BMPR2

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BMPR2
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases BMPR2, BMPR-II, BMPR3, BMR2, BRK-3, POVD1, PPH1, T-ALK, bone morphogenetic protein receptor type 2
External IDs MGI: 1095407 HomoloGene: 929 GeneCards: 659
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001204
NM_033346

NM_007561

RefSeq (protein)

NP_001195.2

NP_031587.1

Location (UCSC) Chr 2: 202.38 – 202.57 Mb Chr 1: 59.76 – 59.88 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase. It binds Bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signalling. 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 it phosphorylates. The Type I receptor phosphorylates an R-SMAD a transcriptional regulator.

Function[edit]

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, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Binds to BMP-7, BMP-2 and, less efficiently, BMP-4. Binding is weak but enhanced by the presence of type I receptors for BMPs.[3] 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.[3] 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.[4]

Oocyte Development[edit]

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.[5] 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.[6]

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.[7]

Clinical significance[edit]

An inactivating mutation in the BMPR2 gene has been linked to pulmonary arterial hypertension.[8]

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.[9] 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.[9]

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.[9]

There have been studies which has correlated BMPR2 with exercise induced elevation of PA pressure by measuring tricuspid regurgitation velocity by echocardiography.[10]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b 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 14828free to read. PMID 10712517. 
  4. ^ 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 313944free to read. PMID 10880444. 
  5. ^ 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. 
  6. ^ 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 3492567free to read. PMID 22825968. 
  7. ^ 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. 
  8. ^ Rabinovitch M (December 2012). "Molecular pathogenesis of pulmonary arterial hypertension". J. Clin. Invest. 122 (12): 4306–13. doi:10.1172/JCI60658. PMC 3533531free to read. PMID 23202738. 
  9. ^ a b c Rabinovitch, Marlene. "Rescuing the BMPR2 Pathway: How and Where Can We Intervene?". Pulmonary Hypertension Association. Retrieved 29 January 2015. 
  10. ^ 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[edit]