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

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

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.

Highlights

Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways
These findings suggest that reduced insulin receptor (IR) plasma membrane (PM) levels might be a contributing factor to insulin resistance in human patients
We have elucidated a feedback regulatory mechanism of IR endocytosis and identified Src homology phosphatase 2 (SHP2) as a molecular target whose inhibition delays insulin-activated IR endocytosis (Fig. 8c). Targeting this feedback regulation of IR endocytosis prolongs the metabolic branch of insulin signaling and improves insulin sensitivity in mice

Summary

Introduction

Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. Insulin binds to the insulin receptor (IR) on the plasma membrane (PM), and triggers phosphorylation-mediated activation of crucial enzymes that regulate glucose and lipid metabolism, and cell growth and division[2,3]. In response to unattached kinetochores, the mitosis arrest deficiency 2 (MAD2) and budding uninhibited by benomyl 1-related 1 (BUBR1) proteins, as subunits of the mitotic checkpoint complex (MCC), inhibit the anaphase-promoting complex/cyclosome bound to its mitotic activator, the cell division cycle 20 (CDC20) protein, to delay chromosome segregation[10,11,12,13]. We have recently discovered a critical role of MAD2, BUBR1, and p31comet in insulin signaling during interphase (Fig. 1a)[18,19]

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