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[摘要]：Termination of signaling of activated G protein-coupled receptors (GPCRs) is essential for maintenance of cellular homeostasis. It is well established that beta-arrestin redistributes to phosphorylated GPCRs and thereby facilitates desensitization of classical G protein-dependent signaling. beta-Arrestin in turn serves as a scaffold to initiate a second wave of signaling. Here, we report a molecular mechanism that regulates the termination of unconventional beta-arrestin-dependent GPCR signaling. We identify protein phosphatase 1 beta (PP1 beta) as a phosphatase for the cluster of phosphorylated threonines ((353)TTETQRT(359)) within the sst(2A) somatostatin receptor carboxyl terminus that mediates beta-arrestin binding using siRNA knock-down screening. We show that PP1 beta-mediated sst(2A) dephosphorylation is initiated directly after receptor activation at or near the plasma membrane. As a functional consequence of diminished PP1 beta activity, we find that somatostatin-and substance P-induced but not epidermal growth factor-induced ERK activation was aberrantly enhanced and prolonged. Thus, we demonstrate a novel mechanism for fine tuning unconventional beta-arrestin-dependent GPCR signaling in that recruitment of PP1 beta to activated GPCRs facilitates GPCR dephosphorylation and, hence, leads to disruption of the beta-arrestin-GPCR complex. |
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