SHP-2 phosphatase controls aryl hydrocarbon receptor-mediated ER stress response in mast cells

Previously we reported that exposure of mouse and human mast cells to aryl hydrocarbon receptor (AhR) ligands resulted in reactive oxygen species (ROS)- and calcium (Ca²⁺)-dependent activation of mast cells in vitro and in vivo. However, the mechanisms through which the AhR-ligand axis mediates stress response, Ca²⁺ signaling and subsequent mast cell activation remain to be fully elucidated. Evidence is provided herein that SHP-2 is critical in regulating AhR-mediated ER stress response and intracellular Ca²⁺ dynamics. We found that an AhR ligand, FICZ, induced significant reduction of intracellular GSH and an increased level of intracellular ROS. Significantly, we showed that in FICZ-treated mast cells, SHP-2 promoted, in a ROS-dependent manner, ER stress response involving primarily the PERK signaling pathway, ATF4 activation and eIF2α phosphorylation, which could be reversed by the addition of an antioxidant, NAC, and was inhibited in cells with SHP-2 knockdown. Our findings suggested that SHP-2 is critical in controlling ER stress signals in response to AhR activation, which provides a new mechanistic insight into how the AhR-ligand axis regulates cellular adaptation to the environmental insult in mast cells.