SGK1 is a signalling hub that controls protein synthesis and proliferation in endothelial cells

Abstract

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.

ETS‐dependent enhancers for endothelial‐specific expression of serum/glucocorticoid‐regulated kinase 1 during mouse embryo development

“…We previously identified SGK1 to be a transcriptional target of BMP9/10‐dependent ALK1 signaling in endothelial cells (Araki et al., 2018). SGK1 mediates the BMP effects on protein synthesis and cell proliferation (Medina‐Jover et al., 2020). Upon the stimulation, phosphorylated SMAD1/5 bound to the consensus element in the human genomic segment corresponding to the mouse 2.9 k‐354 bp (Figure 1a/c).…”

Rethinking growth factors: the case of BMP9 during vessel maturation

“…BMP9 has been shown to downregulate ERK activation in a transcription-dependent manner. Hence, using SMAD1/5/8, BMP9/ALK1 can induce serum and glucocorticoid activated kinase 1 (SGK1) expression ( 53 ), and through a not yet described mechanism, this kinase downregulates ERK activation ( 54 ). SGK1 is one of the three members of the serum glucocorticoid kinases, which forms part of the AGC family of serine/threonine protein kinases ( 55 ).…”

“…In other cell types like fibroblasts, BMP9 can increase the production of matrix components ( 61 ), and its role as a key regulator of fibrosis is under discussion ( 62 ). In endothelial cells, by upregulating SGK1, BMP9 promotes the activation of mTORC1/S6K/S6 axis, which results in an increase in protein synthesis ( 54 ). The increase of SGK1 expression is essential for vessel correct development.…”

Coronavirus disease 2019 (COVID-19), human erythrocytes and the PKC-alpha/-beta inhibitor chelerythrine –possible therapeutic implication

“…Host cell protein synthesis does not necessarily have to be accompanied by its proliferation [74]. This principle can be used by a wide variety of intracellular parasites to proliferate with high velocity, e.g.…”