Insulin-like growth factor I-mediated degradation of insulin receptor substrate-1 is inhibited by epidermal growth factor in prostate epithelial cells

We have sought to determine whether insulin-like growth factor I (IGF-I) re gulates the levels of insulin receptor substrate-1 (IRS-1) in prostate epit helial cells. Exposure of prostate epithelial cells to IGF-I in the absence of other growth factors leads to a reduction in IRS-1 levels. Ubiquitin co ntent of IRS-1 is increased in the presence of ICE-I, and inhibitors of the proteasome prevented the reduction of IRS-1 levels seen following IGF-I ex posure. These results imply that IRS-1 is targeted to the proteasome upon e xposure to IGF-I. The addition of epidermal growth factor (EGF) maintained IRS-1 levels even in the presence of IGF-I and inhibits IGF-I-dependent ubi quitination of IRS-1. Thus, these two growth factors, IGF-I and EGF, had an tagonistic effects on IRS-1 protein levels in prostate epithelial cells. Th is regulation of IRS-1 reveals a novel level of cross-talk between the IGF- I and EGF signal pathways, which may have implications in tumors that harbo r activating mutations in the EGF receptor.