beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1.
| dc.contributor.author | Usui, Isao | |
| dc.contributor.author | Imamura, Takeshi | |
| dc.contributor.author | Huang, Jie | |
| dc.contributor.author | Satoh, Hiroaki | |
| dc.contributor.author | Shenoy, Sudha K | |
| dc.contributor.author | Lefkowitz, Robert J | |
| dc.contributor.author | Hupfeld, Christopher J | |
| dc.contributor.author | Olefsky, Jerrold M | |
| dc.coverage.spatial | United States | |
| dc.date.accessioned | 2013-09-05T14:25:40Z | |
| dc.date.accessioned | 2013-09-05T14:44:04Z | |
| dc.date.issued | 2004-10 | |
| dc.description.abstract | beta-arrestin-1 is an adaptor protein that mediates agonist-dependent internalization and desensitization of G-protein-coupled receptors (GPCRs) and also participates in the process of heterologous desensitization between receptor tyrosine kinases and GPCR signaling. In the present study, we determined whether beta-arrestin-1 is involved in insulin-induced insulin receptor substrate 1 (IRS-1) degradation. Overexpression of wild-type (WT) beta-arrestin-1 attenuated insulin-induced degradation of IRS-1, leading to increased insulin signaling downstream of IRS-1. When endogenous beta-arrestin-1 was knocked down by transfection of beta-arrestin-1 small interfering RNA, insulin-induced IRS-1 degradation was enhanced. Insulin stimulated the association of IRS-1 and Mdm2, an E3 ubiquitin ligase, and this association was inhibited to overexpression of WT beta-arrestin-1, which led by decreased ubiquitin content of IRS-1, suggesting that both beta-arrestin-1 and IRS-1 competitively bind to Mdm2. In summary, we have found the following: (i) beta-arrestin-1 can alter insulin signaling by inhibiting insulin-induced proteasomal degradation of IRS-1; (ii) beta-arrestin-1 decreases the rate of ubiquitination of IRS-1 by competitively binding to endogenous Mdm2, an E3 ligase that can ubiquitinate IRS-1; (iii) dephosphorylation of S412 on beta-arrestin and the amino terminus of beta-arrestin-1 are required for this effect of beta-arrestin on IRS-1 degradation; and (iv) inhibition of beta-arrestin-1 leads to enhanced IRS-1 degradation and accentuated cellular insulin resistance. | |
| dc.identifier | ||
| dc.identifier | 24/20/8929 | |
| dc.identifier.issn | 0270-7306 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | Informa UK Limited | |
| dc.relation.ispartof | Mol Cell Biol | |
| dc.relation.isversionof | 10.1128/MCB.24.20.8929-8937.2004 | |
| dc.relation.replaces | ||
| dc.relation.replaces | 10161/7793 | |
| dc.subject | Acetylcysteine | |
| dc.subject | Animals | |
| dc.subject | Arrestins | |
| dc.subject | Cells, Cultured | |
| dc.subject | Cysteine Proteinase Inhibitors | |
| dc.subject | Fibroblasts | |
| dc.subject | Humans | |
| dc.subject | Insulin | |
| dc.subject | Insulin Receptor Substrate Proteins | |
| dc.subject | Nuclear Proteins | |
| dc.subject | Phosphatidylinositol 3-Kinases | |
| dc.subject | Phosphoproteins | |
| dc.subject | Phosphorylation | |
| dc.subject | Proteasome Endopeptidase Complex | |
| dc.subject | Protein Binding | |
| dc.subject | Proto-Oncogene Proteins | |
| dc.subject | Proto-Oncogene Proteins c-mdm2 | |
| dc.subject | RNA, Small Interfering | |
| dc.subject | Rats | |
| dc.subject | Receptor, Insulin | |
| dc.subject | Serine | |
| dc.subject | Signal Transduction | |
| dc.subject | Ubiquitin | |
| dc.subject | beta-Arrestin 1 | |
| dc.subject | beta-Arrestins | |
| dc.title | beta-arrestin-1 competitively inhibits insulin-induced ubiquitination and degradation of insulin receptor substrate 1. | |
| dc.type | Journal article | |
| duke.contributor.orcid | Lefkowitz, Robert J|0000-0003-1472-7545 | |
| pubs.author-url | ||
| pubs.begin-page | 8929 | |
| pubs.end-page | 8937 | |
| pubs.issue | 20 | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Biochemistry | |
| pubs.organisational-group | Cell Biology | |
| pubs.organisational-group | Chemistry | |
| pubs.organisational-group | Clinical Science Departments | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Medicine | |
| pubs.organisational-group | Medicine, Cardiology | |
| pubs.organisational-group | Pathology | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Trinity College of Arts & Sciences | |
| pubs.publication-status | Published | |
| pubs.volume | 24 |