title: Clathrin-mediated endocytosis of the beta-adrenergic receptor is regulated by phosphorylation/dephosphorylation of beta-arrestin1.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: F T
authors.initials: FT
authors.lastname: Lin
authors.forename: K M
authors.initials: KM
authors.lastname: Krueger
authors.forename: H E
authors.initials: HE
authors.lastname: Kendall
authors.forename: Y
authors.initials: Y
authors.lastname: Daaka
authors.forename: Z L
authors.initials: ZL
authors.lastname: Fredericks
authors.forename: J A
authors.initials: JA
authors.lastname: Pitcher
authors.forename: R J
authors.initials: RJ
authors.lastname: Lefkowitz
mesh_terms: D019943:Amino Acid Substitution; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis; D006801:Humans; D016296:Mutagenesis; D010766:Phosphorylation; D011485:Protein Binding; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D018343:Receptors, Adrenergic, beta-2; D000071557:beta-Arrestins; D012694:Serine