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

In addition to their role in desensitization and internalization of G protein-coupled receptors (GPCRs),beta-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-HT2C receptors, which engage Erk1/2 pathway via a beta-arrestin-dependent mechanism, promotes MEK-dependent beta-arrestin2 phosphorylation at Thr(383), a necessary step for Erk recruitment to the receptor/beta-arrestin complex and Erk activation. Likewise, Thr(383) phosphorylation is involved in beta-arrestin-dependent Erk1/2 stimulation elicited by other GPCRs such as beta(2)-adrenergic, FSH and CXCR4 receptors, but does not affect the beta-arrestin-independent Erk1/2 activation by 5-HT4 receptor. Collectively, these data show that beta-arrestin2 phosphorylation at Thr(383) underlies beta-arrestin-dependent Erk1/2 activation by GPCRs.