β-Arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2
| Autor: | Keith D. Wilkinson, Robert J. Lefkowitz, Arun K. Shukla, Kunhong Xiao, Seungkirl Ahn, Sudha K. Shenoy, Aalok S. Modi, William E. Miller, Magali Berthouze |
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| Rok vydání: | 2009 |
| Předmět: |
genetic structures
Arrestins Vasopressins Ubiquitin-Protein Ligases media_common.quotation_subject Receptors Cell Surface Endosomes Models Biological Cell Line Arrestin Animals Humans Extracellular Signal-Regulated MAP Kinases Internalization Receptor beta-Arrestins G protein-coupled receptor media_common Multidisciplinary biology Beta-Arrestins Ubiquitination Proto-Oncogene Proteins c-mdm2 Biological Sciences Cell biology Ubiquitin ligase Enzyme Activation Kinetics Protein Transport biology.protein Mdm2 sense organs Signal transduction Ubiquitin Thiolesterase Protein Binding Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 106:6650-6655 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0901083106 |
| Popis: | β-Arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seven-transmembrane receptors (7TMRs). Agonist-stimulated ubiquitination of β-arrestin2 mediated by the E3 ubiquitin ligase Mdm2 is critical for rapid β 2 -adrenergic receptor (β 2 AR) internalization. We now report the discovery that the deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) binds β-arrestin2 and leads to the deubiquitination of β-arrestins. USP33 and Mdm2 function reciprocally and favor respectively the stability or lability of the receptor β-arrestin complex, thus regulating the longevity and subcellular localization of receptor signalosomes. Receptors such as the β 2 AR, previously shown to form loose complexes with β-arrestin (“class A”) promote a β-arrestin conformation conducive for binding to the deubiquitinase, whereas the vasopressin V2R, which forms tight β-arrestin complexes (“class B”), promotes a distinct β-arrestin conformation that favors dissociation of the enzyme. Thus, USP33–β-arrestin interaction is a key regulatory step in 7TMR trafficking and signal transmission from the activated receptors to downstream effectors. |
| Databáze: | OpenAIRE |
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