Coordinated regulation by Shp2 tyrosine phosphatase of signaling events controlling insulin biosynthesis in pancreatic β-cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 18; pp. 7531 - 7536
• Main Authors: Zhang, Sharon S, Hao, Ergeng, Yu, Jianxiu, Liu, Wen, Wang, Jing, Levine, Fred, Feng, Gen-Sheng
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05-05-2009; National Acad Sciences
• Subjects: Animals; Beta cells; Biological Sciences; Biosynthesis; Cell Line; Cell lines; Extracellular Signal-Regulated MAP Kinases - metabolism; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Gene expression regulation; Glucose - metabolism; Glucose - pharmacology; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; Insulin; Insulin - biosynthesis; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - enzymology; Insulin-Secreting Cells - metabolism; Mice; Mice, Knockout; Phosphatases; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptors; Trans-Activators - biosynthesis; Trans-Activators - genetics; Type 2 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0811715106

Intracellular signaling by which pancreatic β-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 β-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 β-cells. Therefore, Shp2 acts as a signal coordinator in β-cells, orchestrating multiple pathways controlling insulin biosynthesis to maintain glucose homeostasis.