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PMID:19380737

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Citation

Zhang, SS, Hao, E, Yu, J, Liu, W, Wang, J, Levine, F and Feng, GS (2009) Coordinated regulation by Shp2 tyrosine phosphatase of signaling events controlling insulin biosynthesis in pancreatic beta-cells. Proc. Natl. Acad. Sci. U.S.A. 106:7531-6

Abstract

Intracellular signaling by which pancreatic beta-cells synthesize and secrete insulin in control of glucose homeostasis is not fully understood. Here we show that Shp2, a cytoplasmic tyrosine phosphatase possessing 2 SH2 domains, coordinates signaling events required for insulin biosynthesis in beta-cells. Mice with conditional ablation of the Shp2/Ptpn11 gene in the pancreas exhibited defective glucose-stimulated insulin secretion and impaired glucose tolerance. Consistently, siRNA-mediated Shp2-knockdown in rat insulinoma INS-1 832/13 cells resulted in decreased insulin production and secretion despite an increase in cellular ATP. Shp2 modulates the strength of signals flowing through Akt/FoxO1 and Erk pathways, culminating in control of Pdx1 expression and activity on Ins1 and Ins2 promoters, and forced Pdx1 expression rescued insulin production in Shp2-knockdown beta-cells. Therefore, Shp2 acts as a signal coordinator in beta-cells, orchestrating multiple pathways controlling insulin biosynthesis to maintain glucose homeostasis.

Links

PubMed PMC2678606 Online version:10.1073/pnas.0811715106

Keywords

Animals; Cell Line; Extracellular Signal-Regulated MAP Kinases/metabolism; Forkhead Transcription Factors/metabolism; Glucose/metabolism; Glucose/pharmacology; Homeodomain Proteins/biosynthesis; Homeodomain Proteins/genetics; Insulin/biosynthesis; Insulin/secretion; Insulin-Secreting Cells/drug effects; Insulin-Secreting Cells/enzymology; Insulin-Secreting Cells/secretion; Mice; Mice, Knockout; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism; Proto-Oncogene Proteins c-akt/metabolism; Trans-Activators/biosynthesis; Trans-Activators/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:PDX1

enables

GO:1990841: promoter-specific chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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