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: National Academy of Sciences 2009
• Subjects: adenosine triphosphate; biosynthesis; genes; glucose; glucose tolerance; glycemic control; homeostasis; insulin; insulin secretion; islets of Langerhans; mice; rats
• ISSN: 0027-8424; 1091-6490

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.