H2O2-induced transactivation of EGF receptor requires Src and mediates ERK1/2, but not Akt, activation in renal cells.
Although oxidative stress activates epidermal growth factor receptor (EGFR), ERK1/2, and Akt in a number of cell types, the mechanisms by which oxidative stress activates these kinases are not well defined in renal epithelial cells. Exposure of primary cultures of rabbit renal proximal tubular cells to hydrogen peroxide (H(2)O(2)) stimulated Src, EGFR, ERK1/2, and Akt activation in a time-dependent manner as determined by the phosphorylation of each protein. The Src inhibitor PP1 completely blocked EGFR, ERK1/2, and Akt phosphorylation following H(2)O(2) exposure. In contrast, blockade of the EGFR by AG1478 inhibited phosphorylation of ERK1/2 but not Src or Akt phosphorylation following H(2)O(2) exposure. Exogenous EGF stimulated EGFR, ERK1/2, and Akt activation and the EGFR inhibitor blocked phosphorylation of ERK1/2 and Akt. The presence of PP1, but not AG1478, significantly accelerated H(2)O(2)-induced cell death. These results suggest that Src mediates H(2)O(2)-induced EGFR transactivation. H(2)O(2)- and EGF-induced ERK1/2 activation is mediated by EGFR, whereas Akt is activated by Src independent of EGFR following H(2)O(2) exposure. Src-mediated EGFR transactivation contributes to a survival response following oxidative injury.
Zhuang
Shougang
S
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Schnellmann
Rick G
RG
Zhougang
Shougang
S
D000818:Animals; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011817:Rabbits; D019061:src-Family Kinases / Q000378:metabolism*
D066246:ErbB Receptors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016877:Oxidants; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019061:src-Family Kinases