Phosphorylation of β-arrestin2 at Thr 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), 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 receptors, which engage Erk1/2 pathway via a β-arrestin-dependent mechanism, promotes MEK-dependent β-arrestin2 phosphorylation at Thr, a necessary step for Erk recruitment to the receptor/β-arrestin complex and Erk activation. Likewise, Thr phosphorylation is involved in β-arrestin-dependent Erk1/2 stimulation elicited by other GPCRs such as β-adrenergic, FSH and CXCR4 receptors, but does not affect the β-arrestin-independent Erk1/2 activation by 5-HT receptor. Collectively, these data show that β-arrestin2 phosphorylation at Thr underlies β-arrestin-dependent Erk1/2 activation by GPCRs.