BMPR2

Bone morphogenetic protein receptor type II (BMPR2) is a transmembrane serine/threonine kinase receptor that plays a central role in the bone morphogenetic protein (BMP) signaling pathway. This pathway is part of the transforming growth factor-beta (TGF-β) superfamily and is critical for regulating cellular growth, differentiation, and homeostasis. BMPR2 acts as the type II receptor in the BMP signaling cascade and works in conjunction with type I receptors, such as BMPR1A and BMPR1B, to mediate the effects of BMP ligands. Dysregulation of BMPR2 signaling has been implicated in several pathological conditions, including pulmonary arterial hypertension (PAH), cancer, fibrosis, and cardiovascular diseases. This makes BMPR2 an attractive therapeutic target for drug development.

NCBI Gene ID: 659

UniProtKB ID: Q13873

Structure and Function of BMPR2

BMPR2 is a large protein comprising three major domains:

• Extracellular Ligand-Binding Domain: This domain binds to BMP ligands with low affinity, facilitating ligand capture and signaling initiation. BMPR2 interacts with BMP ligands such as BMP2, BMP4, and BMP7, which are involved in various biological processes.
• Transmembrane Domain: This single-pass domain anchors the receptor in the cell membrane, enabling communication between extracellular BMP ligands and intracellular signaling pathways.
• Intracellular Serine/Threonine Kinase Domain: The kinase domain is responsible for phosphorylating downstream targets. Unlike type I receptors, the kinase domain of BMPR2 is constitutively active and phosphorylates type I receptors upon ligand binding.

In the canonical BMP signaling pathway, BMP ligands bind to BMPR2 and recruit type I receptors. Active BMPR2 phosphorylates the type I receptor, which then phosphorylates receptor-regulated Smads (R-Smads), such as Smad1, Smad5, and Smad8. These phosphorylated Smads form a complex with Smad4, which translocates to the nucleus to regulate target gene expression. In addition to the canonical Smad-dependent pathway, BMPR2 also activates non-Smad signaling pathways, including the p38 MAPK, PI3K/Akt, and Rho GTPase pathways, allowing for a broader range of cellular responses.

Figure 1. Structural overview of the BMPR2 complex. Schematic of the canonical BMPR2 signaling complex implicated in PAH and related vascular disorders (left) and crystal structure of the recombinant BMPR2 kinase domain (right). Secreted dimeric ligands such as BMP9 assemble a heteromeric transmembrane receptor complex consisting of two type I receptors (ALK1 shown) and two type II receptors (BMPR2 shown). Ligand binding stimulates BMPR2-mediated phosphorylation of the GS domain in ALK1, which activates ALK1 for the subsequent recruitment and phosphorylation of SMAD1/5/8 proteins. Two of these phosphorylated SMADs then assemble with SMAD4 as a heterotrimer for nuclear translocation where they bind to promoter regions containing SMAD-binding elements for transcriptional regulation. In the BMPR2 crystal structure the secondary structure elements are labelled and shown as ribbons. ADP is shown in stick representation, and Mg²⁺ ion (cyan) and sulphate molecule (purple) are displayed as spheres. Disordered residues in the activation loop (A-loop) are indicated by a dotted line. (Chaikuad et al., 2019)

Pathological Implications of BMPR2 Dysregulation

BMPR2 plays a critical role in regulating vascular homeostasis, cell proliferation, and apoptosis. Dysregulation of BMPR2 signaling is associated with several diseases, highlighting its potential as a therapeutic target.

• Pulmonary Arterial Hypertension (PAH): Mutations in the BMPR2 gene are the most common genetic cause of hereditary PAH, accounting for approximately 70-80% of cases. PAH is characterized by increased pulmonary vascular resistance due to vascular smooth muscle cell proliferation, endothelial dysfunction and excessive extracellular matrix deposition. BMPR2 mutations result in impaired BMP signaling, leading to dysregulated vascular remodeling and endothelial dysfunction.

Figure 2. Mechanisms for BMPR2 deficiency. ALK: activin-like receptor; BMP: bone morphogenetic protein; BMPR2: bone morphogenetic protein receptor 2; CAV1: caveolin 1; gp-120: envelope glycoprotein GP120; HIV: human immunodeficiency virus; Nef: negative factor; RAGE: receptor for advanced glycation end products; SMAD: mothers against decapentaplegic; SMURF: SMAD-specific E3 ubiquitin protein ligase; Tat: trans-activator of transcription; VEGFR3: Vascular endothelial growth factor receptor 3. (Andruska and Spiekerkoetter, 2018)

• Cancer: BMPR2 has a dual role in cancer, depending on the cellular context. In some cancers, BMPR2 acts as a tumor suppressor, with reduced expression being associated with increased tumor proliferation, invasion and metastasis. For example, loss of BMPR2 expression has been reported in prostate and colorectal cancers. In other cancers, such as glioblastoma, BMPR2 signaling may promote tumor progression by enhancing angiogenesis and invasion.
• Fibrosis: BMPR2 is a key regulator of fibrosis in organs such as lung, liver and kidney. Dysregulated BMP signaling contributes to fibrotic diseases by altering fibroblast activation, extracellular matrix production, and tissue remodeling. For example, reduced BMPR2 signaling has been implicated in idiopathic pulmonary fibrosis (IPF), a progressive and fatal lung disease.
• Cardiovascular Diseases: BMPR2 signaling is critical for maintaining vascular homeostasis and cardiac development. Dysregulation of BMPR2 is associated with diseases such as pulmonary hypertension and congenital heart defects. Restoring BMPR2 activity may have therapeutic potential in these diseases.

Therapeutic Proteins Targeting BMPR2

Therapeutic proteins targeting BMPR2 play a critical role in modulating bone growth, vascular function and lung health. BMPR2 is a key receptor in the transforming growth factor-beta (TGF-β) superfamily and is involved in the regulation of cell growth, differentiation and apoptosis. Dysregulation of BMPR2 signaling has been implicated in diseases such as PAH, bone disorders and certain cancers.

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References

1. Andruska A, Spiekerkoetter E. Consequences of BMPR2 deficiency in the pulmonary vasculature and beyond: contributions to pulmonary arterial hypertension. IJMS. 2018;19(9):2499. doi:10.3390/ijms19092499
2. Chaikuad A, Thangaratnarajah C, von Delft F, Bullock AN. Structural consequences of BMPR2 kinase domain mutations causing pulmonary arterial hypertension. Sci Rep. 2019;9(1):18351. doi:10.1038/s41598-019-54830-7
3. Devendran A, Kar S, Bailey R, Trivieri MG. The role of bone morphogenetic protein receptor type 2 (BMPR2) and the prospects of utilizing induced pluripotent stem cells (iPSCS) in pulmonary arterial hypertension disease modeling. Cells. 2022;11(23):3823. doi:10.3390/cells11233823