BMPR2

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.{{cite journal | vauthors = Gilboa L, Nohe A, Geissendörfer T, Sebald W, Henis YI, Knaus P | title = Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors | journal = Mol. Biol. Cell | volume = 11 | issue = 3 | pages = 1023–35 | date = March 2000 | pmid = 10712517 | pmc = 14828 | doi = 10.1091/mbc.11.3.1023 }} 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. 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.{{cite journal | vauthors = Kirsch T, Nickel J, Sebald W | title = BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II | journal = EMBO J. | volume = 19 | issue = 13 | pages = 3314–24 | date = July 2000 | pmid = 10880444 | pmc = 313944 | doi = 10.1093/emboj/19.13.3314 }}

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 (GDF9). These two protein signaling molecules and their BMPR2-mediated effects play an important role in follicle development in preparation for ovulation.{{cite journal | vauthors = Edwards SJ, Reader KL, Lun S, Western A, Lawrence S, McNatty KP, Juengel JL | title = 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 | journal = Endocrinology | volume = 149 | issue = 3 | pages = 1026–30 | year = 2008 | pmid = 18063682 | doi = 10.1210/en.2007-1328 | doi-access = free }} 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 hyperandrogenism.{{cite journal | vauthors = de Resende LO, Vireque AA, Santana LF, Moreno DA, de Sá Rosa e Silva AC, Ferriani RA, Scrideli CA, Reis RM | title = 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 | journal = J. Assist. Reprod. Genet. | volume = 29 | issue = 10 | pages = 1057–65 | year = 2012 | pmid = 22825968 | pmc = 3492567 | doi = 10.1007/s10815-012-9825-8 }}

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.{{cite journal | vauthors = Paradis F, Novak S, Murdoch GK, Dyck MK, Dixon WT, Foxcroft GR | title = 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 | journal = Reproduction | volume = 138 | issue = 1 | pages = 115–29 | year = 2009 | pmid = 19359354 | doi = 10.1530/REP-08-0538 | doi-access = free }}

At least 70 disease-causing mutations in this gene have been discovered.{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4| bibcode = 2019NatSR...918577S }} An inactivating mutation in the BMPR2 gene has been linked to pulmonary arterial hypertension.{{cite journal | vauthors = Rabinovitch M | title = Molecular pathogenesis of pulmonary arterial hypertension | journal = J. Clin. Invest. | volume = 122 | issue = 12 | pages = 4306–13 | date = December 2012 | pmid = 23202738 | pmc = 3533531 | doi = 10.1172/JCI60658 }}

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.{{cite web|last1=Rabinovitch|first1=Marlene|title=Rescuing the BMPR2 Pathway: How and Where Can We Intervene?|url=http://www.phaonlineuniv.org/Journal/Article.cfm?ItemNumber=1855|archive-url=https://archive.today/20150129183707/http://www.phaonlineuniv.org/Journal/Article.cfm?ItemNumber=1855|url-status=dead|archive-date=January 29, 2015|website=Pulmonary Hypertension Association|access-date=29 January 2015}} 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.

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.

There have been studies which has correlated BMPR2 with exercise induced elevation of PA pressure by measuring tricuspid regurgitation velocity by echocardiography.{{cite journal | vauthors = 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 | title = 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 | journal = Circulation | volume = 119 | issue = 13 | pages = 1747–57 | year = 2009 | pmid = 19307479 | doi = 10.1161/CIRCULATIONAHA.108.800938 | doi-access = free }}

{{Reflist|35em}}

• [http://www.arup.utah.edu/database/BMPR2/BMPR2_welcome.php BMPR2 gene variant database]
• [https://www.ncbi.nlm.nih.gov/books/NBK1485/ GeneReviews/NCBI/NIH/UW entry on Heritable Pulmonary Arterial Hypertension]
• [https://www.ncbi.nlm.nih.gov/omim/178600,600799,178600,600799 OMIM entries on Heritable Pulmonary Arterial Hypertension]
• {{UCSC gene info|BMPR2}}

{{TGF beta signaling}}

{{Growth factor receptors}}

{{Serine/threonine-specific protein kinases}}

{{Enzymes}}

{{TGFβ receptor superfamily modulators}}

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Category:Bone morphogenetic protein

Category:Developmental genes and proteins

Category:TS domain

Category:S/T kinase

Category:Receptors

Category:EC 2.7.11