Endoglin inhibits ERK-induced c-Myc and cyclin D1 expression to impede endothelial cell proliferation.
Endoglin is an endothelial-specific transforming growth factor beta (TGF-β) co-receptor essential for angiogenesis and vascular remodeling. Endoglin regulates a wide range of cellular processes, including cell adhesion, migration, and proliferation, through TGF-β signaling to canonical Smad and Smad-independent pathways. Despite its overall pro-angiogenic role in the vasculature, the underlying mechanism of endoglin action is poorly characterized. We previously identified β-arrestin2 as a binding partner that causes endoglin internalization from the plasma membrane and inhibits ERK signaling towards endothelial migration. In the present study, we examined the mechanistic role of endoglin and β-arrestin2 in endothelial cell proliferation. We show that endoglin impedes cell growth through sustained inhibition of ERK-induced c-Myc and cyclin D1 expression in a TGF-β-independent manner. The down-regulation of c-Myc and cyclin D1, along with growth-inhibition, are reversed when the endoglin/β-arrestin2 interaction is disrupted. Given that TGF-β-induced Smad signaling potently represses c-Myc in most cell types, our findings here show a novel mechanism by which endoglin augments growth-inhibition by targeting ERK and key downstream mitogenic substrates.
Division of Pharmacology, Columbus, OH 43210, USA.
Christopher C
CC
Pan
Jeffrey C
JC
Bloodworth
Karthikeyan
K
Mythreye
Nam Y
NY
Lee
D015703:Antigens, CD / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis*; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D018919:Neovascularization, Physiologic; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors*; D011956:Receptors, Cell Surface / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011956:Receptors, Cell Surface; D016211:Transforming Growth Factor alpha; D019938:Cyclin D1; D048049:Extracellular Signal-Regulated MAP Kinases