Affinage

BMPR2

Bone morphogenetic protein receptor type-2 · UniProt Q13873

Length
1038 aa
Mass
115.2 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BMPR2 is a type II receptor kinase that nucleates BMP signaling by forming a heterodimeric complex with type I receptor kinase domains (e.g. ALK2) through their C-terminal lobes, a scaffold required for GS-domain phosphorylation and activation of canonical SMAD1/5/8 signaling (PMID:34400635). Ligand recognition occurs through a distinct low-affinity epitope on BMP ligands separate from the type I receptor epitope (PMID:10880444), and the intracellular domain is necessary and sufficient for receptor complex assembly (PMID:18321866). Beyond its canonical role, BMPR2 acts as a gatekeeper of receptor pairing: its loss does not abolish SMAD1/5 responses but instead drives formation of mixed BMPR1/TGFβR complexes that potentiate TGFβ-SMAD2/3 and lateral SMAD1/5 signaling (PMID:31826007), and by sequestering shared type II receptors ACVR2A/ACVR2B it restrains activin- and BMP-driven ALK2 signaling (PMID:25663702, PMID:29739878). The long cytoplasmic tail serves as a regulatory platform, binding and phosphorylating the dynein light chain Tctex-1 in an isoform-specific manner disrupted by disease mutations (PMID:14583445) and recruiting additional partners including PKCβ and CtBP (PMID:15188402). BMPR2 restrains non-canonical signaling — TAK1-dependent MAPK, p38, ERK, PI3K, and ARRB2/β-catenin axes — such that its deficiency produces pro-proliferative, hypocontractile, and pro-inflammatory states in vascular cells (PMID:22388934, PMID:26809239, PMID:36744494), and it suppresses apoptosis through stabilization of XIAP independently of SMAD/MAPK (PMID:19782107). Cell-surface abundance is set post-translationally by lysosomal turnover that is opposed by a PINCH-1–Smurf1 ubiquitination axis (PMID:23669347, PMID:31578224), while transcription is repressed by estrogen receptor alpha binding to the BMPR2 promoter (PMID:22348410) and promoted by GATA-6, whose TWIST1-driven degradation lowers BMPR2 (PMID:32692930). Loss-of-function BMPR2 mutations cause haploinsufficiency, predominantly via nonsense-mediated decay, and are the major molecular cause of pulmonary arterial hypertension (PMID:18321866); BMPR2 deficiency in pulmonary vascular cells drives endothelial apoptosis, paracrine smooth-muscle proliferation, mitochondrial dysfunction, and inflammatory amplification underlying the disease (PMID:22034596, PMID:25863249, PMID:24446489). BMPR2 additionally functions across diverse tissues, controlling uterine decidualization and placentation (PMID:23676498), skeletal bone mass via activin signaling competition (PMID:25663702), adipocyte lipolysis (PMID:32350411), and dendrite stabilization in neurons through ligand-gated control of LIMK (PMID:34161760).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2000 High

    Established how BMP ligands are recognized by BMPR-II versus the type I receptor, defining the molecular basis of receptor engagement.

    Evidence BMP-2 mutagenesis and binding to receptor ectodomains with C2C12 bioassay

    PMID:10880444

    Open questions at the time
    • Did not resolve the assembled tetrameric receptor architecture
    • Affinity contributions of full-length membrane receptors not addressed
  2. 2003 High

    Identified the long cytoplasmic tail as a functional signaling platform by showing isoform-specific binding and phosphorylation of the dynein light chain Tctex-1, linking BMPR-II to disease mutations in exon 12.

    Evidence Yeast two-hybrid, Co-IP, in vitro kinase assay, immunofluorescence

    PMID:14583445

    Open questions at the time
    • Functional consequence of Tctex-1 phosphorylation undefined
    • Role in dynein-dependent transport not established
  3. 2004 Medium

    Mapped the cytoplasmic tail interactome, linking BMPR-II to MAPK, apoptosis, transcription, and kinase pathways through distinct binding sites.

    Evidence GST pull-down, 2D gel, MALDI-TOF-MS, immunodetection

    PMID:15188402

    Open questions at the time
    • Only PKCβ and CtBP confirmed; remaining 31 interactions unvalidated
    • No functional assignment to individual interactions
  4. 2008 High

    Resolved the molecular mechanism of PAH-causing mutations, establishing nonsense-mediated decay-driven haploinsufficiency and demonstrating the intracellular domain is necessary and sufficient for complex formation.

    Evidence Splicing/NMD analysis and cell-based BMPR-II activity assays

    PMID:18321866

    Open questions at the time
    • Heterogeneous missense defects not mechanistically unified
    • Downstream pathway consequences of haploinsufficiency not addressed here
  5. 2009 Medium

    Defined a SMAD/MAPK-independent anti-apoptotic function of BMPR2 via XIAP stabilization, expanding its role beyond transcriptional signaling.

    Evidence Co-IP, ubiquitination assay, caspase and viability assays in MEFs

    PMID:19782107

    Open questions at the time
    • Cell-type specificity (absent in SMCs) unexplained
    • Mechanism of XIAP de-ubiquitination not identified
  6. 2011 Medium

    Connected BMPR2 mutation to vascular cytoskeletal defects via Rac1 activation and identified ACE2 as a corrective intervention in vivo.

    Evidence Rac1 activity assays, mutant transfection, rhACE2 in transgenic mice

    PMID:22180660

    Open questions at the time
    • Mechanism linking BMPR2 to Rac1 not defined
    • How ACE2 corrects Rac1 unclear
  7. 2011 Medium

    Showed mutant BMPR-II drives paracrine smooth-muscle proliferation through endothelial secretion of TGF-β1 and FGF2, a non-cell-autonomous disease mechanism.

    Evidence Adenoviral mutant expression, conditioned media, neutralizing antibodies and inhibitors

    PMID:22034596

    Open questions at the time
    • Upstream control of cytokine secretion not defined
    • In vivo relevance of paracrine loop not tested here
  8. 2012 High

    Identified TAK1 as the mediator coupling BMPR-II deficiency to SMAD-independent MAPK-driven proliferation and survival, with the interaction lost in disease mutants.

    Evidence Primary PASMCs, Co-IP, reporter assays, inhibitor rescue, in vivo rat models

    PMID:22388934

    Open questions at the time
    • Structural basis of TAK1-BMPR-II interaction unknown
    • Relative contribution versus other non-canonical pathways unquantified
  9. 2012 Medium

    Established direct transcriptional repression of BMPR2 by estrogen receptor alpha, providing a basis for sex differences in BMPR2 expression.

    Evidence EMSA, luciferase reporter, ERα transfection, in vivo mouse studies

    PMID:22348410

    Open questions at the time
    • In vivo physiological impact on disease not fully resolved
    • Interaction with other promoter regulators unaddressed
  10. 2013 High

    Demonstrated pharmacological activation of BMPR2 signaling: FK506 via FKBP12 release and chloroquine via blocked lysosomal degradation, restoring signaling in patient cells.

    Evidence Reporter screen, FKBP12 binding, SMAD/MAPK phospho-assays, in vivo models, patient endothelial cells

    PMID:23669347 PMID:23867624

    Open questions at the time
    • Identity of the lysosomal targeting/turnover machinery incompletely defined
    • Off-target/calcineurin-independent contributions of FK506 not separated in all contexts
  11. 2013 High

    Revealed an essential developmental role for BMPR2 in uterine decidualization and placentation through control of IL-15, VEGF, angiopoietin, and corin signaling.

    Evidence Uterine-specific conditional knockout, histology, gene expression

    PMID:23676498

    Open questions at the time
    • Direct versus indirect regulation of each downstream factor unresolved
    • Relevant cell type within decidua not fully defined
  12. 2014 High

    Dissected an inflammatory amplification mechanism whereby reduced BMPR2 prolongs p38 activity and derepresses GM-CSF translation via GADD34-PP1 and stress-granule disruption.

    Evidence siRNA, phospho-protein and stress-granule assays, GM-CSF ELISA, mouse infusion/blockade

    PMID:24446489

    Open questions at the time
    • How BMPR2 loss sustains p38 activity mechanistically unclear
    • Generalizability beyond TNF stimulation untested
  13. 2015 High

    Established BMPR2 as a regulator of endothelial mitochondrial biogenesis, metabolism, and survival, linking its loss to glycolytic shift and apoptosis.

    Evidence EC-specific Bmpr2 deletion, siRNA, mitochondrial function assays, patient PAECs

    PMID:25863249

    Open questions at the time
    • Signaling route from receptor to biogenesis regulators not mapped
    • Reversibility of metabolic defects untested
  14. 2015 High

    Identified BMP9 as the preferred protective ligand for endothelial integrity and showed BMP9 reverses established PAH across multiple models, defining a therapeutic ligand axis.

    Evidence R899X knock-in mice, apoptosis/monolayer assays, BMP9 in three PAH models

    PMID:26076038

    Open questions at the time
    • Receptor complex specificity for BMP9 protection not fully resolved
    • Durability of BMP9 effect untested
  15. 2015 High

    Revealed BMPR2 sets ligand competition at the receptor level, sequestering type II receptors so that its loss selectively augments activin signaling and bone mass.

    Evidence Skeletal progenitor conditional knockout, BMP/activin signaling and sequestration assays

    PMID:25663702

    Open questions at the time
    • Stoichiometric basis of receptor competition not structurally defined
    • Tissue-specific differences in competition outcome unexplained
  16. 2018 Medium

    Generalized the gatekeeper model, showing BMPR2 loss potentiates ALK2 signaling by permitting ACVR2A/ACVR2B oligomerization with ALK2 in myeloma cells.

    Evidence siRNA knockdown, SMAD1/5/8 phospho-assays in myeloma and HepG2 cells

    PMID:29739878

    Open questions at the time
    • Proposed oligomerization mechanism not directly shown by structural method
    • Single knockdown approach without reciprocal validation
  17. 2019 High

    Demonstrated that BMPR2 loss reroutes receptor pairing into mixed BMPR1/TGFβR complexes and triggers fibrillin-1/integrin mechano-complex changes that retrieve active TGFβ, mechanistically unifying canonical and matrix-driven dysregulation.

    Evidence siRNA, receptor complex Co-IP, fibrillin-1 IF, integrin/contractility assays, patient tissue

    PMID:31826007

    Open questions at the time
    • Order of events between receptor mispairing and matrix changes unresolved
    • Quantitative balance of lateral versus canonical signaling unclear
  18. 2019 High

    Linked BMPR2 in EC-SMC contact to a collagen IV–ILK–JNK–Notch1 axis that maintains EC proliferative metabolism via PFKFB3 and histone acetylation.

    Evidence Co-culture, double-heterozygous mouse model, ChIP-seq, FRET, Notch1 deletion

    PMID:30582451

    Open questions at the time
    • Direct receptor-level trigger for collagen IV production not defined
    • Whether this axis operates in human disease tissue untested here
  19. 2019 High

    Established the PINCH-1–Smurf1 axis controlling BMPR2 protein stability and linked ECM stiffness to BMP signaling output in stem cell differentiation.

    Evidence Co-IP, ubiquitination assay, epistatic knockdown/overexpression, ECM stiffness culture

    PMID:31578224

    Open questions at the time
    • How ECM stiffness raises PINCH-1 levels not defined
    • Relevance to vascular BMPR2 turnover not tested
  20. 2019 High

    Defined a TWIST1–GATA-6 transcriptional circuit controlling BMPR2 expression, identifying GATA-6 as a direct positive promoter regulator counteracted by TWIST1-driven degradation.

    Evidence SMC-specific TWIST1 knockout, ChIP, IP-MS, in vivo PH models

    PMID:32692930

    Open questions at the time
    • Upstream signals controlling TWIST1 in SMCs unclear
    • Interaction with ERα-mediated repression not integrated
  21. 2019 Medium

    Extended BMPR2 function to adipocyte metabolism, showing it is required for TNFα-stimulated lipolysis, fatty acid oxidation, and protection from mitochondria-mediated cell death.

    Evidence Adipocyte conditional knockout, lipolysis, perilipin phosphorylation, FAO assays

    PMID:32350411

    Open questions at the time
    • Direct signaling route from BMPR2 to perilipin phosphorylation unknown
    • Systemic metabolic consequences not detailed
  22. 2021 High

    Resolved the structural basis of receptor activation, showing the ALK2-BMPR2 kinase domains form a C-terminal-lobe heterodimer that scaffolds the active tetramer and is targeted by PAH mutations.

    Evidence HDX-MS, SAXS, MD simulations, SMAD signaling with disease mutants

    PMID:34400635

    Open questions at the time
    • High-resolution crystal/cryo-EM structure of full tetramer not obtained
    • Generality across all type I receptors not tested
  23. 2021 Medium

    Uncovered a BMPR2-SMAD4/6-YY1 axis maintaining HCMV latency in myeloid progenitors, identifying BMPR2 as a target for latency reversal.

    Evidence iPSC and patient myeloid latency models, BMPR2 inhibition, miR-29a/YY1 assays

    PMID:34061599

    Open questions at the time
    • Direct versus indirect SMAD4/6 control of YY1 not fully separated
    • Pharmacological specificity of BMPR2 inhibition uncertain
  24. 2021 High

    Demonstrated a ligand-gated function of BMPR-2 in neurons, controlling dendrite stabilization through inhibition or release of LIMK activity.

    Evidence CRISPR KO screen, in utero electroporation, rescue, FRET imaging, Rac1 epistasis

    PMID:34161760

    Open questions at the time
    • Biochemical mechanism of LIMK inhibition by apo-BMPR-2 undefined
    • Whether disease mutations affect this neuronal function untested
  25. 2022 Medium

    Identified SMOC1 as a calcium-sensitive direct BMPR-II binder that restrains p38 signaling and apoptosis, adding a ligand-independent modulator.

    Evidence Co-IP, domain mapping, p38 phospho-assays, calcification models

    PMID:33757126

    Open questions at the time
    • Reciprocal validation of SMOC1-BMPR-II binding limited
    • Physiological context beyond calcification unclear
  26. 2023 High

    Defined the integrated non-canonical signaling derangement of BMPR2-deficient smooth muscle and identified ARRB2 as a tractable node whose reduction restores the contractile phenotype.

    Evidence SMC-specific knockout, human/patient PASMC siRNA, phosphoprotein analysis, ARRB2 rescue, hemodynamics

    PMID:36744494

    Open questions at the time
    • How BMPR2 loss elevates ARRB2 mechanistically unknown
    • Integration with TAK1/p38 pathways not unified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse cytoplasmic-tail partners, receptor-competition gatekeeping, and tissue-specific phenotypes are mechanistically integrated into a single quantitative model of BMPR2 signaling output remains unresolved.
  • No unified model linking canonical SMAD output to the many non-canonical and matrix-driven effects
  • Tissue specificity of partner usage undefined
  • Structural model of the full ligand-bound tetramer incomplete

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 3 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3
Partners
ALK2CTBPPKCBSMOC1SMURF1TAK1TCTEX-1XIAP
Complex memberships
BMP type I/II receptor heterotetramer (ALK2-BMPR2)ILK mechano-complex (matrix-associated)PINCH-1-Smurf1-BMPR2 axis

Evidence

Reading pass · 28 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 assembled from determinants of a single monomer (epitope 2), distinct from the high-affinity BMPR-IA binding epitope 1. Mutations in epitope 2 produce BMP-2 antagonists that partially or completely inhibit BMP-2 activity, defining the receptor recognition mechanism. BMP-2 mutant proteins analyzed for binding to receptor ectodomains; C2C12 cell bioassay The EMBO journal High 10880444
2003 Tctex-1, a dynein light chain, interacts with the cytoplasmic domain of BMPR-II and is phosphorylated by BMPR-II. This interaction is isoform-specific (requiring the long cytoplasmic tail encoded partly by exon 12) and is disrupted by PPH disease-causing mutations within exon 12. BMPR-II and Tctex-1 co-localize in pulmonary vascular endothelium and smooth muscle. Yeast two-hybrid, co-immunoprecipitation, in vitro phosphorylation assay, immunofluorescence co-localization Human molecular genetics High 14583445
2004 GST pull-down with BMPR-II cytoplasmic domain constructs identified 33 interacting proteins including PKCβ and CtBP (confirmed by immunodetection), and showed that the C-terminal tail of BMPR-II provides distinct binding sites for regulatory proteins linking BMP signaling to MAP kinase pathway, apoptosis, transcription, PKCβ, and PKA. GST pull-down assay, 2D gel electrophoresis, MALDI-TOF-MS, immunodetection confirmation Proteomics Medium 15188402
2008 PAH-causing BMPR2 nonsense and frameshift mutations trigger nonsense-mediated decay (NMD), establishing haploinsufficiency as the predominant molecular mechanism. Missense mutations cause heterogeneous functional defects including impaired type I receptor phosphorylation and altered receptor complex stoichiometry. The intracellular domain of BMPR-II is both necessary and sufficient for receptor complex interaction. Enzymatic and fluorescence activity-based assays, splicing analysis, NMD inhibition, cell-based BMPR-II activity assays Human molecular genetics High 18321866
2009 GDF5 and BMP2 prevent apoptosis in mouse embryonic fibroblasts (but not smooth muscle cells) via BMPR2. The mechanism involves BMPR2 stimulating the interaction with XIAP, reducing XIAP ubiquitination and increasing XIAP protein stability, which then inactivates activated caspases. This anti-apoptotic effect does not depend on Smad or MAPK signaling. Co-immunoprecipitation, ubiquitination assay, BMPR2 loss-of-function, caspase activity assay, cell viability assay Biochimica et biophysica acta Medium 19782107
2011 BMPR2 mutations in pulmonary microvascular endothelial cells activate the Rho GTPase Rac1, causing cytoskeletal defects. Exogenous recombinant ACE2 corrects Rac1 defects in vitro and reverses established PAH in vivo in Rosa26-Bmpr2R899X transgenic mice. Expression arrays, Rac1 activity assay, stable transfection of BMPR2 mutations, in vivo mouse model with rhACE2 treatment American journal of physiology. Lung cellular and molecular physiology Medium 22180660
2011 Mutant BMPR-II expression in pulmonary arterial endothelial cells increases susceptibility to apoptosis and causes secretion of elevated TGF-β1 and FGF2, which stimulate pulmonary arterial smooth muscle cell proliferation. Neutralizing antibodies to TGF-β1 or inhibitors of ALK-5 or FGFR1 blocked this paracrine proliferative effect. Adenoviral overexpression of wild-type or kinase-deficient BMPR-II mutant in PAECs, conditioned media experiments, ELISA, TGF-β bioassay, neutralizing antibodies, small molecule inhibitors Pulmonary circulation Medium 22034596
2012 BMPR-II deficiency promotes activation of SMAD-independent MAPK pathways via TGFβ-associated kinase 1 (TAK1), resulting in pro-proliferative and anti-apoptotic responses in pulmonary arterial smooth muscle cells. TAK1 interacts with BMPR-II and inhibits BMP-responsive reporter activity; this interaction is greatly reduced by PAH-causing BMPR2 mutations. Primary PASMCs from knock-in mice, TAK1-MAPK inhibition rescue experiments, reporter assay, co-immunoprecipitation, in vivo rat PAH models Human molecular genetics High 22388934
2012 Estrogen receptor alpha directly binds to a conserved site in the BMPR2 promoter (demonstrated by gel-shift/EMSA assay), and increased estrogen receptor alpha expression correlates with decreased BMPR2 transcription. Exogenous estrogen decreases BMPR2 expression in proliferating cells. Quantitative RT-PCR, gel mobility shift assay (EMSA), luciferase reporter assay, estrogen receptor transfection in cell culture, in vivo mouse studies Biology of sex differences Medium 22348410
2013 FK506 (tacrolimus) activates BMPR2 signaling via a dual mechanism: as a calcineurin inhibitor and by releasing FKBP12 from type I receptors ALK1, ALK2, and ALK3, thereby activating downstream SMAD1/5 and MAPK signaling and ID1 gene regulation. Low-dose FK506 reversed dysfunctional BMPR2 signaling in PAH patient endothelial cells and reversed established PAH in multiple rodent models. High-throughput luciferase reporter screen, FKBP12 binding assay, SMAD1/5 and MAPK phosphorylation assays, in vivo rat PAH models, conditional Bmpr2 deletion mouse model The Journal of clinical investigation High 23867624
2013 Chloroquine increases cell surface expression of BMPR-II protein by inhibiting lysosomal degradation, independent of transcription. Cell surface BMPR-II has rapid turnover that is blocked by chloroquine. This restores BMP9-induced BMPR-II signaling (Id1, miR21, miR27a expression) in endothelial cells from PAH patients with BMPR-II mutations. Protein synthesis inhibition, cell surface expression assay, siRNA knockdown, BMP9 signaling assays (Id1, miR21/27a), blood outgrowth endothelial cells from PAH patients Human molecular genetics Medium 23669347
2013 Uterine decidua-specific deletion of Bmpr2 in mice leads to midgestation decidualization defects, abnormal vascular development, trophoblast defects, and deficiency of uterine natural killer cells. Absence of BMPR2 signaling in the uterine decidua suppresses IL-15, VEGF, angiopoietin, and corin signaling, resulting in placental abruption and fetal demise. Conditional Bmpr2 knockout (uterine-specific Cre), histology, immunofluorescence, gene expression analysis The Journal of clinical investigation High 23676498
2014 Reduced BMPR2 in pulmonary artery endothelial cells, upon TNF stimulation, leads to prolonged phospho-p38 MAPK activity, increased GADD34-PP1 phosphatase activity, dephosphorylation of eIF2α, and consequent derepression of GM-CSF mRNA translation by disrupting stress granule formation. This mechanism increases GM-CSF production, macrophage recruitment, and exacerbates PAH. siRNA knockdown, phospho-protein analysis, stress granule assays, GADD34-PP1 activity assay, GM-CSF ELISA, GM-CSF infusion and blockade in mouse models The Journal of experimental medicine High 24446489
2015 BMPR2 deficiency in pulmonary arterial endothelial cells impairs mitochondrial biogenesis regulators (p53, PGC1α, NRF2, TFAM), reduces mitochondrial membrane potential and ATP production, induces mitochondrial DNA deletion and apoptosis during reoxygenation. In normoxia, BMPR2 reduction increases glycolysis, induces mitochondrial fission, and promotes a pro-inflammatory state. EC-specific Bmpr2 deletion mouse model, siRNA knockdown in PAECs, mitochondrial function assays (membrane potential, ATP, mtDNA), gene expression analysis Cell metabolism High 25863249
2015 BMP9 is the preferred ligand for BMPR-II-mediated prevention of apoptosis and enhancement of monolayer integrity in pulmonary arterial endothelial cells, including those from PAH patients with BMPR2 mutations. Administration of BMP9 reversed established PAH in BMPR2 R899X knock-in mice and in monocrotaline and Sugen/hypoxia rat models. BMPR2 R899X knock-in mouse model generation, apoptosis assays, endothelial monolayer integrity assays, in vivo BMP9 administration in three PAH models Nature medicine High 26076038
2015 Loss of BMPR2 in mouse skeletal progenitor cells selectively impairs activin signaling but has no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. BMPR2 availability mediates receptor-level competition between BMPs and activins for ACVR2A/ACVR2B. Conditional Bmpr2 knockout in skeletal progenitors (Bmpr2-cKO mice), bone mass measurement, BMP and activin signaling assays, activin sequestration experiments Journal of cell science High 25663702
2016 BMPR2 gene delivery increases Smad1/5/8 signaling and reduces Smad2/3 signaling (switching TGF-β-Smad2/3 to BMPR2-Smad1/5/8), and also increases PI3K signaling and decreases p38-MAPK phosphorylation in vivo. These changes are associated with amelioration of PAH in the monocrotaline rat model. Adenoviral BMPR2 gene delivery to human pulmonary endothelial cells and in vivo rat PAH model, Western blotting for Smad and non-Smad signaling Respirology (Carlton, Vic.) Medium 26809239
2018 BMPR2 knockdown in multiple myeloma cells potentiates activin A-, activin B-, BMP6-, BMP7-, and BMP9-induced SMAD1/5/8 signaling through wild-type ALK2. The proposed mechanism is that BMPR2 inhibits ALK2-mediated signaling by preventing ALK2 from oligomerizing with ACVR2A and ACVR2B, which are required for ALK2 activation by activins and several BMPs. siRNA knockdown of BMPR2, SMAD1/5/8 phosphorylation assays, cell death assays in myeloma and HepG2 cells Journal of cell science Medium 29739878
2019 BMPR2 deficiency in endothelial cells does not abolish BMP-SMAD1/5 responses but instead promotes formation of mixed heteromeric receptor complexes (BMPR1/TGFβR1/TGFβR2), enabling enhanced TGFβ-SMAD2/3 and lateral TGFβ-SMAD1/5 signaling. Loss of BMPR2 also causes ectopic fibrillin-1 accumulation with active β1-integrin in ILK mechano-complexes at cell junctions, increasing integrin-dependent contractility and retrieval of active TGFβ from latent fibrillin-bound depots. BMPR2 siRNA knockdown, SMAD phosphorylation assays, co-immunoprecipitation of receptor complexes, fibrillin-1 immunofluorescence, integrin adhesion/spreading assays, actomyosin contractility assays, patient tissue analysis PLoS biology High 31826007
2019 In SMC-EC contact cocultures, BMPR2 in both cell types is required to produce collagen IV, which activates ILK. ILK directs phospho-JNK to the EC membrane, stabilizing presenilin1 and releasing Notch1 intracellular domain (N1ICD) to promote EC proliferation. N1ICD maintains EC proliferative capacity by increasing mitochondrial mass and inducing PFKFB3, which is required for citrate-dependent H3K27 acetylation at enhancer sites. Co-culture experiments, EC-SMC Bmpr2 double heterozygous mouse model, carotid injury model, ChIP-seq, FRET imaging, conditional Notch1 deletion mice Circulation research High 30582451
2019 TWIST1-dependent degradation of GATA-6 in smooth muscle cells reduces BMPR2 expression; GATA-6 directly binds to the BMPR2 promoter and promotes its expression. SMC-specific TWIST1 deficiency or silencing restored GATA-6-dependent BMPR2 expression and attenuated PH development. SMC-specific TWIST1 knockout mice, TWIST1 silencing in rats, chromatin immunoprecipitation (ChIP), immunoprecipitation (mass spectrometry), Western blotting American journal of respiratory and critical care medicine High 32692930
2019 BMPR2 knockout in adipocytes impairs TNFα-stimulated lipolysis by inhibiting perilipin phosphorylation, leading to failure of fatty acid oxidation and oxidative phosphorylation, and consequent mitochondria-mediated apoptosis and pyroptosis with elevated inflammation. Conditional BMPR2 knockout in adipocytes, lipolysis assays, perilipin phosphorylation assay, fatty acid oxidation assay, apoptosis/pyroptosis assays Communications biology Medium 32350411
2019 A PINCH-1–Smurf1–BMPR2 signaling axis links extracellular matrix stiffness to mesenchymal stem cell osteogenic differentiation. PINCH-1 interacts with Smurf1, preventing Smurf1 from ubiquitinating and degrading BMPR2. ECM stiffening increases PINCH-1 levels, thereby protecting BMPR2 from degradation and augmenting BMP signaling. Depletion of either Smurf1 or BMPR2 blocks PINCH-1-induced osteogenic differentiation. Co-immunoprecipitation, ubiquitination assay, PINCH-1/Smurf1/BMPR2 knockdown and overexpression, soft/stiff ECM culture, osteogenic differentiation assays The Journal of cell biology High 31578224
2021 The kinase domain of the type I receptor ALK2 and the type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. This heterodimer serves as the scaffold for assembly of active tetrameric receptor complexes enabling phosphorylation of the GS domain and activation of SMADs. PAH-causing mutations in BMPR2 target this kinase domain heterodimer interface. Hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS), molecular dynamics (MD) simulations, SMAD signaling assays with PAH-associated mutants Nature communications High 34400635
2021 BMPR2 signaling through SMAD4/SMAD6 maintains high YY1 levels in latently HCMV-infected undifferentiated myeloid cells. BMPR2-activated SMAD4/6 inhibits TGFβ receptor signaling, preventing induction of hsa-miR-29a that would degrade YY1. Pharmacological targeting of BMPR2 in progenitor cells results in YY1 degradation and loss of HCMV latency. iPSC model of HCMV latency, patient-derived myeloid progenitors, BMPR2 pharmacological inhibition, SMAD4/6 pathway analysis, miR-29a measurement, YY1 protein assays, T cell killing assays mBio Medium 34061599
2021 BMPR-2 in developing mitral cell dendrites inhibits LIMK activity in the absence of ligands, permitting dendrite destabilization. Ligand-bound BMPR-2 releases LIMK inhibition to stabilize dendrites. LIMK activated by NMDARs via Rac1 facilitates selective dendrite stabilization through F-actin formation. CRISPR-Cas9-based knockout screening, in utero electroporation, rescue experiments with Bmpr2 re-expression, BMP antagonist/agonist overexpression, Rac1 genetic experiments, FRET imaging of LIMK activity Cell reports High 34161760
2022 SMOC1 binds directly to BMPR-II (via amino acids 372–383 of its EF-hand calcium-binding domain, shown by co-immunoprecipitation) and inhibits BMP2-induced phosphorylation of p38 (p-p38). Under high calcium conditions, SMOC1 loses its ability to bind BMPR-II, promoting p-p38 and cell apoptosis. Co-immunoprecipitation, domain-mapping with truncation mutants, p38 phosphorylation assays, p38 inhibitor experiments, in vitro and in vivo calcification models Cardiovascular research Medium 33757126
2023 Loss of BMPR2 in smooth muscle cells causes upregulation of pERK1/2-pP38-pSMAD2/3, elevation of β-arrestin2 (ARRB2), pAKT inactivation of GSK3-beta, CTNNB1 nuclear translocation, and reduction in RHOA and RAC1, resulting in hypocontractile and hyperproliferative PASMC phenotype. Decreasing ARRB2 in BMPR2-deficient SMC restores normal signaling and reverses the aberrant phenotype. SMC-specific Bmpr2 knockout mice, siRNA in human PASMC, PASMC from PAH patients with BMPR2 mutations, phosphoprotein analysis, ARRB2 knockdown rescue experiments, echocardiography and hemodynamic measurements Circulation research High 36744494

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. American journal of human genetics 861 10903931
2000 Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. Journal of medical genetics 528 11015450
2015 Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nature medicine 410 26076038
2013 FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. The Journal of clinical investigation 359 23867624
2016 BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. The Lancet. Respiratory medicine 343 26795434
2006 Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Human mutation 301 16429395
2000 BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II. The EMBO journal 212 10880444
2015 BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. Cell metabolism 197 25863249
2019 Inflammation induces endothelial-to-mesenchymal transition and promotes vascular calcification through downregulation of BMPR2. The Journal of pathology 157 30430573
2011 Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. The European respiratory journal 153 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
2002 BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. The European respiratory journal 145 12358323
2006 Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proceedings of the American Thoracic Society 141 17065373
2014 Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. The Journal of experimental medicine 130 24446489
1997 Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation 118 9193425
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
2003 Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension. Human molecular genetics 103 14583445
2019 Smooth Muscle Contact Drives Endothelial Regeneration by BMPR2-Notch1-Mediated Metabolic and Epigenetic Changes. Circulation research 101 30582451
2018 TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family. International journal of molecular sciences 101 30200294
2012 BMPR2 expression is suppressed by signaling through the estrogen receptor. Biology of sex differences 101 22348410
2019 Bmpr2 Mutant Rats Develop Pulmonary and Cardiac Characteristics of Pulmonary Arterial Hypertension. Circulation 100 30586714
2019 BMPR2 acts as a gatekeeper to protect endothelial cells from increased TGFβ responses and altered cell mechanics. PLoS biology 95 31826007
2023 BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension. Circulation research 94 36603064
2021 17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin. The Journal of clinical investigation 90 33497359
2013 The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations. Human molecular genetics 88 23669347
2011 Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension. American journal of physiology. Lung cellular and molecular physiology 84 22180660
2021 Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation. The European respiratory journal 83 33380512
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
2016 BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension. The European respiratory journal 78 27811071
2004 Proteins associated with type II bone morphogenetic protein receptor (BMPR-II) and identified by two-dimensional gel electrophoresis and mass spectrometry. Proteomics 77 15188402
2000 QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31-34 in Old Order Amish. Circulation 77 10859286
2012 BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFβ-TAK1-MAPK pathways in PAH. Human molecular genetics 71 22388934
2018 Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension. International journal of molecular sciences 66 30149506
2000 Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. American journal of respiratory and critical care medicine 65 10712363
2011 Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. Respiratory research 55 21801371
2011 Physiologic and molecular consequences of endothelial Bmpr2 mutation. Respiratory research 53 21696628
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 52 34256859
2012 Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers. The American journal of cardiology 50 22632830
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
2019 HMGB1/TLR4 promotes hypoxic pulmonary hypertension via suppressing BMPR2 signaling. Vascular pharmacology 45 30610955
2023 Dysregulated Smooth Muscle Cell BMPR2-ARRB2 Axis Causes Pulmonary Hypertension. Circulation research 44 36744494
2001 Pph1 from Myxococcus xanthus is a protein phosphatase involved in vegetative growth and development. Molecular microbiology 44 11298281
2015 Loss of BMPR2 leads to high bone mass due to increased osteoblast activity. Journal of cell science 43 25663702
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 42 26589479
2009 TGF-beta and BMPR-II pharmacology--implications for pulmonary vascular diseases. Current opinion in pharmacology 42 19321386
2023 Vascular-Parenchymal Cross-Talk Promotes Lung Fibrosis through BMPR2 Signaling. American journal of respiratory and critical care medicine 40 36917778
2011 Expression of mutant BMPR-II in pulmonary endothelial cells promotes apoptosis and a release of factors that stimulate proliferation of pulmonary arterial smooth muscle cells. Pulmonary circulation 40 22034596
2021 Approaches to treat pulmonary arterial hypertension by targeting BMPR2: from cell membrane to nucleus. Cardiovascular research 39 33399862
2016 BMPR2 gene therapy for PAH acts via Smad and non-Smad signalling. Respirology (Carlton, Vic.) 39 26809239
2014 BMPR2 inhibition induced apoptosis and autophagy via destabilization of XIAP in human chondrosarcoma cells. Cell death & disease 38 25501832
2008 Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Human molecular genetics 37 18321866
2014 Novel mutations in BMPR2, ACVRL1 and KCNA5 genes and hemodynamic parameters in patients with pulmonary arterial hypertension. PloS one 35 24936649
2014 BMPR2 loss in fibroblasts promotes mammary carcinoma metastasis via increased inflammation. Molecular oncology 35 25205038
2015 BMPR2 gene delivery reduces mutation-related PAH and counteracts TGF-β-mediated pulmonary cell signalling. Respirology (Carlton, Vic.) 34 26689975
2009 GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP. Biochimica et biophysica acta 34 19782107
2007 Characterization of the BMPR2 5'-untranslated region and a novel mutation in pulmonary hypertension. American journal of respiratory and critical care medicine 33 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 32 34818449
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 32 32692930
2021 Significance of BMPR2 mutations in pulmonary arterial hypertension. Respiratory investigation 31 34023242
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 Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization. Nature communications 30 34400635
2020 Novel Advances in Modifying BMPR2 Signaling in PAH. Genes 29 33374819
2017 ALK2/ALK3-BMPR2/ACVR2A Mediate BMP2-Induced Downregulation of Pentraxin 3 Expression in Human Granulosa-Lutein Cells. Endocrinology 29 28977600
2007 Hepatocyte growth factor up-regulates the expression of the bone morphogenetic protein (BMP) receptors, BMPR-IB and BMPR-II, in human prostate cancer cells. International journal of oncology 28 17203235
2023 Discovery of Highly Potent and BMPR2-Selective Kinase Inhibitors Using DNA-Encoded Chemical Library Screening. Journal of medicinal chemistry 26 36719862
2018 Fasudil inhibits neutrophil-endothelial cell interactions by regulating the expressions of GRP78 and BMPR2. Experimental cell research 26 29481792
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
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 23 23579436
2012 ALK2 and BMPR2 knockdown and endothelin-1 production by pulmonary microvascular endothelial cells. Microvascular research 23 23142694
2020 Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis. Respiratory research 22 32028950
2015 Mutation in BMPR2 Promoter: A 'Second Hit' for Manifestation of Pulmonary Arterial Hypertension? PloS one 22 26167679
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
2021 The role of TGF-β or BMPR2 signaling pathway-related miRNA in pulmonary arterial hypertension and systemic sclerosis. Arthritis research & therapy 20 34819148
2019 BMPR2-expressing bone marrow-derived endothelial-like progenitor cells alleviate pulmonary arterial hypertension in vivo. Respirology (Carlton, Vic.) 20 30977250
2018 5-HTT, BMPR2, EDN1, ENG, KCNA5 gene polymorphisms and susceptibility to pulmonary arterial hypertension: A meta-analysis. Gene 20 30218748
2015 Inhibition of FGFR Signaling With PD173074 Ameliorates Monocrotaline-induced Pulmonary Arterial Hypertension and Rescues BMPR-II Expression. Journal of cardiovascular pharmacology 20 26535780
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
2024 Emerging role of BMPs/BMPR2 signaling pathway in treatment for pulmonary fibrosis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 39142248
2022 SPARC-related modular calcium binding 1 regulates aortic valve calcification by disrupting BMPR-II/p-p38 signalling. Cardiovascular research 19 33757126
2021 PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation. Science signaling 19 33500333
2021 A BMPR2/YY1 Signaling Axis Is Required for Human Cytomegalovirus Latency in Undifferentiated Myeloid Cells. mBio 19 34061599
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
2011 BMPR-II is dispensable for formation of the limb skeleton. Genesis (New York, N.Y. : 2000) 19 21538804
2017 Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension. Scientific reports 18 28507310
2021 BMPR-2 gates activity-dependent stabilization of primary dendrites during mitral cell remodeling. Cell reports 17 34161760
2019 A PINCH-1-Smurf1 signaling axis mediates mechano-regulation of BMPR2 and stem cell differentiation. The Journal of cell biology 17 31578224
2011 Variation in BMPR1B, TGFRB1 and BMPR2 and control of dizygotic twinning. Twin research and human genetics : the official journal of the International Society for Twin Studies 17 21962132

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