| | |  | | | | Record from Web of Science® | | | | | | |
| beta-arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase |
|
|
| Author(s): Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 280 Issue: 26 Pages: 24412-24419 Published: JUL 1 2005 |
| Times Cited: 48 References: 39 |
| Abstract: The insulin-like growth factor-1 receptor ( IGF-1R) plays important roles in physiological growth and aging as well as promoting several crucial functions in cancer cells. However, the molecular mechanisms involved in expression and down- regulation of IGF-1R are still poorly understood. Here we provide evidence that beta-arrestin, otherwise known to be involved in the regulation of G protein- coupled receptors, serves as an adaptor to bring the oncoprotein E3 ubiquitin ligase MDM2 to the IGF-1R. In this way, beta-arrestin acts as a crucial component in the ubiquitination and down-regulation of the receptor. Both MDM2 and beta-arrestin co-immunoprecipitated with the IGF-1R. The beta-arrestin isoform 1 appeared to be more strongly associated with the receptor than isoform 2, and in a molecular context it was 4-fold more efficient in inducing polyubiquitination of IGF-1R, a reaction that required the presence of beta-arrestin and MDM2. Ligand stimulation accelerated IGF-1R ubiquitination. In mouse P6 cells (overexpressing human IGF-1R) absence of beta-arrestin 1, but not of beta-arrestin 2, blocked ubiquitination of IGF-1R. Conversely, in the two studied human melanoma cell lines both beta-arrestin isoforms seemed to be involved in IGF-1R ubiquitination. However, because depletion of beta-arrestin 1 almost completely eliminated degradation, and IGF-1 induced down-regulation of the receptor in these cells, whereas beta-arrestin 2 only had a partial effect, beta-arrestin 1 seems to the more important isoform in affecting the expression of IGF-1R. To our knowledge this is the first study demonstrating a defined molecular role of beta-arrestin with direct relevance to cell growth and cancer. |
| Document Type: Article |
| Language: English |
| Reprint Address: Larsson, O (reprint author), Karolinska Hosp, Ctr Canc, Dept Oncol & Pathol, Div Cellular & Mol Tumor Pathol, R8-04, SE-17176 Stockholm, Sweden |
Addresses:
1. Karolinska Hosp, Ctr Canc, Dept Oncol & Pathol, Div Cellular & Mol Tumor Pathol, SE-17176 Stockholm, Sweden
2. Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA
3. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: 939ZT |
| ISSN: 0021-9258 |
| DOI: 10.1074/jbc.M501129200 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |