Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling
Abstract
Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH)
- OSTI Identifier:
- 1566812
- Grant/Contract Number:
- 1R01GM124096
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; checkpoints; endocytosis; insulin signalling; x-ray crystallography
Citation Formats
Choi, Eunhee, Kikuchi, Sotaro, Gao, Haishan, Brodzik, Karolina, Nassour, Ibrahim, Yopp, Adam, Singal, Amit G., Zhu, Hao, and Yu, Hongtao. Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling. United States: N. p., 2019.
Web. doi:10.1038/s41467-019-09318-3.
Choi, Eunhee, Kikuchi, Sotaro, Gao, Haishan, Brodzik, Karolina, Nassour, Ibrahim, Yopp, Adam, Singal, Amit G., Zhu, Hao, & Yu, Hongtao. Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling. United States. https://doi.org/10.1038/s41467-019-09318-3
Choi, Eunhee, Kikuchi, Sotaro, Gao, Haishan, Brodzik, Karolina, Nassour, Ibrahim, Yopp, Adam, Singal, Amit G., Zhu, Hao, and Yu, Hongtao. Mon .
"Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling". United States. https://doi.org/10.1038/s41467-019-09318-3. https://www.osti.gov/servlets/purl/1566812.
@article{osti_1566812,
title = {Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling},
author = {Choi, Eunhee and Kikuchi, Sotaro and Gao, Haishan and Brodzik, Karolina and Nassour, Ibrahim and Yopp, Adam and Singal, Amit G. and Zhu, Hao and Yu, Hongtao},
abstractNote = {Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.},
doi = {10.1038/s41467-019-09318-3},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {Mon Apr 01 00:00:00 EDT 2019},
month = {Mon Apr 01 00:00:00 EDT 2019}
}
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Structural basis of the activation of type 1 insulin-like growth factor receptor
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Structural basis of the activation of type 1 insulin-like growth factor receptor
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Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway
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