Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway

Insulin receptor substrate (IRS) proteins are important intracellular molec ules that mediate insulin receptor tyrosine kinase signaling. A decreased c ontent of IRS proteins has been found in insulin-resistant states in animal s, humans, and cultured cells under various conditions. However, the molecu lar mechanism that controls cellular levels of IRS proteins is unknown. We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. The insulin-induced degradation of I RS-1 can be prevented by pretreatment with lactacystin, a specific inhibito r for proteasome degradation, These data demonstrate, for the first time, t hat insulin-induced degradation of IRS-1 is mediated by the proteasome degr adation pathway. IRS-2 can escape from the insulin-induced proteasome degra dation, suggesting the existence of specific structural requirements for th is degradation process.