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

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1473
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

Dual Specificity Phosphatase 1
insulin
phosphatases
regulators
Insulin Receptor
homology
Insulin Receptor Substrate Proteins
Endocytosis
Phosphoric Monoester Hydrolases
Insulin
Feedback
Insulin Resistance
Vesicular Transport Adaptor Proteins
Chromosome Segregation
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Growth
Phosphorylation
Mitosis
spindles

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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 C; Singal, Amit; Zhu, Hao; Yu, Hongtao.

In: Nature communications, Vol. 10, No. 1, 1473, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Gao, Haishan

AU - Brodzik, Karolina

AU - Nassour, Ibrahim

AU - Yopp, Adam C

AU - Singal, Amit

AU - Zhu, Hao

AU - Yu, Hongtao

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