Integrin alpha1beta1 regulates epidermal growth factor receptor activation by controlling peroxisome proliferator-activated receptor gamma-dependent caveolin-1 expression.
Integrin alpha1beta1 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 alpha1beta1-mediated EGFR activation. Integrin alpha1-null mesangial cells (MCs) have reduced Cav-1 levels, and reexpression of the integrin alpha1 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 alpha1-null MCs decreases EGFR-mediated ROS production. We further show that integrin alpha1-null MCs have increased levels of activated extracellular signal-regulated kinase (ERK), which leads to reduced activation of peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor that positively regulates Cav-1 expression. Moreover, activation of PPARgamma or inhibition of ERK increases Cav-1 levels in the integrin alpha1-null MCs. Finally, we show that glomeruli of integrin alpha1-null mice have reduced levels of Cav-1 and activated PPARgamma but increased levels of phosphorylated EGFR both at baseline and following injury. Thus, integrin alpha1beta1 negatively regulates EGFR activation by positively controlling Cav-1 levels, and the ERK/PPARgamma axis plays a key role in regulating integrin alpha1beta1-dependent Cav-1 expression and consequent EGFR-mediated ROS production.
Chen
Xiwu
X
Department of Medicine, Division of Nephrology, Medical Center North B3109, Vanderbilt University, Nashville, TN 37232, USA. xiwu.chen@vanderbilt.edu
Whiting
Carrie
C
Borza
Corina
C
Hu
Wen
W
Mont
Stacey
S
Bulus
Nada
N
Zhang
Ming-Zhi
MZ
Harris
Raymond C
RC
Zent
Roy
R
Pozzi
Ambra
A
D000818:Animals; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D039222:Integrin alpha1beta1 / Q000172:deficiency / Q000378:metabolism*; D050527:Mesangial Cells / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism
D051242:Caveolin 1; D039222:Integrin alpha1beta1; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases