Phosphorylation of β-arrestin2 at Thr³⁸³ by MEK underlies β-arrestin-dependent activation of Erk1/2 by GPCRs.

Abstract

In addition to their role in desensitization and internalization of G protein-coupled receptors (GPCRs), β-arrestins are essential scaffolds linking GPCRs to Erk1/2 signaling. However, their role in GPCR-operated Erk1/2 activation differs between GPCRs and the underlying mechanism remains poorly characterized. Here, we show that activation of serotonin 5-HT_2C receptors, which engage Erk1/2 pathway via a β-arrestin-dependent mechanism, promotes MEK-dependent β-arrestin2 phosphorylation at Thr³⁸³, a necessary step for Erk recruitment to the receptor/β-arrestin complex and Erk activation. Likewise, Thr³⁸³ phosphorylation is involved in β-arrestin-dependent Erk1/2 stimulation elicited by other GPCRs such as β₂-adrenergic, FSH and CXCR4 receptors, but does not affect the β-arrestin-independent Erk1/2 activation by 5-HT₄ receptor. Collectively, these data show that β-arrestin2 phosphorylation at Thr³⁸³ underlies β-arrestin-dependent Erk1/2 activation by GPCRs.