Activator of G-protein signaling 8 (AGS8), also known as fibronectin type III domain containing 1 (FNDC1), is an accessory protein for heterotrimeric G-proteins involved in various cellular processes. The interaction between AGS8 and Gβγ subunit is a critical step in AGS8-mediated signaling, and a peptide that disrupts this interaction inhibited angiogenic events. To explore the broader potential of AGS8 biology, we investigated small molecules that block the AGS8-Gβγ interaction. Using a yeast-based system, in which cell growth depends on AGS8-mediated activation of G-protein pathway, we screened compounds from the RIKEN NPDepo library and identified one compound that effectively inhibited the formation of the AGS8-Gβγ complex. Consistent with the effects observed in AGS8 knockdown or peptide-treated cells, this compound attenuated VEGF-induced phosphorylation of signaling molecules and inhibited tube formation and migration of HUVECs. These data demonstrate the potential of the AGS8 inhibitor as a research tool and a therapeutic application.
Hossain et al. (Tue,) studied this question.