The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals.
The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals.
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发表时间：
2002-02
影响因子：
4
通讯作者：
L. Luttrell;R. Lefkowitz
中科院分区：
文献类型：
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作者：
L. Luttrell;R. Lefkowitz
β-arrestins是一种功能广泛的适配器蛋白，与大多数G蛋白偶联受体(GPCRs)在激动剂结合和G蛋白偶联受体激动剂(GRKs)磷酸化后形成复合体。它们在同源脱敏和GPCR隔离等相互关联的过程中发挥着核心作用，这些过程导致G蛋白激活的终止。与GPCRs结合的β-arrestin既能使受体从异源三聚体G蛋白上解偶联，又能将它们靶向笼状蛋白包裹的小孔以进行内吞作用。最近的数据表明，β-抑制素也可以作为gpr信号转导。它们可以与几种信号蛋白形成复合体，包括Src家族酪氨酸激酶以及ERK1/2和JNK3 MAP激酶级联的组成部分。通过将这些激酶招募到激动剂占据的GPCRs，β-抑制素在受体上赋予不同的信号活动。β-arrestin-Src复合体被认为可以调节GPCR的内吞作用，触发ERK1/2的激活，并介导中性粒细胞脱颗粒。通过充当ERK1/2和JNK3级联的支架，β-拦阻蛋白既促进了GPCR刺激的MAP激酶的激活，又将活性MAPK靶向细胞内的特定位置。因此，它们与GPCRs的结合可能启动第二波信号转导，代表了一种新的GPCRs信号转导机制。
beta-Arrestins are versatile adapter proteins that form complexes with most G-protein-coupled receptors (GPCRs) following agonist binding and phosphorylation of receptors by G-protein-coupled receptor kinases (GRKs). They play a central role in the interrelated processes of homologous desensitization and GPCR sequestration, which lead to the termination of G protein activation. beta-arrestin binding to GPCRs both uncouples receptors from heterotrimeric G proteins and targets them to clathrin-coated pits for endocytosis. Recent data suggest that beta-arrestins also function as GPCR signal transducers. They can form complexes with several signaling proteins, including Src family tyrosine kinases and components of the ERK1/2 and JNK3 MAP kinase cascades. By recruiting these kinases to agonist-occupied GPCRs, beta-arrestins confer distinct signaling activities upon the receptor. beta-arrestin-Src complexes have been proposed to modulate GPCR endocytosis, to trigger ERK1/2 activation and to mediate neutrophil degranulation. By acting as scaffolds for the ERK1/2 and JNK3 cascades, beta-arrestins both facilitate GPCR-stimulated MAP kinase activation and target active MAP kinases to specific locations within the cell. Thus, their binding to GPCRs might initiate a second wave of signaling and represent a novel mechanism of GPCR signal transduction.