Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling

Eunhee Choi, Sotaro Kikuchi, Haishan Gao, Karolina Brodzik, Ibrahim Nassour, Adam Yopp, Amit G. Singal, Hao Zhu and Hongtao Yu ()
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Eunhee Choi: University of Texas Southwestern Medical Center
Sotaro Kikuchi: University of Texas Southwestern Medical Center
Haishan Gao: University of Texas Southwestern Medical Center
Karolina Brodzik: University of Texas Southwestern Medical Center
Ibrahim Nassour: University of Texas Southwestern Medical Center
Adam Yopp: University of Texas Southwestern Medical Center
Amit G. Singal: University of Texas Southwestern Medical Center
Hao Zhu: University of Texas Southwestern Medical Center
Hongtao Yu: University of Texas Southwestern Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09318-3

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