Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction

Abstract

Endoglin is a transmembrane accessory receptor for transforming growth factor-beta (TGF-beta) that is predominantly expressed on proliferating endothelial cells in culture and on angiogenic blood vessels in vivo. Endoglin, as well as other TGF-beta signalling components, is essential during angiogenesis. Mutations in endoglin and activin receptor-like kinase 1 (ALK1), an endothelial specific TGF-beta type I receptor, have been linked to the vascular disorder, hereditary haemorrhagic telangiectasia. However, the function of endoglin in TGF-beta/ALK signalling has remained unclear. Here we report that endoglin is required for efficient TGF-beta/ALK1 signalling, which indirectly inhibits TGF-beta/ALK5 signalling. Endothelial cells lacking endoglin do not grow because TGF-beta/ALK1 signalling is reduced and TGF-beta/ALK5 signalling is increased. Surviving cells adapt to this imbalance by downregulating ALK5 expression in order to proliferate. The ability of endoglin to promote ALK1 signalling also explains why ectopic endoglin expression in endothelial cells promotes proliferation and blocks TGF-beta-induced growth arrest by indirectly reducing TGF-beta/ALK5 signalling. Our results indicate a pivotal role for endoglin in the balance of ALK1 and ALK5 signalling to regulate endothelial cell proliferation.

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression

“…Studies have shown that signalling of TGFβ/ALK1–Smad1/5 stimulates EC migration and proliferation 48. Inhibition of endoglin in ECs, which is a part of the TGFβ receptor complex, potentiates TGFβ/ALK1 signalling,49, 50 resulting in reduced proliferation 51, 52. TGFβ binds to its specific receptors including TGFβR3.…”

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

“…Endoglin serves as an auxiliary receptor for TGF‐β signaling and is predominantly expressed in proliferating ECs and in tissues undergoing angiogenesis 37. Endoglin promotes ALK1‐mediated Smad1/5 signaling and inhibits ALK5‐mediated Smad2/3 signaling, leading to enhanced EC proliferation and angiogenesis 17, 18, 38, 39. Inhibiting endoglin expression by specific knockdown inhibits TGF‐β/ALK1 signaling and potentiates TGF‐β/ALK5 signaling,40, 41 resulting in reduced proliferation 19.…”

“…Mutation or abnormal expression of endoglin is the etiological reason for hereditary hemorrhagic telangiectasia or preeclampsia, respectively, which are closely related to malformation and dysfunction of blood vessels 14, 15. Inhibiting endoglin by gene knockdown in ECs inhibits TGF‐β/ALK1 signaling, and potentiates TGF‐β/ALK5 signaling,16, 17, 18 resulting in reduced proliferation 17, 19. In contrary, endoglin overexpression suppresses TGF‐β/ALK5 signaling 20, 21.…”

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

“…In endothelial cells, endoglin associates at the cell surface with the type I and type II TGF-b receptors and has a key role in modulating downstream signaling to the Smad transducer proteins (Guerrero-Esteo et al, 2002;Lebrin et al, 2004). The importance of endoglin acting as a TGF-b co-receptor in these events is evidenced by the observation that mutations in either ENG or the type I receptor ALK1 give rise to the vascular disorder hereditary hemorrhagic telangiectasia (McAllister et al, 1994;Johnson et al, 1996).…”