Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Prog Mol Biol Transl Sci. 2013;118:115-47. doi: 10.1016/B978-0-12-394440-5.00005-X.
The discovery that, in addition to mediating G protein-coupled receptor (GPCR) desensitization and endocytosis, arrestins bind to diverse catalytically active nonreceptor proteins and act as ligand-regulated signaling scaffolds led to a paradigm shift in the study of GPCR signal transduction. Research over the past decade has solidified the concept that arrestins confer novel GPCR-signaling capacity by recruiting protein and lipid kinase, phosphatase, phosphodiesterase, and ubiquitin ligase activity into receptor-based multiprotein "signalsome" complexes. Signalsomes regulate downstream pathways controlled by Src family nonreceptor tyrosine kinases, mitogen-activated protein kinases, protein kinase B (AKT), glycogen synthase kinase 3, protein phosphatase 2A, nuclear factor-κB, and several others, imposing spatial and temporal control on their function. While many arrestin-bound kinases and phosphatases are involved in the control of cytoskeletal rearrangement, vesicle endocytosis, exocytosis, and cell migration, other signals reach into the nucleus, affecting cell proliferation, apoptosis, and survival. Indeed, the kinase/phosphatase network regulated by arrestins may be fully as diverse as that regulated by heterotrimeric G proteins.
除了介导 G 蛋白偶联受体 (GPCR) 的脱敏和内吞作用外， arrestin 还与多种具有催化活性的非受体蛋白结合，并作为配体调节的信号支架，这一发现导致了 GPCR 信号转导研究的范式转变。过去十年的研究巩固了这样一个概念，即 arrestin 通过将蛋白和脂质激酶、磷酸酶、磷酸二酯酶和泛素连接酶活性募集到基于受体的多蛋白“信号小体”复合物中，赋予 GPCR 信号新的能力。信号小体调节由Src 家族非受体酪氨酸激酶、丝裂原活化蛋白激酶、蛋白激酶 B (AKT)、糖原合成酶激酶 3、蛋白磷酸酶 2A、核因子-κB 和其他几种激酶控制的下游途径，对其功能施加时空控制。虽然许多与 arrestin 结合的激酶和磷酸酶参与细胞骨架重排、囊泡内吞作用、胞吐作用和细胞迁移的控制，但其他信号进入细胞核，影响细胞增殖、凋亡和存活。事实上，由 arrestin 调节的激酶/磷酸酶网络可能与异三聚体 G 蛋白调节的网络一样多样化。
