Rapid Dephosphorylation of G Protein-coupled Receptors by Protein Phosphatase 1β Is Required for Termination of β-Arrestin-dependent Signaling
Rapid Dephosphorylation of G Protein-coupled Receptors by Protein Phosphatase 1β Is Required for Termination of β-Arrestin-dependent Signaling
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DOI：
10.1074/jbc.m111.224899
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发表时间：
2011-09-23
影响因子：
4.8
通讯作者：
Schulz, Stefan
中科院分区：
文献类型：
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作者：
Poell, Florian;Doll, Christian;Schulz, Stefan
终止激活的G蛋白偶联受体（gpcr）的信号传导对于维持细胞稳态至关重要。众所周知，β -抑制蛋白会重新分配给磷酸化的gpcr，从而促进经典G蛋白依赖信号的脱敏。抑制素反过来作为支架启动第二波信号传导。在这里，我们报告了一种调节非常规β -抑制蛋白依赖的GPCR信号终止的分子机制。通过siRNA敲除筛选，我们发现蛋白磷酸酶1 β (PP1 β)是sst（2A）生长抑素受体羧基端磷酸化苏氨酸簇(（353)TTETQRT(359)）的磷酸酶，该酶介导β -抑制素结合。我们发现PP1 β介导的sst（2A）去磷酸化是在质膜或质膜附近的受体激活后直接启动的。作为PP1 β活性降低的功能后果，我们发现生长抑素和p物质诱导的ERK激活异常增强和延长，而不是表皮生长因子诱导的ERK激活。因此，我们证明了一种微调非常规β -抑制蛋白依赖的GPCR信号的新机制，即PP1 β募集到激活的GPCR，促进GPCR去磷酸化，从而导致β -抑制蛋白-GPCR复合物的破坏。
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.