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

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

  • Nat Commun. 2019 Apr 1;10(1):1473. doi: 10.1038/s41467-019-09318-3.
Eunhee Choi 1,  Sotaro Kikuchi 1,  Haishan Gao 1,  Karolina Brodzik 1,  Ibrahim Nassour 2,  Adam Yopp 2,  Amit G Singal 2,  Hao Zhu 2,  Hongtao Yu 3
Affiliations

Affiliations

  • 1 Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX, 75390, USA.
  • 2 Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX, 75390, USA.
  • 3 Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX, 75390, USA. hongtao.yu@utsouthwestern.edu.
PMID: 30931927 DOI: 10.1038/s41467-019-09318-3
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.

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