Coordinated Regulation by Shp2 Tyrosine Phosphatase of Signaling events Controlling Insulin Biosynthesis in β‐cells

Abstract

Pancreatic β‐cell dysfunction contributes to the development of all forms of diabetes. However, molecular signaling defects underlying β cell failure are not fully understood. Shp2 is a widely expressed protein tyrosine phosphatase (PTP) with two SH2 domains. Shp2 is implicated in pathways activated by receptor tyrosine kinases (RTKs) or cytokine receptors. In particular, Shp2 binds to tyrosine‐phosphorylated IRS proteins and functions in insulin‐regulated glucose metabolism in insulin‐responsive tissues. However, whether Shp2 plays a biological role in insulin‐producing pancreatic β cells is unclear. We generated conditional mutant mice in which Shp2 is selectively deleted in the pancreas (Shp2Panc‐/−). Shp2Panc‐/− mice exhibit reduced glucose‐stimulated insulin secretion and progressively impaired glucose tolerance. Shp2‐deficient β‐cells show attenuated insulin gene expression and reduced insulin content. Consistently, siRNA‐mediated Shp2 knockdown in rat insulinoma INS‐1 832/13 cells resulted in significantly decreased insulin secretion and disrupted expression profile of several β‐cell specific genes. Biochemical analyses revealed defects in the Akt/FoxO1 and Erk pathways, leading to decreased Pdx1 expression/activity and insulin biosynthesis in Shp2‐deficient β‐cells. Therefore, this study identifies Shp2 as a signal coordinator in β‐cells, which orchestrates multiple pathways controlling insulin biosynthesis to maintain glucose homeostasis.