The Arf Gap Agap2 Interacts With Beta-Arrestin2 And Regulates Beta(2)-Adrenergic Receptor Recycling And Erk Activation

AGAP2 [Ad (ADP-ribosylation factor) GAP (GTPase-activating protein) with GTP-binding-protein-like, ankyrin repeat and PH (pleckstrin homology) domains] is a multidomain Arf GAP that was shown to promote the fast recycling of transferrin receptors. In the present study we tested the hypothesis that AGAP2 regulates the trafficking of beta(2)-adrenergic receptors. We found that AGAP2 formed a complex with beta-arrestin1 and beta-arrestin2, proteins that are known to regulate beta(2)-adrenergic receptor signalling and trafficking. AGAP2 co-localized with beta-arrestin2 on the plasma membrane, and knockdown of AGAP2 expression reduced plasma membrane association of beta-arrestin2 upon beta(2)-adrenergic receptor activation. AGAP2 also co-localized with internalized beta(2)-adrenergic receptors on endosomes, and overexpression of AGAP2 slowed accumulation of beta(2)-adrenergic receptor in the perinuclear recycling endosomes. In contrast, knockdown of AGAP2 expression prevented the recycling of the beta(2)-adrenergic receptor back to the plasma membrane. In addition, AGAP2 formed a complex with endogenous ERK (extracellular-signal-regulated kinase) and overexpression of AGAP2 potentiated ERK phosphorylation induced by beta(2)-adrenergic receptors. Taken together, these results support the hypothesis that AGAP2 plays a role in the signalling and recycling of beta(2)-adrenergic receptors.