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EGF‐induced ERK‐activation downstream of FAK requires rac1‐NADPH oxidase
Author(s) -
Flinder Liv Ingrid,
Timofeeva Olga A.,
Rosseland Carola M.,
Wierød Lene,
Huitfeldt Henrik S.,
Skarpen Ellen
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22563
Subject(s) - rac1 , nadph oxidase , mapk/erk pathway , microbiology and biotechnology , downstream (manufacturing) , chemistry , rac gtp binding proteins , reactive oxygen species , signal transduction , biology , business , marketing
Reactive oxygen species (ROS) function as signaling molecules mainly by reversible oxidation of redox‐sensitive target proteins. ROS can be produced in response to integrin ligation and growth factor stimulation through Rac1 and its effector protein NADPH oxidase. One of the central roles of Rac1‐NADPH oxidase is actin cytoskeletal rearrangement, which is essential for cell spreading and migration. Another important regulator of cell spread is focal adhesion kinase (FAK), a coordinator of integrin and growth factor signaling. Here, we propose a novel role for NADPH oxidase as a modulator of the FAK autophosphorylation site. We found that Rac1‐NADPH oxidase enhanced the phosphorylation of FAK at Y397. This site regulates FAK's ability to act as a scaffold for EGF‐mediated signaling, including activation of ERK. Accordingly, we found that EGF‐induced activation of FAK at Y925, the following activation of ERK, and phosphorylation of FAK at the ERK‐regulated S910‐site depended upon NADPH oxidase. Furthermore, the inhibition of NADPH oxidase caused excessive focal adhesions, which is in accordance with ERK and FAK being modulators of focal adhesion dissociation. Our data suggest that Rac1 through NADPH oxidase is part of the signaling pathway constituted by FAK, Rac1, and ERK that regulates focal adhesion disassembly during cell spreading. J. Cell. Physiol. 226: 2267–2278, 2011. © 2010 Wiley‐Liss, Inc.