Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 20, Issue 5, Pages 1489-1496Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.20.5.1489-1496.2000
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Funding
- NCI NIH HHS [P50CA58183, P50 CA058183, R01CA74285, R01 CA074285, P30 CA054174, K01CA77674] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA074285, P50CA058183, K01CA077674, P30CA054174] Funding Source: NIH RePORTER
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Insulin receptor substrate 1 (IRS-1) is a critical adapter protein involved in both insulin and insulin-like growth factor (IGF) signaling. Due to the fact that alteration of IRS-1 levels can affect the sensitivity and response to both insulin and IGF-I, we examined the ability of each of these ligands to affect IRS-1 expression. IGF-I (10 nM) stimulation of MCF-7 breast cancer cells caused a transient tyrosine phosphorylation of IRS-1 that was maximal at 15 min and decreased thereafter, The decrease in tyrosine phosphorylation of IRS 1 was paralleled by an apparent decrease in IRS 1 levels. The IGF mediated decrease in IRS-1 expression was posttranscriptional and due to a decrease in the half-life of the IRS-1 protein. Insulin (10 nM) caused tyrosine phosphorylation of IRS-1 but not degradation, whereas high concentrations of insulin (10 mu M) resulted in degradation of IRS-1, IGF-I (10 nM) stimulation resulted in transient IRS-1 phosphorylation and extracellular signal-related kinase (ERK) activation. In contrast, insulin (10 nM) caused sustained IRS-1 phosphorylation and ERK activation. Inhibition of 268 proteasome activity by the use of lactacystin or MG132 completely blocked IGF-mediated degradation of IRS-1, Furthermore, coimmunoprecipitation experiments showed an association between ubiquitin and IRS-1 that was increased by treatment of cells with IGF-I, Finally, IGF-mediated degradation of IRS-1 was blocked by inhibition of phosphatidylinositol 3'-kinase activity but was not affected by inhibition of ERK, suggesting that this may represent a direct negative-feedback mechanism resulting from downstream IRS-1 signaling. We conclude that TGF-I can cause ligand-mediated degradation of IRS-1 via the ubiquitin-mediated 268 proteasome and a phosphatidylinositol 3'-kinase-dependent mechanism and that control of degradation may have profound effects on downstream activation of signaling pathways.
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