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mTORC1介导的丝氨酸磷酸化通过SCFβ-TRCP E3泛素连接酶促进IRS-1降解。

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

作者信息

Yoneyama Yosuke, Inamitsu Tomomi, Chida Kazuhiro, Iemura Shun-Ichiro, Natsume Tohru, Maeda Tatsuya, Hakuno Fumihiko, Takahashi Shin-Ichiro

机构信息

Department of Animal Resource Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.

Translational Research Center, Fukushima Medical University, Fukushima-city, Fukushima 960-8031, Japan.

出版信息

iScience. 2018 Jul 27;5:1-18. doi: 10.1016/j.isci.2018.06.006. Epub 2018 Jun 18.

DOI:10.1016/j.isci.2018.06.006
PMID:30240640
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6123863/
Abstract

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 SCF 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.

摘要

胰岛素受体底物 IRS-1 是胰岛素和胰岛素样生长因子（IGF）受体酪氨酸激酶的关键底物，介导它们的代谢和促生长作用。IRS-1 的蛋白酶体降解在下游激酶 mTOR 复合物 1（mTORC1）激活后被诱导，从而构成一个负反馈环。然而，其潜在机制仍知之甚少。在此，我们报告 IRS-1 的丝氨酸 422 位点被 mTORC1 磷酸化，并且在长时间 IGF 刺激诱导的 IRS-1 降解中是必需的。丝氨酸 422 的磷酸化随后募集 SCF E3 连接酶复合物，该复合物催化 IRS-1 的泛素化。磷酸化依赖性 IRS-1 降解导致在缺乏 mTORC1 负调节因子 TSC2 的细胞中对 IGF 的生长和存活反应受损。抑制 IRS-1 降解可促进 IGF 刺激的细胞中 Akt 的持续激活。我们的工作阐明了 IRS-1-mTORC1 反馈环的本质，并阐明了其在 IGF 信号转导时间调控中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/d337a0114cde/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/4782e1f6be12/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/dd6b230adc73/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/db503a39e005/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/52f7503210f8/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/9d6d3b78e6c8/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/e36b92725790/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/363a46a76dd4/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/d337a0114cde/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/4782e1f6be12/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/dd6b230adc73/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/db503a39e005/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/52f7503210f8/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/9d6d3b78e6c8/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/e36b92725790/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/363a46a76dd4/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b3ef/6123863/d337a0114cde/gr7.jpg

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