BMPR2

BMPR2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2HLQ, 3G2F
Identifiers
Aliases	BMPR2 , BMPR-II, BMPR3, BMR2, BRK-3, POVD1, PPH1, T-ALK, bone morphogenetic protein receptor type 2
External IDs	OMIM: 600799 MGI: 1095407 HomoloGene: 929 GeneCards: BMPR2
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2q33.1-q33.2 Start 202,376,327 bp [1] End 202,567,751 bp [1]
Gene location (Mouse) Chr. Chromosome 1 (mouse) [2] Band 1|1 C2 Start 59,802,559 bp [2] End 59,918,173 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in visceral pleura lower lobe of lung urethra parietal pleura right lung tibia right ventricle pons middle temporal gyrus spinal ganglia Top expressed in cumulus cell ciliary body iris carotid body right lung lobe substantia nigra molar retinal pigment epithelium pineal gland subiculum More reference expression data BioGPS n/a
Gene ontology Molecular function transmembrane receptor protein serine/threonine kinase activity ATP binding protein serine/threonine kinase activity activin receptor activity, type II BMP binding protein kinase activity protein binding kinase activity growth factor binding metal ion binding nucleotide binding transferase activity BMP receptor activity transforming growth factor beta-activated receptor activity transforming growth factor beta receptor activity, type II SMAD binding Cellular component integral component of membrane caveola spanning component of plasma membrane dendrite neuronal cell body membrane cell surface integral component of plasma membrane plasma membrane cytoplasm basal plasma membrane apical plasma membrane extracellular space nucleoplasm postsynaptic density receptor complex Biological process endothelial cell apoptotic process positive regulation of epithelial cell migration transmembrane receptor protein serine/threonine kinase signaling pathway negative regulation of vasoconstriction positive regulation of endothelial cell proliferation endochondral bone morphogenesis positive regulation of endothelial cell migration lymphangiogenesis positive regulation of pathway-restricted SMAD protein phosphorylation anterior/posterior pattern specification regulation of cell population proliferation lung alveolus development negative regulation of cell growth transcription by RNA polymerase II regulation of lung blood pressure protein phosphorylation positive regulation of axon extension involved in axon guidance artery development blood vessel remodeling BMP signaling pathway mesoderm formation vascular endothelial growth factor receptor signaling pathway signal transduction proteoglycan biosynthetic process positive regulation of cartilage development maternal placenta development endothelial cell proliferation cellular response to starvation negative regulation of DNA biosynthetic process chondrocyte development negative regulation of systemic arterial blood pressure positive regulation of osteoblast differentiation retina vasculature development in camera-type eye cellular response to BMP stimulus phosphorylation venous blood vessel development brain development retina development in camera-type eye positive regulation of BMP signaling pathway limb development positive regulation of bone mineralization negative regulation of chondrocyte proliferation lymphatic endothelial cell differentiation mitral valve morphogenesis pharyngeal arch artery morphogenesis tricuspid valve morphogenesis outflow tract septum morphogenesis atrioventricular valve morphogenesis activin receptor signaling pathway cardiac muscle tissue development outflow tract morphogenesis endocardial cushion development negative regulation of cell proliferation involved in heart valve morphogenesis positive regulation of ossification positive regulation of transcription by RNA polymerase II ventricular septum morphogenesis atrial septum morphogenesis semi-lunar valve development transforming growth factor beta receptor signaling pathway pattern specification process aortic valve development pulmonary valve development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 659 12168 Ensembl ENSG00000204217 ENSMUSG00000067336 UniProt Q13873 O35607 RefSeq (mRNA) NM_001204 NM_033346 NM_007561 RefSeq (protein) NP_001195 NP_031587 Location (UCSC) Chr 2: 202.38 – 202.57 Mb Chr 1: 59.8 – 59.92 Mb PubMed search [3] [4]
Wikidata
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Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase encoded by the BMPR2 gene. It binds bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signaling. BMPs are involved in a host of cellular functions including osteogenesis, cell growth and cell differentiation. Signaling in the BMP pathway begins with the binding of a BMP to the type II receptor. This causes the recruitment of a BMP type I receptor, which the type II receptor phosphorylates. The type I receptor phosphorylates an R-SMAD, a transcriptional regulator.

Function

Unlike the TGFβ type II receptor, which has a high affinity for TGF-β1, BMPR2 does not have a high affinity for BMP-2, BMP-7 and BMP-4, unless it is co-expressed with a type I BMP receptor. On ligand binding, a receptor complex is formed, consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. They bind to BMP-7, BMP-2 and, less efficiently, BMP-4. Binding is weak but enhanced by the presence of type I receptors for BMPs. ^[5] In TGF beta signaling all of the receptors exist in homodimers before ligand binding. In the case of BMP receptors only a small fraction of the receptors exist in homomeric forms before ligand binding. Once a ligand has bound to a receptor, the amount of homomeric receptor oligomers increase, suggesting that the equilibrium shifts towards the homodimeric form. ^[5] The low affinity for ligands suggests that BMPR2 may differ from other type II TGF beta receptors in that the ligand may bind the type I receptor first. ^[6]

Oocyte Development

BMPR2 is expressed on both human and animal granulosa cells, and is a crucial receptor for bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF 9). These two protein signaling molecules and their BMPR2-mediated effects play an important role in follicle development in preparation for ovulation. ^[7] However, BMPR2 can't bind BMP15 and GDF9 without the assistance of bone morphogenetic protein receptor 1B (BMPR1B) and transforming growth factor β receptor 1 (TGFβR1) respectively. There is evidence that the BMPR2 signaling pathway is disrupted in the case of polycystic ovary syndrome, possibly by hyperaldosterism. ^[8]

It appears that the hormones estrogen and follicle stimulating hormone (FSH) have roles in regulating expression of BMPR2 in granulosa cells. Experimental treatment in animal models with estradiol with or without FSH increased BMPR2 mRNA expression while treatment with FSH alone decreased BMPR2 expression. However, in human granulosa-like tumor cell line (KGN), treatment with FSH increased BMPR2 expression. ^[9]

Clinical significance

At least 70 disease-causing mutations in this gene have been discovered. ^[10] An inactivating mutation in the BMPR2 gene has been linked to pulmonary arterial hypertension. ^[11]

BMPR2 functions to inhibit the proliferation of vascular smooth muscle tissue. It functions by promoting the survival of pulmonary arterial endothelial cells, therefore preventing arterial damage and adverse inflammatory responses. It also inhibits pulmonary arterial proliferation in response to growth factors, which prevents the closing of arteries by proliferating endothelial cells. ^[12] When this gene is inhibited, vascular smooth muscle proliferates and can cause pulmonary hypertension, which, among other things, can lead to cor pulmonale, a condition that causes the right side of the heart to fail. The dysfunction of BMPR2 can also lead to an elevation in pulmonary arterial pressure due to an adverse response of the pulmonary circuit to injury. ^[12]

It is especially important to screen for BMPR2 mutations in relatives of patients with idiopathic pulmonary hypertension, for these mutations are present in >70% of familial cases. ^[12]

There have been studies which has correlated BMPR2 with exercise induced elevation of PA pressure by measuring tricuspid regurgitation velocity by echocardiography. ^[13]

References

1. GRCh38: Ensembl release 89: ENSG00000204217 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000067336 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Gilboa L, Nohe A, Geissendörfer T, Sebald W, Henis YI, Knaus P (March 2000). "Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors". Mol. Biol. Cell. 11 (3): 1023–35. doi:10.1091/mbc.11.3.1023. PMC   14828 . PMID   10712517.
6. Kirsch T, Nickel J, Sebald W (July 2000). "BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II". EMBO J. 19 (13): 3314–24. doi:10.1093/emboj/19.13.3314. PMC   313944 . PMID   10880444.
7. Edwards SJ, Reader KL, Lun S, Western A, Lawrence S, McNatty KP, Juengel JL (2008). "The cooperative effect of growth and differentiation factor-9 and bone morphogenetic protein (BMP)-15 on granulosa cell function is modulated primarily through BMP receptor II". Endocrinology. 149 (3): 1026–30. doi: 10.1210/en.2007-1328 . PMID   18063682.
8. de Resende LO, Vireque AA, Santana LF, Moreno DA, de Sá Rosa e Silva AC, Ferriani RA, Scrideli CA, Reis RM (2012). "Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation". J. Assist. Reprod. Genet. 29 (10): 1057–65. doi:10.1007/s10815-012-9825-8. PMC   3492567 . PMID   22825968.
9. Paradis F, Novak S, Murdoch GK, Dyck MK, Dixon WT, Foxcroft GR (2009). "Temporal regulation of BMP2, BMP6, BMP15, GDF9, BMPR1A, BMPR1B, BMPR2 and TGFBR1 mRNA expression in the oocyte, granulosa and theca cells of developing preovulatory follicles in the pig". Reproduction. 138 (1): 115–29. doi: 10.1530/REP-08-0538 . PMID   19359354.
10. Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC   6901466 . PMID   31819097.
11. Rabinovitch M (December 2012). "Molecular pathogenesis of pulmonary arterial hypertension". J. Clin. Invest. 122 (12): 4306–13. doi:10.1172/JCI60658. PMC   3533531 . PMID   23202738.
12. Rabinovitch, Marlene. "Rescuing the BMPR2 Pathway: How and Where Can We Intervene?". Pulmonary Hypertension Association. Retrieved 29 January 2015.^{[ permanent dead link ]}
13. Grünig E, Weissmann S, Ehlken N, Fijalkowska A, Fischer C, Fourme T, Galié N, Ghofrani A, Harrison RE, Huez S, Humbert M, Janssen B, Kober J, Koehler R, Machado RD, Mereles D, Naeije R, Olschewski H, Provencher S, Reichenberger F, Retailleau K, Rocchi G, Simonneau G, Torbicki A, Trembath R, Seeger W (2009). "Stress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia". Circulation. 119 (13): 1747–57. doi: 10.1161/CIRCULATIONAHA.108.800938 . PMID   19307479.

External links

• BMPR2 gene variant database
• GeneReviews/NCBI/NIH/UW entry on Heritable Pulmonary Arterial Hypertension
• OMIM entries on Heritable Pulmonary Arterial Hypertension
• Human BMPR2 genome location and BMPR2 gene details page in the UCSC Genome Browser .