Insulin/insulin-like growth factor (IGF) stimulation abrogates an association between a deubiquitinating enzyme USP7 and insulin receptor substrates (IRSs) followed by proteasomal degradation of IRSs

详细信息    查看全文

• 作者：Hidehito Yoshihara ; Toshiaki Fukushima ; Fumihiko Hakuno ; Yasushi Saeki ; Keiji Tanaka ; Akihiro Ito ; Minoru Yoshida ; Shun-ichiro Iemura ; Tohru Natsume ; Tomoichiro Asano ; Kazuhiro Chida ; Leonard Girnita ; Shin-Ichiro Takahashi
• 关键词：IRS ; insulin receptor substrate ; IGF ; insulin-like growth factor ; PI3K ; phosphatidylinositol 3-kinase ; SH2 ; src homology region 2 ; USP7 ; ubiquitin specific protease 7 ; Grb2 ; growth factor receptor-bound protein 2 ; Erk ; extracellular signal-regulated kinas
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 出版时间：22 June, 2012
• 年：2012
• 卷：423
• 期：1
• 页码：122-127
• 全文大小：470 K

文摘

Insulin receptor substrates (IRSs) play central roles in insulin/insulin-like growth factor (IGF) signaling and mediate a variety of their bioactivities. IRSs are tyrosine-phosphorylated by activated insulin receptor/IGF-I receptor tyrosine kinase in response to insulin/IGF, and are recognized by signaling molecules possessing the SH2 domain such as phosphatidylinositol 3-kinase (PI3K), leading to the activation of downstream pathways. Recent studies have suggested that degradation of IRSs by the ubiquitin-proteasome pathway leads to impaired insulin/IGF signaling, but the precise mechanism underlying the process is still unclear. In this study, we identified deubiquitinating enzyme ubiquitin specific protease 7 (USP7) as an IRS-2-interacting protein and demonstrated that deubiquitinase activity of USP7 plays important roles in IRS-2 stabilization through the ubiquitin-proteasome pathway. In addition, insulin treatment dissociated USP7 from IRS-2, leading to degradation of IRS-2. This dissociation was prevented by treatment with LY294002, a PI3K inhibitor, indicating that insulin activation of the PI3K pathway leads to dissociation of IRS-2 from USP7 and IRS-2 degradation. We obtained similar results for IRS-1 in cells treated with insulin and for IRS-2 in cells treated with IGF-I. Taken together, this is the first report demonstrating that USP7 is an IRS-1/2 deubiquitinating enzyme forming a negative feedback loop in insulin/IGF signaling.