Lung cellular and molecular physiology 151 15286002
2006 Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proceedings of the American Thoracic Society 140 17065373
1997 Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation 118 9193425
2008 Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 112 18503968
2006 Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 112 16717148
2013 BMPR2 is required for postimplantation uterine function and pregnancy maintenance. The Journal of clinical investigation 105 23676498
2018 TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family. International journal of molecular sciences 100 30200294
2012 BMPR2 expression is suppressed by signaling through the estrogen receptor. Biology of sex differences 100 22348410
2019 Smooth Muscle Contact Drives Endothelial Regeneration by BMPR2-Notch1-Mediated Metabolic and Epigenetic Changes. Circulation research 99 30582451
2019 Bmpr2 Mutant Rats Develop Pulmonary and Cardiac Characteristics of Pulmonary Arterial Hypertension. Circulation 97 30586714
2013 Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension. American journal of respiratory cell and molecular biology 94 23590310
2019 BMPR2 acts as a gatekeeper to protect endothelial cells from increased TGFβ responses and altered cell mechanics. PLoS biology 92 31826007
2023 BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension. Circulation research 85 36603064
2011 Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension. American journal of physiology. Lung cellular and molecular physiology 84 22180660
2005 Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genetics in medicine : official journal of the American College of Medical Genetics 83 15775752
2021 Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation. The European respiratory journal 82 33380512
2009 Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Respiratory research 80 19785764
2008 Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. American journal of physiology. Heart and circulatory physiology 79 18552156
2000 QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31-34 in Old Order Amish. Circulation 77 10859286
2010 Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. Respiratory research 71 20534176
2012 BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFβ-TAK1-MAPK pathways in PAH. Human molecular genetics 67 22388934
2018 Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension. International journal of molecular sciences 65 30149506
2012 Role of BMPR2 alternative splicing in heritable pulmonary arterial hypertension penetrance. Circulation 55 22923426
2011 Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. Respiratory research 54 21801371
2011 Physiologic and molecular consequences of endothelial Bmpr2 mutation. Respiratory research 53 21696628
2012 Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers. The American journal of cardiology 50 22632830
2008 Synergistic heterozygosity for TGFbeta1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension. Genetics in medicine : official journal of the American College of Medical Genetics 50 18496036
2021 Exosomal miR-100-5p inhibits osteogenesis of hBMSCs and angiogenesis of HUVECs by suppressing the BMPR2/Smad1/5/9 signalling pathway. Stem cell research & therapy 49 34256859
2011 Oxidative injury is a common consequence of BMPR2 mutations. Pulmonary circulation 49 21904662
2013 Crosstalk between TGF-β/Smad3 and BMP/BMPR2 signaling pathways via miR-17-92 cluster in carotid artery restenosis. Molecular and cellular biochemistry 47 24378993
2005 Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension. American journal of physiology. Heart and circulatory physiology 47 16024566
2020 Dysregulation of BMP9/BMPR2/SMAD signalling pathway contributes to pulmonary fibrosis and pulmonary hypertension induced by bleomycin in rats. British journal of pharmacology 46 33080042
2018 BMPR2 inhibits activin and BMP signaling via wild-type ALK2. Journal of cell science 46 29739878
2016 MicroRNA 17-92 cluster regulates proliferation and differentiation of bovine granulosa cells by targeting PTEN and BMPR2 genes. Cell and tissue research 46 27221279
2001 Pph1 from Myxococcus xanthus is a protein phosphatase involved in vegetative growth and development. Molecular microbiology 44 11298281
2019 HMGB1/TLR4 promotes hypoxic pulmonary hypertension via suppressing BMPR2 signaling. Vascular pharmacology 43 30610955
2023 Dysregulated Smooth Muscle Cell BMPR2-ARRB2 Axis Causes Pulmonary Hypertension. Circulation research 42 36744494
2020 Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling. Arteriosclerosis, thrombosis, and vascular biology 42 32998516
2015 Loss of BMPR2 leads to high bone mass due to increased osteoblast activity. Journal of cell science 42 25663702
2009 TGF-beta and BMPR-II pharmacology--implications for pulmonary vascular diseases. Current opinion in pharmacology 42 19321386
2015 Raf/ERK drives the proliferative and invasive phenotype of BMPR2-silenced pulmonary artery endothelial cells. American journal of physiology. Lung cellular and molecular physiology 40 26589479
2021 Approaches to treat pulmonary arterial hypertension by targeting BMPR2: from cell membrane to nucleus. Cardiovascular research 39 33399862
2008 BMPR2 mutation in a patient with pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia. American journal of medical genetics. Part A 39 18792970
2023 Vascular-Parenchymal Cross-Talk Promotes Lung Fibrosis through BMPR2 Signaling. American journal of respiratory and critical care medicine 38 36917778
2016 BMPR2 gene therapy for PAH acts via Smad and non-Smad signalling. Respirology (Carlton, Vic.) 38 26809239
2014 BMPR2 inhibition induced apoptosis and autophagy via destabilization of XIAP in human chondrosarcoma cells. Cell death & disease 38 25501832
2011 Attenuation of leukocyte recruitment via CXCR1/2 inhibition stops the progression of PAH in mice with genetic ablation of endothelial BMPR-II. Blood 38 21900197
2008 Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Human molecular genetics 37 18321866
2007 Demographic features, BMPR2 status and outcomes in distal chronic thromboembolic pulmonary hypertension. Thorax 36 17287300
2018 Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 35 29587293
2014 Novel mutations in BMPR2, ACVRL1 and KCNA5 genes and hemodynamic parameters in patients with pulmonary arterial hypertension. PloS one 35 24936649
2009 GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP. Biochimica et biophysica acta 34 19782107
2018 CCL5 deficiency rescues pulmonary vascular dysfunction, and reverses pulmonary hypertension via caveolin-1-dependent BMPR2 activation. Journal of molecular and cellular cardiology 33 29374556
2007 Characterization of the BMPR2 5'-untranslated region and a novel mutation in pulmonary hypertension. American journal of respiratory and critical care medicine 32 17641158
2021 The LPS induced pyroptosis exacerbates BMPR2 signaling deficiency to potentiate SLE-PAH. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 31 34818449
2017 Inhibition of ID1-BMPR2 Intrinsic Signaling Sensitizes Glioma Stem Cells to Differentiation Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 31 29208670
2021 Significance of BMPR2 mutations in pulmonary arterial hypertension. Respiratory investigation 30 34023242
2020 TWIST1 Drives Smooth Muscle Cell Proliferation in Pulmonary Hypertension via Loss of GATA-6 and BMPR2. American journal of respiratory and critical care medicine 30 32692930
2017 Endogenous Parathyroid Hormone Promotes Fracture Healing by Increasing Expression of BMPR2 through cAMP/PKA/CREB Pathway in Mice. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 30 28578352
2017 ALK2/ALK3-BMPR2/ACVR2A Mediate BMP2-Induced Downregulation of Pentraxin 3 Expression in Human Granulosa-Lutein Cells. Endocrinology 29 28977600
2021 Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization. Nature communications 28 34400635
2020 Novel Advances in Modifying BMPR2 Signaling in PAH. Genes 28 33374819
2015 Structural Mechanism Underlying the Specific Recognition between the Arabidopsis State-Transition Phosphatase TAP38/PPH1 and Phosphorylated Light-Harvesting Complex Protein Lhcb1. The Plant cell 28 25888588
2018 Fasudil inhibits neutrophil-endothelial cell interactions by regulating the expressions of GRP78 and BMPR2. Experimental cell research 26 29481792
2017 Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling. Pulmonary circulation 26 28828907
2017 BMPR2 promotes invasion and metastasis via the RhoA-ROCK-LIMK2 pathway in human osteosarcoma cells. Oncotarget 25 28938584
2022 An organ-on-chip model of pulmonary arterial hypertension identifies a BMPR2-SOX17-prostacyclin signalling axis. Communications biology 24 36344664
2019 miR-100-3p inhibits cell proliferation and induces apoptosis in human gastric cancer through targeting to BMPR2. Cancer cell international 24 31889906
2022 Hsa_circ_0001485 promoted osteogenic differentiation by targeting BMPR2 to activate the TGFβ-BMP pathway. Stem cell research & therapy 23 36064455
2021 Combination Therapy with STAT3 Inhibitor Enhances SERCA2a-Induced BMPR2 Expression and Inhibits Pulmonary Arterial Hypertension. International journal of molecular sciences 23 34502015
2014 Identification of a new intronic BMPR2-mutation and early diagnosis of heritable pulmonary arterial hypertension in a large family with mean clinical follow-up of 12 years. PloS one 23 24621962
2020 Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis. Respiratory research 22 32028950
2015 Hepatic Shunting of Eggs and Pulmonary Vascular Remodeling in Bmpr2(+/-) Mice with Schistosomiasis. American journal of respiratory and critical care medicine 22 26308618
2013 Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension. Genetics in medicine : official journal of the American College of Medical Genetics 22 23579436
2012 ALK2 and BMPR2 knockdown and endothelin-1 production by pulmonary microvascular endothelial cells. Microvascular research 22 23142694
2020 BMPR2 promotes fatty acid oxidation and protects white adipocytes from cell death in mice. Communications biology 21 32350411
2019 BMPR2 dysfunction impairs insulin signaling and glucose homeostasis in cardiomyocytes. American journal of physiology. Lung cellular and molecular physiology 21 31850803
2017 BMPR2 and HIF1-α overexpression in resected osteosarcoma correlates with distant metastasis and patient survival. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 21 29142464
2003 Primary pulmonary hypertension after amfepramone (diethylpropion) with BMPR2 mutation. The European respiratory journal 21 14516151
2000 A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. The International PPH Consortium. Genomics 21 10964520
2020 4PBA Restores Signaling of a Cysteine-substituted Mutant BMPR2 Receptor Found in Patients with Pulmonary Arterial Hypertension. American journal of respiratory cell and molecular biology 20 32255665
2018 5-HTT, BMPR2, EDN1, ENG, KCNA5 gene polymorphisms and susceptibility to pulmonary arterial hypertension: A meta-analysis. Gene 20 30218748
2010 BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension. American journal of physiology. Lung cellular and molecular physiology 20 20562228
2022 SPARC-related modular calcium binding 1 regulates aortic valve calcification by disrupting BMPR-II/p-p38 signalling. Cardiovascular research 19 33757126
2022 CircGSAP alleviates pulmonary microvascular endothelial cells dysfunction in pulmonary hypertension via regulating miR-27a-3p/BMPR2 axis. Respiratory research 19 36403044
2017 Clinical significance linked to functional defects in bone morphogenetic protein type 2 receptor, BMPR2. BMB reports 19 28391780
2014 Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension. Drug discovery today 19 24794464
2017 Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension. Scientific reports 18 28507310