title: PKCβII inhibits the ubiquitination of β-arrestin2 in an autophosphorylation-dependent manner.
abstract: GPCR kinase 2 (GRK2)/β-arrestins and protein kinase A (PKA)/protein kinase C (PKC) mediate homologous and heterologous regulations of GPCRs, respectively. Conventional protein kinase C enzymes (PKCs), as exemplified by PKCβII, selectively inhibit internalization of dopamine D2 receptor and β2 adrenoceptor in a β-arrestin- but not GRK2-dependent manner. PKCβII interacts with β-arrestin2 upon autophosphorylation at T250, and inhibits the receptor internalization by decreasing the ubiquitination of β-arrestin2. PKCβII interferes with the interaction between β-arrestin2 and MDM2 in the cytosol, resulting in the redistribution of MDM2 to the nucleus. Subsequently, deubiquitination of β-arrestin2 and inhibition of agonist-induced receptor internalization follow. Thus, our study suggests that the extent of β-arrestin ubiquitination and the autophosphorylation status of PKCs determine PKCβII-mediated inhibition of homologous regulatory processes of GPCRs.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, South Korea.
authors.forename: Mei
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, South Korea.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, South Korea.
authors.forename: Shuohan
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, South Korea.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, CHA University, Seongnam, Gyeonggi-do, South Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Dongguk University, Goyang, Gyeonggi-do, South Korea.
authors.forename: Moo-Yeol
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, South Korea. Electronic address: kmkim@jnu.ac.kr.
authors.forename: Kyeong-Man
authors.initials: KM
authors.lastname: Kim
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D010766:Phosphorylation; D064546:Protein Kinase C beta / Q000378:metabolism*; D021381:Protein Transport; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D054875:Ubiquitination; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D051736:Proto-Oncogene Proteins c-mdm2; D064546:Protein Kinase C beta
keywords: Autophosphorylation; Conventional PKC; G protein-coupled receptor; GPCR kinase 2; Ubiquitination; β-Arrestin