BMPR2

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Bone morphogenetic protein receptor, type II (serine/threonine kinase)
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BMPR2 ; BMPR-II; BMPR3; BMR2; BRK-3; PPH1; T-ALK
External IDs OMIM600799 HomoloGene929 GeneCards: BMPR2 Gene
EC number 2.7.11.30
Orthologs
Species Human Mouse
Entrez 659 12168
Ensembl ENSG00000204217 ENSMUSG00000067336
UniProt Q13873 O35607
RefSeq (mRNA) NM_001204 NM_007561
RefSeq (protein) NP_001195 NP_031587
Location (UCSC) Chr 2:
203.24 – 203.43 Mb
Chr 1:
59.76 – 59.87 Mb
PubMed search [1] [2]

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.[1] 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.[1] 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.[2]

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.[3] 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.[4]

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.[5]

Clinical significance[edit]

An inactivating mutation in the BMPR2 gene has been linked to primary pulmonary hypertension.[6]

BMPR2 functions (among others) to inhibit the proliferation of vascular smooth muscle so when this gene is altered vascular smooth muscle proliferates and leads to pulmonary hypertension which among other things can lead to cor pulmonale. BMPR2 mutations are especially important screening the relatives of patients with familial or idiopathic pulmonary hypertension. There have been studies which has correlated BMPR2 with exercise induced elevation of PA pressure by measuring tricuspid regurgitation velocity by echocardiography. Reference-http://circ.ahajournals.org/content/119/13/1747.abstract)</nowiki>]

References[edit]

  1. ^ 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 14828. PMID 10712517. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 

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