Regulation of arrestin-3 phosphorylation by casein kinase II

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Arrestins play an important role in regulating the function of G protein-coupled receptors including receptor desensitization, internalization, down-regulation, and signaling via nonreceptor tyrosine kinases and mitogen-activated protein kinases. Previous studies have revealed that arrestins themselves are also subject to regulation. In the present study, we focused on identifying potential mechanisms involved in regulating the function of arrestin-3. Using metabolic labeling, phosphoamino acid analysis, and mutagenesis studies, we found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. Functional analysis reveals that mutants mimicking the phosphorylated (T382E) and dephosphorylated (T382A or T382V) states of arrestin-3 promote beta(2)-adrenergic receptor internalization and bind clathrin, beta-adaptin, and Src to comparable levels as wild type arrestin-3. This suggests that the phosphorylation of arrestin-3 does not directly regulate interaction with endocytic (clathrin, beta-adaptin) or signaling (Src) components and is in contrast to arrestin-2, where phosphorylation appears to regulate interaction with clathrin and Src. However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex. Differences between the regulatory roles of arrestin-2 and -3 phosphorylation may contribute to the different cellular functions of these proteins in G protein-coupled receptor signaling and regulation.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
2002-05
Language
English
Article Type
Article
Keywords

PROTEIN-COUPLED RECEPTORS; BETA-ADRENERGIC-RECEPTOR; CLATHRIN-MEDIATED ENDOCYTOSIS; BETA(2)-ADRENERGIC RECEPTOR; VISUAL ARRESTIN; ACTIVATION; BETA-ARRESTIN1; INTERNALIZATION; RESENSITIZATION; UBIQUITINATION

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.277, no.19, pp.16837 - 16846

ISSN
0021-9258
DOI
10.1074/jbc.M201379200
URI
http://hdl.handle.net/10203/240871
Appears in Collection
MSE-Journal Papers(저널논문)
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