Clinical significance linked to functional defects in bone morphogenetic protein type 2 receptor, BMPR2

Abstract

Bone morphogenetic protein type 2 receptor (BMPR2) is one of the transforming growth factor-β (TGF-β) superfamily receptors, performing diverse roles during embryonic development, vasculogenesis, and osteogenesis. Human BMPR2 consists of 1,038 amino acids, and contains functionally conserved extracellular, transmembrane, kinase, and C-terminal cytoplasmic domains. Bone morphogenetic proteins (BMPs) engage the tetrameric complex, composed of BMPR2 and its corresponding type 1 receptors, which initiates SMAD proteins-mediated signal transduction leading to the expression of target genes implicated in the development or differentiation of the embryo, organs and bones. In particular, genetic alterations of BMPR2 gene are associated with several clinical disorders, including representative pulmonary arterial hypertension, cancers, and metabolic diseases, thus demonstrating the physiological importance of BMPR2. In this mini review, we summarize recent findings regarding the molecular basis of BMPR2 functions in BMP signaling, and the versatile roles of BMPR2. In addition, various aspects of experimentally validated pathogenic mutations of BMPR2 and the linked human diseases will also be discussed, which are important in clinical settings for diagnostics and treatment.

A PINCH-1–Smurf1 signaling axis mediates mechano-regulation of BMPR2 and stem cell differentiation

“…S2 A, lane 3) and assessed the effects on Smad1/5 phosphorylation and MSC differentiation. Consistent with previous studies Yang et al, 2010;Zeng et al, 2012;Cao et al, 2015;Kim et al, 2017), overexpression of 3f-BMPR2 enhanced Smad1/5 phosphorylation ( Fig. S2 A), resulting in augmented OD and reduced AD ( Fig.…”

Increased estrogen levels altered microRNA expression in prostate and plasma of rats dosed with sex hormones

“…The BMPR2 protein encoded to Bmpr2 gene is well known and studied and is a member of the transforming growth factor‐β (TGF‐β) super family. The complex of BMPR2 and its ligands BMPs (especially BMP2, 4, 6, and 7) controls many physiological functions (eg, cell growth and differentiation, osteogenesis, embryonic/vascular development, Kim et al reported the expression levels of Bmpr2 gene was negatively correlated with the recurrence in prostate cancer. Kobayashi et alreported BMP7‐BMPR2 complex involved in bone metastasis of prostate cancer.…”

Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population

“…These residues are highly homologous regions among the TGF-β family and are evolutionarily conserved among many species, including invertebrates (Table S2), and must play indispensable and crucial roles for kinase activity, although these functions have not been clarified experimentally. 49 Exon 11 (57 amino acids) encodes the serine/threonine kinase and the CTD in its 5 0 and 3 0 sides, respectively. p.Arg491 is located in the end of the KD (Figure 3B), is highly conserved evolutionarily, and is frequently found as missense mutations throughout the BMPR2 gene, as was the case for 2 independent families among our study 11 Machado et al, 17,26,27,39 Wang et al, 31 Girerd et al, 32 Liu et al, 33 Pfarr et al, 34 Thomson et al, 36 International PPH consortium, 41 Kerstjens-Frederikse et al 42 (rs137852741) Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension; HPAH, heritable pulmonary arterial hypertension.…”

“…with the c-Src tyrosine kinase. 49 Others have reported on links FIGURE 2 Mutation of c.1276G>A works in 2 ways. A, Genomic sequence of the c.1276G>A mutated allele.…”

“…The p.Cys420 mutation was found in our patients (Table ). These residues are highly homologous regions among the TGF‐β family and are evolutionarily conserved among many species, including invertebrates (Table S2), and must play indispensable and crucial roles for kinase activity, although these functions have not been clarified experimentally …”