UC San Diego

The pancreatic [beta] cell plays essential role in glucose homeostasis by secretion of the hormone insulin to meet metabolic demand. Previous studies revealed that the insulin signaling pathway is important for [beta]-cell growth and function. Shp2 is a ubiquitously expressed protein tyrosine phophatase (PTP) that possesses two Src- homology 2 (SH2) domains at the N-terminus and a classic PTP domain. This phosphatase is demonstrated to mediate the insulin signaling through interaction with insulin receptor (IR) and insulin receptor substrate (IRS) in insulin responsive tissues. However, the function of Shp2 in pancreatic beta cells is still enigmatic. Here we show that Shp2 acts to coordinate multiple signaling events 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 INS-1 832/13 cells resulted in decreased insulin production and secretion, despite an increase of cellular ATP content, in response to glucose challenge. Shp2 modulates strength of signals flowing through the Akt/FoxO1 and Erk pathways, culminating in the control of Pdx1 expression and its activity on the Ins1 and Ins2 promoters, and forced expression of Pdx1 rescued attenuated insulin production in Shp2 knockdown [beta]-cells. Therefore, this study identifies Shp2 as a novel signal coordinator in [beta]- cells, orchestrating multiple pathways controlling insulin biosynthesis for maintaining glucose homeostasis