Integrin α1β1 Regulates Epidermal Growth Factor Receptor Activation by Controlling Peroxisome Proliferator-Activated Receptor γ-Dependent Caveolin-1 Expression

Integrin alpha 1 beta 1 negatively regulates the generation of profibrotic reactive oxygen species (ROS) by inhibiting epidermal growth factor receptor (EGFR) activation; however, the mechanism by which it does this is unknown. In this study, we show that caveolin-1 (Cav-1), a scaffolding protein that binds integrins and controls growth factor receptor signaling, participates in integrin alpha 1 beta 1-mediated EGFR activation. Integrin alpha 1-null mesangial cells (MCs) have reduced Cav-1 levels, and reexpression of the integrin alpha 1 subunit increases Cav-1 levels, decreases EGFR activation, and reduces ROS production. Downregulation of Cav-1 in wild-type MCs increases EGFR phosphorylation and ROS synthesis, while overexpression of Cav-1 in the integrin alpha 1-null MCs decreases EGFR-mediated ROS production. We further show that integrin alpha 1-null MCs have increased levels of activated extracellular signal-regulated kinase (ERK), which leads to reduced activation of peroxisome proliferator-activated receptor gamma(PPAR gamma), a transcription factor that positively regulates Cav-1 expression. Moreover, activation of PPAR gamma or inhibition of ERK increases Cav-1 levels in the integrin alpha 1-null MCs. Finally, we show that glomeruli of integrin alpha 1-null mice have reduced levels of Cav-1 and activated PPAR gamma but increased levels of phosphorylated EGFR both at baseline and following injury. Thus, integrin alpha 1 beta 1 negatively regulates EGFR activation by positively controlling Cav-1 levels, and the ERK/PPAR gamma axis plays a key role in regulating integrin alpha 1 beta 1-dependent Cav-1 expression and consequent EGFR-mediated ROS production.