Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling.
Adaptor Protein Complex 2
/ metabolism
Animals
Endocytosis
Feedback, Physiological
Hep G2 Cells
Humans
Insulin
/ metabolism
Insulin Receptor Substrate Proteins
/ metabolism
Insulin Resistance
M Phase Cell Cycle Checkpoints
MAP Kinase Signaling System
Mice
Phosphorylation
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ metabolism
Receptor, Insulin
/ metabolism
Signal Transduction
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 04 2019
01 04 2019
Historique:
received:
31
08
2018
accepted:
25
02
2019
entrez:
2
4
2019
pubmed:
2
4
2019
medline:
17
4
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30931927
doi: 10.1038/s41467-019-09318-3
pii: 10.1038/s41467-019-09318-3
pmc: PMC6443781
doi:
Substances chimiques
Adaptor Protein Complex 2
0
IRS1 protein, human
0
IRS2 protein, human
0
Insulin
0
Insulin Receptor Substrate Proteins
0
Irs1 protein, mouse
0
Irs2 protein, mouse
0
Receptor, Insulin
EC 2.7.10.1
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1473Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM124096
Pays : United States
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