Shenoy Sudha K
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Methods Enzymol. 2014;535:351-70. doi: 10.1016/B978-0-12-397925-4.00020-1.
The two homologous mammalian proteins called β-arrestin1 (also known as arrestin2) and β-arrestin2 (also called arrestin3) are now widely accepted as endocytic and signaling adaptors for G protein-coupled receptors (GPCRs), growth factor receptors, and ion channels. The sustained interactions of β-arrestins with activated GPCRs have been shown to correlate with the agonist-induced ubiquitination on distinct domains in the β-arrestin molecule. Additionally, ubiquitination of β-arrestin promotes its interaction with proteins that mediate endocytosis (e.g., clathrin) and signaling (e.g., c-RAF). Recent studies have demonstrated that deubiquitination of β-arrestin by specific deubiquitinating enzymes (DUBs) acts as an important regulatory mechanism, which determines the stability of β-arrestin-GPCR binding and fine-tunes β-arrestin-dependent signaling to downstream kinases. Accordingly, ubiquitination/deubiquitination of β-arrestin can serve as an on/off switch for its signaling and endocytic functions. Moreover, by regulating the stability and localization of signalosomes, deubiquitination of β-arrestins by DUBs imparts spatial and temporal resolution in GPCR signaling.
两种同源的哺乳动物蛋白，即β抑制蛋白1（也称为抑制蛋白2）和β抑制蛋白2（也称为抑制蛋白3），现在已被广泛认为是G蛋白偶联受体（GPCR）、生长因子受体和离子通道的内吞和信号转导衔接蛋白。β抑制蛋白与活化的GPCR的持续相互作用已被证明与β抑制蛋白分子不同结构域上激动剂诱导的泛素化有关。此外，β抑制蛋白的泛素化促进了它与介导内吞作用（如网格蛋白）和信号转导（如c-RAF）的蛋白质的相互作用。最近的研究表明，特定去泛素化酶（DUB）对β抑制蛋白的去泛素化作用是一种重要的调节机制，它决定了β抑制蛋白-GPCR结合的稳定性，并对β抑制蛋白依赖的下游激酶信号转导进行微调。因此，β抑制蛋白的泛素化/去泛素化可以作为其信号转导和内吞功能的开关。此外，通过调节信号小体的稳定性和定位，DUB对β抑制蛋白的去泛素化作用在GPCR信号转导中赋予了空间和时间分辨率。
