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

Choi, Eunhee; Kikuchi, Sotaro; Gao, Haishan; Brodzik, Karolina; Nassour, Ibrahim; Yopp, Adam; Singal, Amit G.; Zhu, Hao; Yu, Hongtao

doi:10.1038/s41467-019-09318-3

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

Journal Article · Mon Apr 01 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-09318-3· OSTI ID:1566812

Choi, Eunhee ^[1]; Kikuchi, Sotaro ^[1]; Gao, Haishan ^[1]; Brodzik, Karolina ^[1]; Nassour, Ibrahim ^[1]; Yopp, Adam ^[1]; Singal, Amit G. ^[1];

^[1];

^[1]

Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: 1R01GM124096

OSTI ID:: 1566812

Journal Information:: Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 51 works

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59 BASIC BIOLOGICAL SCIENCES
checkpoints
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x-ray crystallography

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

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