Mitotic Checkpoint Regulators Control Insulin Signaling and Metabolic Homeostasis

Eunhee Choi, Xiangli Zhang, Chao Xing, Hongtao Yu

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Insulin signaling regulates many facets of animal physiology. Its dysregulation causes diabetes and other metabolic disorders. The spindle checkpoint proteins MAD2 and BUBR1 prevent precocious chromosome segregation and suppress aneuploidy. The MAD2 inhibitory protein p31comet promotes checkpoint inactivation and timely chromosome segregation. Here, we show that whole-body p31comet knockout mice die soon after birth and have reduced hepatic glycogen. Liver-specific ablation of p31comet causes insulin resistance, hyperinsulinemia, glucose intolerance, and hyperglycemia and diminishes the plasma membrane localization of the insulin receptor (IR) in hepatocytes. MAD2 directly binds to IR and facilitates BUBR1-dependent recruitment of the clathrin adaptor AP2 to IR. p31comet blocks the MAD2-BUBR1 interaction and prevents spontaneous clathrin-mediated IR endocytosis. BUBR1 deficiency enhances insulin sensitivity in mice. BUBR1 depletion in hepatocytes or the expression of MAD2-binding-deficient IR suppresses the metabolic phenotypes of p31comet ablation. Our findings establish a major IR regulatory mechanism and link guardians of chromosome stability to nutrient metabolism.

Original languageEnglish (US)
Pages (from-to)567-581
Number of pages15
JournalCell
Volume166
Issue number3
DOIs
StatePublished - Jul 28 2016

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M Phase Cell Cycle Checkpoints
Insulin Receptor
Homeostasis
Insulin
Chromosomes
Chromosome Segregation
Ablation
Insulin Resistance
Hepatocytes
Vesicular Transport Adaptor Proteins
Clathrin
Chromosomal Instability
Liver Glycogen
Glucose Intolerance
Physiology
Hyperinsulinism
Aneuploidy
Cell membranes
Medical problems
Endocytosis

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mitotic Checkpoint Regulators Control Insulin Signaling and Metabolic Homeostasis. / Choi, Eunhee; Zhang, Xiangli; Xing, Chao; Yu, Hongtao.

In: Cell, Vol. 166, No. 3, 28.07.2016, p. 567-581.

Research output: Contribution to journalArticle

Choi, Eunhee ; Zhang, Xiangli ; Xing, Chao ; Yu, Hongtao. / Mitotic Checkpoint Regulators Control Insulin Signaling and Metabolic Homeostasis. In: Cell. 2016 ; Vol. 166, No. 3. pp. 567-581.
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