The Role of Posttranslational Modifications in Endothelial BMP Signaling

Abstract

Bone Morphogenetic Protein (BMP) signaling plays a crucial role in endothelial cell (EC) biology, particularly in regulating vascular development and angiogenesis. Posttranslational modifications, such as ubiquitination and palmitoylation, have emerged as essential mechanisms for fine-tuning the activity of BMP receptors and downstream SMAD proteins. Despite their significance, the specific roles of these modifications in endothelial BMP signaling remain poorly understood, particularly in ECs. This study aimed to investigate how Posttranslational modifications, specifically ubiquitination and palmitoylation, regulate BMP signaling in ECs, focusing on the differential regulation of BMP receptors and SMAD proteins. Our findings reveal that ALK2 protein levels, despite being expressed at transcript levels in both arterial and venous ECs, are specifically downregulated in arterial ECs through Notch signaling-induced ubiquitination and subsequent lysosomal degradation. This regulation is mediated by the Notch-SPSB1 axis, which selectively targets ALK2 for degradation, ensuring a BMP signaling bias in venous ECs. Furthermore, SMAD1, rather than SMAD5, was found to be the primary transducer of BMP signals in ECs. Notably, palmitoylation of SMAD1 is critical for its nuclear localization and activation in response to BMP ligands, whereas SMAD5 is minimally affected by this modification in ECs. Chemical inhibition or mutation-based disruption of palmitoylation significantly impaired SMAD1 signaling, demonstrating the importance of lipid-based modifications in BMP signal transduction. This study provides novel insights into the Posttranslational regulation of BMP signaling in ECs, highlighting the roles of ubiquitination and palmitoylation in modulating the activity of BMP receptors and SMAD proteins. The differential regulation of BMP signaling in arterial and venous ECs through these modifications underscores the complexity of endothelial heterogeneity and its significance in vascular development.