Integrin alpha1beta1 controls reactive oxygen species synthesis by negatively regulating epidermal growth factor receptor-mediated Rac activation.
Integrins control many cell functions, including generation of reactive oxygen species (ROS) and regulation of collagen synthesis. Mesangial cells, found in the glomerulus of the kidney, are able to produce large amounts of ROS via the NADPH oxidase. We previously demonstrated that integrin alpha1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by alpha1-null mesangial cells. In the present studies, we describe the mechanism whereby integrin alpha1-null mesangial cells produce excessive ROS. Integrin alpha1-null mesangial cells have constitutively increased basal levels of activated Rac1, which result in its increased translocation to the cell membrane, excessive ROS production, and consequent collagen IV deposition. Basal Rac1 activation is a direct consequence of ligand-independent increased epidermal growth factor receptor (EGFR) phosphorylation in alpha1-null mesangial cells. Thus, our study demonstrates that integrin alpha1beta1-EGFR cross talk is a key step in negatively regulating Rac1 activation, ROS production, and excessive collagen synthesis, which is a hallmark of diseases characterized by irreversible fibrosis.
Chen
Xiwu
X
Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN 37232, USA.
Abair
Tristin D
TD
Ibanez
Maria R
MR
Su
Yan
Y
Frey
Mark R
MR
Dise
Rebecca S
RS
Polk
D Brent
DB
Singh
Amar B
AB
Harris
Raymond C
RC
Zent
Roy
R
Pozzi
Ambra
A
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D048430:Cell Shape; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D015536:Down-Regulation; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D039222:Integrin alpha1beta1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D038981:Receptors, Collagen / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D039222:Integrin alpha1beta1; D008024:Ligands; D051567:Proto-Oncogene Proteins c-vav; D017382:Reactive Oxygen Species; D038981:Receptors, Collagen; C490565:Vav2 protein, mouse; D003094:Collagen; D066246:ErbB Receptors; D020744:rac GTP-Binding Proteins