PKCβII inhibits the ubiquitination of β-arrestin2 in an autophosphorylation-dependent manner

•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...

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Bibliographic Details
Published in:FEBS letters 2015-12, Vol.589 (24), p.3929-3937
Main Authors: Zheng, Mei, Zhang, Xiaohan, Guo, Shuohan, Zhang, Xiaowei, Choi, Hyun Jin, Lee, Moo-Yeol, Kim, Kyeong-Man
Format: Article
Language:English
Subjects:
Animals
Arrestins - metabolism
Autophosphorylation
beta-Arrestins
Conventional PKC
Endocytosis
G protein-coupled receptor
GPCR kinase 2
HEK293 Cells
Humans
Intracellular Space - metabolism
Phosphorylation
Protein Kinase C beta - metabolism
Protein Transport
Proto-Oncogene Proteins c-mdm2 - metabolism
Rats
Receptors, G-Protein-Coupled - metabolism
Ubiquitination
β-Arrestin
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Summary:•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. 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.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2015.10.031