BMPR2 is a type II serine/threonine kinase receptor that mediates bone morphogenetic protein (BMP) signaling through formation of heterotetrameric receptor complexes with type I receptors 1. Upon ligand binding, BMPR2 phosphorylates and activates type I receptors, which then phosphorylate SMAD transcriptional regulators and activate p38MAPK signaling cascades 1. The receptor also mediates signaling through activin A and promotes adipogenesis via GDF6 2. Functionally, BMPR2 negatively regulates smooth muscle and chondrocyte proliferation while promoting endothelial cell differentiation and lung vascular development. BMPR2 mutations and dysregulation are strongly associated with pulmonary arterial hypertension (PAH) pathogenesis 3. Loss of BMPR2 in pulmonary artery smooth muscle cells promotes a hyperproliferative, hypocontractile phenotype mediated by elevated β-arrestin2 (ARRB2) and abnormal MAPK/SMAD signaling 4. In endothelial cells, impaired BMPR2 signaling promotes endothelial-to-mesenchymal transition and pyroptosis through cathepsin L-mediated BMPR2 degradation and GSDME activation 3 5. Epigenetically, BMPR2 promoter hypermethylation contributes to PAH progression; SIN3a-mediated prevention of this methylation represents a therapeutic strategy 6. SMURF1 ubiquitylates and degrades BMPR2; allosteric HECT inhibitors prevent this degradation and normalize BMP signaling in PAH models 7. Clinically, sotatercept demonstrates consistent efficacy in PAH treatment regardless of BMPR2 mutation status 8.