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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Eunhee Choi & Sotaro Kikuchi & Haishan Gao & Karolina Brodzik & Ibrahim Nassour & Adam Yopp & Amit G. Singal & Hao Zhu & Hongtao Yu, 2019. "Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09318-3
    DOI: 10.1038/s41467-019-09318-3
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    Cited by:

    1. András Zeke & Tamás Takács & Péter Sok & Krisztina Németh & Klára Kirsch & Péter Egri & Ádám Levente Póti & Isabel Bento & Gábor E. Tusnády & Attila Reményi, 2022. "Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Junhee Park & Jie Li & John P. Mayer & Kerri A. Ball & Jiayi Wu & Catherine Hall & Domenico Accili & Michael H. B. Stowell & Xiao-chen Bai & Eunhee Choi, 2022. "Activation of the insulin receptor by an insulin mimetic peptide," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Weidong An & Catherine Hall & Jie Li & Albert Hung & Jiayi Wu & Junhee Park & Liwei Wang & Xiao-chen Bai & Eunhee Choi, 2024. "Activation of the insulin receptor by insulin-like growth factor 2," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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