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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Line
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Forkhead Box Protein O1
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Forkhead Transcription Factors / metabolism
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Glucose / metabolism
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Glucose / pharmacology
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Homeodomain Proteins / biosynthesis
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Homeodomain Proteins / genetics
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Insulin / biosynthesis*
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Insulin / metabolism
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Insulin Secretion
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / enzymology*
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Insulin-Secreting Cells / metabolism
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Mice
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Mice, Knockout
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
Substances
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Homeodomain Proteins
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Insulin
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Trans-Activators
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pancreatic and duodenal homeobox 1 protein
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Ptpn11 protein, mouse
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Glucose