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首页> 外文期刊>Cellular Signalling >RACK1 and beta-arrestin2 attenuate dimerization of PDE4 cAMP phosphodiesterase PDE4D5
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RACK1 and beta-arrestin2 attenuate dimerization of PDE4 cAMP phosphodiesterase PDE4D5

机译：RACK1和β-arrestin2减弱PDE4 cAMP磷酸二酯酶PDE4D5的二聚作用

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PDE4 family cAMP-selective cyclic nucleotide phosphodiesterases are important in the regulation of cAMP abundance in numerous systems, and thereby play an important role in the regulation of PKA and EPAC activity and the phosphorylation of CREB. We have used the yeast 2-hybrid system to demonstrate recently that long PDE4 isoforms form homodimers, consistent with data obtained recently by structural studies. The long PDE4 isoform PDE4D5 interacts selectively with beta-arrestin2, implicated in the regulation of G-protein-coupled receptors and other cell signaling components, and also with the beta-propeller protein RACK1. In the present study, we use 2-hybrid approaches to demonstrate that RACK1 and beta-arrestin2 inhibit the dimerization of PDE4D5. We also show that serine-to-alanine mutations at PICA and ERK1/2 phosphorylation sites on PDE4D5 detectably ablate dimerization. Conversely, phospho-mimic serine-to-aspartate mutations at the MK2 and oxidative stress kinase sites ablate dimerization. Analysis of PDE4D5 that is locked into the dimeric configuration by the formation of a trans disulfide bond between Ser261 and Ser602 shows that RACK1 interacts strongly with both the monomeric and dimeric forms, but that beta-arrestin2 interacts exclusively with the monomeric form. This is consistent with the concept that beta-arrestin2 can preferentially recruit the monomeric, or "open," form of PDE4D5 to beta 2-adrenergic receptors, where it can regulate cAMP signaling. (C) 2015 Elsevier Inc. All rights reserved.
机译：PDE4家族的cAMP选择环核苷酸磷酸二酯酶在许多系统中的cAMP丰度调节中很重要，因此在PKA和EPAC活性的调节以及CREB的磷酸化中起着重要的作用。我们最近使用酵母2杂交系统来证明长PDE4同工型形成同型二聚体，这与最近通过结构研究获得的数据一致。较长的PDE4同工型PDE4D5与β-arrestin2选择性相互作用，与G蛋白偶联受体和其他细胞信号转导成分的调节有关，也与β-螺旋蛋白RACK1相互作用。在本研究中，我们使用2杂交方法来证明RACK1和β-arrestin2抑制PDE4D5的二聚化。我们还显示，PDE4D5上PICA和ERK1 / 2磷酸化位点的丝氨酸到丙氨酸突变可检测地消融二聚化。相反，MK2和氧化应激激酶位点的磷酸模拟丝氨酸到天冬氨酸突变消除了二聚化。通过在Ser261和Ser602之间形成反式二硫键而锁定为二聚体构型的PDE4D5的分析表明，RACK1与单体和二聚体形式都强烈相互作用，但β-arrestin2仅与单体形式相互作用。这与以下概念一致：β-arrestin2可以优先将PDE4D5的单体形式或“开放”形式募集到β2-肾上腺素受体，在那里它可以调节cAMP信号传导。 （C）2015 Elsevier Inc.保留所有权利。

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