Lin F T, Krueger K M, Kendall H E, Daaka Y, Fredericks Z L, Pitcher J A, Lefkowitz R J
Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Biol Chem. 1997 Dec 5;272(49):31051-7. doi: 10.1074/jbc.272.49.31051.
beta-Arrestins serve a dual regulatory role in the life cycle of G protein-coupled receptors such as the beta2-adrenergic receptor. First, they mediate rapid desensitization by binding to G protein-coupled receptor kinase-phosphorylated receptors. Second, they target the receptors for internalization into endosomal vesicles, wherein receptor dephosphorylation and resensitization occur. Here we report that phosphorylation of a carboxyl-terminal serine (Ser-412) in beta-arrestin1 regulates its endocytotic but not its desensitization function. Cytoplasmic beta-arrestin1 is constitutively phosphorylated and is recruited to the plasma membrane by agonist stimulation of the receptors. At the plasma membrane, beta-arrestin1 is rapidly dephosphorylated, a process that is required for its clathrin binding and receptor endocytosis but not for its receptor binding and desensitization. Once internalized, beta-arrestin1 is rephosphorylated. Thus, as with the classical endocytic adaptor protein complex AP2, beta-arrestin1 functions as a clathrin adaptor in receptor endocytosis which is regulated by dephosphorylation at the plasma membrane.
β抑制蛋白在G蛋白偶联受体（如β2肾上腺素能受体）的生命周期中发挥双重调节作用。首先，它们通过与G蛋白偶联受体激酶磷酸化的受体结合来介导快速脱敏。其次，它们将受体靶向内化到内体小泡中，在那里发生受体去磷酸化和再敏化。在此我们报告，β抑制蛋白1羧基末端丝氨酸（Ser-412）的磷酸化调节其内化功能，但不调节其脱敏功能。细胞质中的β抑制蛋白1组成性磷酸化，并通过受体的激动剂刺激被募集到质膜。在质膜上，β抑制蛋白1迅速去磷酸化，这一过程是其网格蛋白结合和受体内化所必需的，但不是其受体结合和脱敏所必需的。一旦内化，β抑制蛋白1会重新磷酸化。因此，与经典的内吞衔接蛋白复合物AP2一样，β抑制蛋白1在受体内化过程中作为网格蛋白衔接蛋白发挥作用，该过程受质膜去磷酸化调节。
