β-Arrestin regulation of myosin light chain phosphorylation promotes AT1aR-mediated cell contraction and migration.
β-Arrestin regulation of myosin light chain phosphorylation promotes AT1aR-mediated cell contraction and migration.
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DOI：
10.1371/journal.pone.0080532
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lefkowitz RJ
中科院分区：
文献类型：
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作者：
Simard E;Kovacs JJ;Miller WE;Kim J;Grandbois M;Lefkowitz RJ
在过去的十年中，已经确定G蛋白偶联受体（GPCR）不仅通过典型的G蛋白介导的机制发出信号，而且还通过无处不在的细胞支架β-arrestin-1和β-arrestin-2发出信号。先前的研究已经暗示β-抑制蛋白作为响应于GPCR刺激的肌动蛋白重组的调节剂，同时也是伴随细胞运动的膜突起事件所需的。肌球蛋白轻链（MLC）的周期性磷酸化和激活是细胞主动运动中最关键的事件之一，它是细胞收缩和运动所必需的。我们已经鉴定了肌球蛋白轻链磷酸酶靶向亚基（myosin light chain phosphatase Targeting Subunit，MYPT-1）作为β-arrestins的结合伴侣，并发现β-arrestins在调节磷酸化肌球蛋白轻链的周转中发挥作用。作为对血管紧张素1a型受体（AT 1aR）刺激的响应，MLC磷酸化被快速而有效地诱导。我们发现β-arrestin-2促进MLC的去磷酸化，而β-arrestin 1以相反的方式限制MLC的去磷酸化。有趣的是，β-arrestin-1或2的丢失阻断磷酸化MLC周转，并导致细胞收缩减少，如原子力显微镜（AFM）所监测的。此外，通过使用β-arrestin偏向配体[Sar 1，Ile 4，Ile 8]-Ang，我们证明AT 1aR介导的细胞运动涉及β-arrestin依赖性成分。这表明β-抑制蛋白-1和2对MLC磷酸化状态的相互调节导致细胞收缩性和随后的趋化运动所需的MLC磷酸化状态的转换。
Over the last decade, it has been established that G-protein-coupled receptors (GPCRs) signal not only through canonical G-protein-mediated mechanisms, but also through the ubiquitous cellular scaffolds β-arrestin-1 and β-arrestin-2. Previous studies have implicated β-arrestins as regulators of actin reorganization in response to GPCR stimulation while also being required for membrane protrusion events that accompany cellular motility. One of the most critical events in the active movement of cells is the cyclic phosphorylation and activation of myosin light chain (MLC), which is required for cellular contraction and movement. We have identified the myosin light chain phosphatase Targeting Subunit (MYPT-1) as a binding partner of the β-arrestins and found that β-arrestins play a role in regulating the turnover of phosphorylated myosin light chain. In response to stimulation of the angiotensin Type 1a Receptor (AT1aR), MLC phosphorylation is induced quickly and potently. We have found that β-arrestin-2 facilitates dephosphorylation of MLC, while, in a reciprocal fashion, β-arrestin 1 limits dephosphorylation of MLC. Intriguingly, loss of either β-arrestin-1 or 2 blocks phospho-MLC turnover and causes a decrease in the contraction of cells as monitored by atomic force microscopy (AFM). Furthermore, by employing the β-arrestin biased ligand [Sar1,Ile4,Ile8]-Ang, we demonstrate that AT1aR-mediated cellular motility involves a β-arrestin dependent component. This suggests that the reciprocal regulation of MLC phosphorylation status by β-arrestins-1 and 2 causes turnover in the phosphorylation status of MLC that is required for cell contractility and subsequent chemotaxic motility.
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影响因子：
3.7
作者：
Auger-Messier, M;Turgeon, ES;Guillemette, G
通讯作者：
Guillemette, G
影响因子：
4.8
作者：
Amano, M;Ito, M;Kaibuchi, K
通讯作者：
Kaibuchi, K
影响因子：
64.8
作者：
Goodman, OB;Krupnick, JG;Benovic, JL
通讯作者：
Benovic, JL
影响因子：
4.8
作者：
Wei, HJ;Ahn, S;Lefkowitz, RJ
通讯作者：
Lefkowitz, RJ
DOI：
10.1038/nrm2786
发表时间：
2009-11
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
通讯作者：
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