Diverse injurious stimuli reduce protein tyrosine phosphatase-μ expression and enhance epidermal growth factor receptor signaling in human airway epithelia

In response to injury, airway epithelia utilize an epidermal growth factor (EGF) receptor (EGFR) signaling program to institute repair and restitution. Protein tyrosine phosphatases (PTPs) counterregulate EGFR autophosphorylation and downstream signaling. PTP mu is highly expressed in lung epithelia and can be localized to intercellular junctions where its ectodomain homophilically interacts with PTP mu ectodomain expressed on neighboring cells. We asked whether PTP mu expression might be altered in response to epithelial injury and whether altered PTP mu expression might influence EGFR signaling. In A549 cells, diverse injurious stimuli dramatically reduced PTP mu protein expression. Under basal conditions, small interfering RNA (siRNA)-induced silencing of PTP mu increased EGFR Y992 and Y1068 phosphorylation. In the presence of EGF, PTP mu knockdown increased EGFR Y845, Y992, Y1045, Y1068, Y1086, and Y1173 but not Y1148 phosphorylation. Reduced PTP mu expression increased EGF-stimulated phosphorylation of Y992, a docking site for phospholipase C (PLC)gamma(1), activation of PLC gamma(1) itself, and increased cell migration in both wounding and chemotaxis assays. In contrast, overexpression of PTP mu decreased EGF-stimulated EGFR Y992 and Y1068 phosphorylation. Therefore, airway epithelial injury profoundly reduces PTP mu expression, and PTP mu depletion selectively increases phosphorylation of specific EGFR tyrosine residues, PLC gamma(1) activation, and cell migration, providing a novel mechanism through which epithelial integrity may be restored.