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