Endoglin as a BMP9 co-receptor in vascular endothelial cells: prodomain displacement and TGFBRII recruitment

Endoglin (ENG) is a single-pass transmembrane protein highly expressed in vascular endothelial cells (ECs), where it plays fundamental roles in EC functions. ENG is implicated in several cardiovascular disorders including hereditary haemorrhagic telangiectasia, pulmonary arterial hypertension (PAH) and preeclampsia. However, molecular mechanisms underlying ENG function are not fully understood. Initially identified as a co-receptor for TGF-β signalling, ENG's extracellular domain was later found to only bind BMP9 and BMP10 with high affinity. The relationship between these two observations is unclear. Here, we provide evidence for two primary functions of co-receptor ENG. First, ENG efficiently displaces prodomains from BMP9 and BMP10, enabling effective capturing of both ligands from the circulation. Second, ENG binds to and recruits TGFBRII into the BMP9 signalling complex, thereby explaining ENG's involvement in both TGF-β and BMP9 pathways. We identify BMP9 target genes NOG and ADAMTSL2 as preferentially dependent on ENG and show that their transcript levels have strong positive correlation with ENG in human lung tissues; the expression levels of all three genes are significantly reduced in PAH. Our findings address an important gap in our understanding on ENG biology and provide crucial insight for therapeutic targeting these pathways in vascular diseases.