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

ABSTRACT: In addition to their role in desensitization and internalization of G protein-coupled receptors (GPCRs), ?-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 ?-arrestin-dependent mechanism, promotes MEK-dependent ?-arrestin2 phosphorylation at Thr383, a necessary step for Erk recruitment to the receptor/?-arrestin complex and Erk activation. Likewise, Thr383 phosphorylation is involved in ?-arrestin-dependent Erk1/2 stimulation elicited by other GPCRs such as ?2-adrenergic, FSH and CXCR4 receptors, but does not affect the ?-arrestin-independent Erk1/2 activation by 5-HT4 receptor. Collectively, these data show that ?-arrestin2 phosphorylation at Thr383 underlies ?-arrestin-dependent Erk1/2 activation by GPCRs.

SUBMITTER: Cassier E 

PROVIDER: S-EPMC5325621 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Phosphorylation of β-arrestin2 at Thr<sup>383</sup> by MEK underlies β-arrestin-dependent activation of Erk1/2 by GPCRs.

Cassier Elisabeth E   Gallay Nathalie N   Bourquard Thomas T   Claeysen Sylvie S   Bockaert Joël J   Crépieux Pascale P   Poupon Anne A   Reiter Eric E   Marin Philippe P   Vandermoere Franck F  

eLife 20170207

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<sub>2C</sub> receptors, which engage Erk1/2 pathway via a β-arrestin-dependent mechanism, promotes MEK-dependent β-arrestin2 phosphorylation  ...[more]

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