PKC beta II inhibits the ubiquitination of beta-arrestin2 in an autophosphorylation-dependent manner

Abstract

GPCR kinase 2 (GRK2)/beta-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 PKC beta II, selectively inhibit internalization of dopamine D-2 receptor and beta(2) adrenoceptor in a beta-arrestin- but not GRK2-dependent manner. PKC beta II interacts with beta-arrestin2 upon autophosphorylation at T250, and inhibits the receptor internalization by decreasing the ubiquitination of beta-arrestin2. PKC beta II interferes with the interaction between beta-arrestin2 and MDM2 in the cytosol, resulting in the redistribution of MDM2 to the nucleus. Subsequently, deubiquitination of beta-arrestin2 and inhibition of agonist-induced receptor internalization follow. Thus, our study suggests that the extent of beta-arrestin ubiquitination and the autophosphorylation status of PKCs determine PKC beta II-mediated inhibition of homologous regulatory processes of GPCRs. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.