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

TL;DR

This study reveals how endoglin helps in both TGF-β and BMP9 signaling in blood vessel cells, offering new insights for treating vascular diseases.

Contribution

The study identifies ENG as a dual-function co-receptor that displaces prodomains and recruits TGFBRII in BMP9 signaling.

Findings

ENG displaces prodomains from BMP9 and BMP10, enabling ligand capture.

ENG recruits TGFBRII into the BMP9 signaling complex, linking it to TGF-β pathways.

ENG-dependent genes NOG and ADAMTSL2 are reduced in pulmonary arterial hypertension.

Abstract

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.

This study provides new insights into the role of endoglin (ENG) as a co-receptor in endothelial cells and addresses a gap-in-knowledge on how ENG could be involved in both TGF-β and BMP9 signalling. Such knowledge greatly facilitates therapeutic targeting of ENG-related pathways.

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