TY - JOUR
T1 - Integrin α1β1 controls reactive oxygen species synthesis by negatively regulating epidermal growth factor receptor-mediated Rac activation
AU - Chen, Xiwu
AU - Abair, Tristin D.
AU - Ibanez, Maria R.
AU - Su, Yan
AU - Frey, Mark R.
AU - Dise, Rebecca S.
AU - Polk, D. Brent
AU - Singh, Amar B.
AU - Harris, Raymond C.
AU - Zent, Roy
AU - Pozzi, Ambra
PY - 2007/5
Y1 - 2007/5
N2 - 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 α1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by α1-null mesangial cells. In the present studies, we describe the mechanism whereby integral α1-null mesangial cells produce excessive ROS. Integrili α1-null mesangial cells have constitatively 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 α1-null mesangial cells. Thus, our study demonstrates that integrin α1β1-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.
AB - 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 α1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by α1-null mesangial cells. In the present studies, we describe the mechanism whereby integral α1-null mesangial cells produce excessive ROS. Integrili α1-null mesangial cells have constitatively 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 α1-null mesangial cells. Thus, our study demonstrates that integrin α1β1-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.
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U2 - 10.1128/MCB.01476-06
DO - 10.1128/MCB.01476-06
M3 - Article
C2 - 17339338
AN - SCOPUS:34247626764
SN - 0270-7306
VL - 27
SP - 3313
EP - 3326
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 9
ER -