Bone morphogenetic protein receptor type II orBMPR2 is aserine/threonine receptor kinase encoded by theBMPR2 gene. It bindsbone morphogenetic proteins, members of theTGF beta superfamily ofligands, which are involved inparacrine signaling. BMPs are involved in a host of cellular functions includingosteogenesis,cell growth andcell differentiation. Signaling in theBMP pathway begins with the binding of a BMP to the type II receptor. This causes the recruitment of aBMP type I receptor, which the type II receptor phosphorylates. The type I receptor phosphorylates anR-SMAD, a transcriptional regulator.
Unlike the TGFβ type II receptor, which has a high affinity for TGF-β1, BMPR2 does not have a high affinity forBMP-2,BMP-7 andBMP-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 transmembraneserine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, thenbind 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] InTGF beta signaling all of the receptors exist inhomodimers before ligand binding. In the case of BMP receptors only a small fraction of the receptors exist in homomeric forms beforeligand binding. Once a ligand has bound to a receptor, the amount of homomeric receptor oligomers increase, suggesting that theequilibrium 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]
BMPR2 is expressed on both human and animalgranulosa cells, and is a crucial receptor forbone morphogenetic protein 15 (BMP15) andgrowth differentiation factor 9 (GDF9). These two protein signaling molecules and their BMPR2-mediated effects play an important role infollicle development in preparation forovulation.[7] However, BMPR2 can't bind BMP15 and GDF9 without the assistance ofbone morphogenetic protein receptor 1B (BMPR1B) andtransforming growth factor β receptor 1 (TGFβR1) respectively. There is evidence that the BMPR2 signaling pathway is disrupted in the case ofpolycystic ovary syndrome, possibly byhyperandrogenism.[8]
It appears that the hormonesestrogen andfollicle stimulating hormone (FSH) have roles in regulating expression of BMPR2 in granulosa cells. Experimental treatment in animal models withestradiol 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]
At least 70 disease-causing mutations in this gene have been discovered.[10] An inactivating mutation in theBMPR2 gene has been linked topulmonary arterial hypertension.[11]
BMPR2 functions to inhibit the proliferation ofvascular 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 tocor 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 forBMPR2 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 measuringtricuspid regurgitation velocity byechocardiography.[13]
