BMP9 is a cytokine involved in the maturation phase of the angiogenic process that signals through its serine/threonine receptor ALK1 and its coreceptor endoglin. In this paper, we explain how BMP9 directs the regulation of endothelial cell proliferation blockage while in turn stimulating protein synthesis. To achieve this, BMP9 promotes SGK1 synthesis and activation through mTORC2 in order to stimulate the mTORC1/S6K/S6 axis. Moreover, BMP9 blocks proliferation also through SGK1 by reducing the activity of the MEK/ERK signalling pathway. Inhibition of SGK1 activity is sufficient to prevent BMP9-mediated inhibition of ERK, leading to an increase in endothelial cell proliferation. Overall, our findings reveal that SGK1 is a key player during angiogenesis, mediating the pro-quiescent and maturation effects of BMP9/ALK1.
Angiogenesis is an essential process for correct development and physiology. This mechanism is tightly regulated by many signals that activate several pathways, which are constantly interacting with each other. There is mounting evidence that BMP9/ALK1 pathway is essential for a correct vessel maturation. Alterations in this pathway lead to the development of hereditary haemorrhagic telangiectasias. However, little was known about the BMP9 signalling cascade until the last years. Recent reports have shown that while BMP9 arrests cell cycle, it promotes the activation of anabolic pathways to enhance endothelial maturation. In light of these evidence, a new criterion for the classification of cytokines is proposed here, based on the physiological objective of the activation of anabolic routes. Whether this activation by a growth factor is needed to sustain mitosis or to promote a specific function such as matrix formation, is a critical characteristic that need to be considered to classify growth factors. Hence, the state-of-the-art of BMP9/ALK1 signalling is reviewed here, as well as its implications in normal and pathogenic angiogenesis.
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