The study investigates the role of β-arrestins in the activation and targeting of extracellular signal-regulated kinase 2 (ERK2) following stimulation of angiotensin II type 1a receptors (AT1aR). Using confocal immunofluorescence microscopy and biochemical approaches, the researchers found that angiotensin stimulation triggers β-arrestin-2 binding to the receptor and internalization of AT1aR-β-arrestin complexes. Activated ERK2 redistributes into endosomal vesicles containing AT1aR-β-arrestin complexes, reflecting the formation of multi-protein complexes involving AT1aR, β-arrestin-2, and components of the ERK cascade (cRaf-1, MEK1, and ERK2). Coexpression of cRaf-1 enhances the binding of ERK2 to β-arrestin-2 and increases ERK2 phosphorylation, suggesting that β-arrestins function as scaffolds to facilitate cRaf-1 and MEK-dependent ERK2 activation and as targeting proteins to direct activated ERK2 to specific subcellular locations. The findings provide insights into how β-arrestins regulate ERK2 activation and subcellular localization in response to receptor stimulation.The study investigates the role of β-arrestins in the activation and targeting of extracellular signal-regulated kinase 2 (ERK2) following stimulation of angiotensin II type 1a receptors (AT1aR). Using confocal immunofluorescence microscopy and biochemical approaches, the researchers found that angiotensin stimulation triggers β-arrestin-2 binding to the receptor and internalization of AT1aR-β-arrestin complexes. Activated ERK2 redistributes into endosomal vesicles containing AT1aR-β-arrestin complexes, reflecting the formation of multi-protein complexes involving AT1aR, β-arrestin-2, and components of the ERK cascade (cRaf-1, MEK1, and ERK2). Coexpression of cRaf-1 enhances the binding of ERK2 to β-arrestin-2 and increases ERK2 phosphorylation, suggesting that β-arrestins function as scaffolds to facilitate cRaf-1 and MEK-dependent ERK2 activation and as targeting proteins to direct activated ERK2 to specific subcellular locations. The findings provide insights into how β-arrestins regulate ERK2 activation and subcellular localization in response to receptor stimulation.