Serine Phosphorylation by mTORC1 Promotes IRS-1 Degradation through SCFβ-TRCP E3 Ubiquitin Ligase

• Main Authors: Yosuke Yoneyama, Tomomi Inamitsu, Kazuhiro Chida, Shun-Ichiro Iemura, Tohru Natsume, Tatsuya Maeda, Fumihiko Hakuno, Shin-Ichiro Takahashi
• Format: Article
• Language: English
• Published: Elsevier 2018-07-01
• Series: iScience
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004218300828

Summary: The insulin receptor substrate IRS-1 is a key substrate of insulin and insulin-like growth factor (IGF) receptor tyrosine kinases that mediates their metabolic and growth-promoting actions. Proteasomal degradation of IRS-1 is induced following activation of the downstream kinase mTOR complex 1 (mTORC1) to constitute a negative feedback loop. However, the underlying mechanism remains poorly understood. Here we report that Ser 422 of IRS-1 is phosphorylated by mTORC1 and required for IRS-1 degradation induced by prolonged IGF stimulation. Phosphorylation of Ser 422 then recruits the SCFβ-TRCP E3 ligase complex, which catalyzes IRS-1 ubiquitination. Phosphorylation-dependent IRS-1 degradation contributes to impaired growth and survival responses to IGF in cells lacking TSC2, a negative regulator of mTORC1. Inhibition of IRS-1 degradation promotes sustained Akt activation in IGF-stimulated cells. Our work clarifies the nature of the IRS-1-mTORC1 feedback loop and elucidates its role in temporal regulation of IGF signaling. : Biochemistry; Biochemical Mechanism; Molecular Physiology; Molecular Interaction Subject Areas: Biochemistry, Biochemical Mechanism, Molecular Physiology, Molecular Interaction