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. A novel regulatory mechanism for the endocytosis of GPCRs is proposed. Conventional PKCs, exemplified as PKCβII, inhibit the internalization of GPCRs. PKCβII inhibits the ubiquitination of β-arrestin2 in an autophosphorylation-dependent manner. Interaction between MDM2 and β-arrestin2 is inhibited by PKCβII in the cytosol, and MDM2 is redistributed to the nucleus.
Original language | English |
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Pages (from-to) | 3929-3937 |
Number of pages | 9 |
Journal | FEBS Letters |
Volume | 589 |
Issue number | 24 |
DOIs | |
State | Published - 21 Dec 2015 |
Keywords
- Autophosphorylation
- Conventional PKC
- G protein-coupled receptor
- GPCR kinase 2
- Ubiquitination
- β-Arrestin