Activator of G-protein signaling 8 is involved in VEGF-mediated signal processing during angiogenesis.

Activator of G-protein signaling 8 (AGS8, also known as FNDC1) is a receptor-independent accessory protein for the Gβγ subunit, which was isolated from rat heart subjected to repetitive transient ischemia with the substantial development of collaterals. Here, we report the role of AGS8 in vessel formation by endothelial cells. Knockdown of AGS8 by small interfering RNA (siRNA) inhibited vascular endothelial growth factor (VEGF)-induced tube formation, as well as VEGF-stimulated cell growth and migration. VEGF stimulated the phosphorylation of the VEGF receptor-2 (VEGFR-2, also known as KDR), ERK1/2 and p38 MAPK; however, knockdown of AGS8 inhibited these signaling events. Signal alterations by AGS8 siRNA were associated with a decrease of cell surface VEGFR-2 and an increase of VEGFR-2 in the cytosol. Endocytosis blockers did not influence the decrease of VEGFR-2 by AGS8 siRNA, suggesting the involvement of AGS8 in VEGFR-2 trafficking to the plasma membrane. VEGFR-2 formed a complex with AGS8 in cells, and a peptide designed to disrupt AGS8-Gβγ interaction inhibited VEGF-induced tube formation. These data suggest a potential role for AGS8-Gβγ in VEGF signal processing. AGS8 might play a key role in tissue adaptation by regulating angiogenic events.