Open AccessIntegrin α1β1 Regulates Epidermal Growth Factor Receptor Activation by Controlling Peroxisome Proliferator-Activated Receptor γ-Dependent Caveolin-1 Expression
Author(s) -
Xiwu Chen,
Carrie Whiting,
Corina M. Borza,
Wen Yang Hu,
Stacey Mont,
Nada Bulus,
Mingzhi Zhang,
Raymond C. Harris,
Roy Zent,
Ambra Pozzi
Publication year - 2010
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00892-09
Subject(s) - biology , mapk/erk pathway , integrin , epidermal growth factor receptor , microbiology and biotechnology , caveolin 1 , collagen receptor , downregulation and upregulation , signal transduction , peroxisome proliferator activated receptor , kinase , proto oncogene tyrosine protein kinase src , cancer research , receptor , biochemistry , gene
Integrin α1β1 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 α1β1-mediated EGFR activation. Integrin α1-null mesangial cells (MCs) have reduced Cav-1 levels, and reexpression of the integrin α1 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 α1-null MCs decreases EGFR-mediated ROS production. We further show that integrin α1-null MCs have increased levels of activated extracellular signal-regulated kinase (ERK), which leads to reduced activation of peroxisome proliferator-activated receptor γ (PPARγ), a transcription factor that positively regulates Cav-1 expression. Moreover, activation of PPARγ or inhibition of ERK increases Cav-1 levels in the integrin α1-null MCs. Finally, we show that glomeruli of integrin α1-null mice have reduced levels of Cav-1 and activated PPARγ but increased levels of phosphorylated EGFR both at baseline and following injury. Thus, integrin α1β1 negatively regulates EGFR activation by positively controlling Cav-1 levels, and the ERK/PPARγ axis plays a key role in regulating integrin α1β1-dependent Cav-1 expression and consequent EGFR-mediated ROS production.