@article{8da60b07fc81452197f7f3e8891af13f,
title = "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.",
author = "Eunhee Choi and Sotaro Kikuchi and Haishan Gao and Karolina Brodzik and Ibrahim Nassour and Adam Yopp and Singal, {Amit G.} and Hao Zhu and Hongtao Yu",
note = "Funding Information: We thank Drs. Joseph Goldstein, Michael Brown, David Mangelsdorf, and Philipp Scherer for advice on animal experiments and helpful discussions, Dr. Melanie Cobb for advice on MEK inhibitors and helpful discussions, Dr. Sandra Schmid for advice on IR endocytosis and key reagents, Dr. Zhonghui Lin for advice on structural analysis, Drs. James A. Richardson and John Shelton for advice on histopathology, and Dr. Xuelian Luo for advice on protein purification and helpful discussions. We are grateful to the Animal Resource Center at University of Texas Southwestern Medical Center for assistance with mouse maintenance, Metabolic Phenotyping Core for assistance with analysis of insulin and C-peptide, and the Histopathology Core for assistance with tissue processing and sectioning. This work is supported by the Clayton Foundation and the National Institutes of Health (1R01GM124096). H.Y. is an Investigator with the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-09318-3",
language = "English (US)",
volume = "10",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}