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Fer-Mediated Cortactin Phosphorylation Is Associated with Efficient Fibroblast Migration and Is Dependent on Reactive Oxygen Species Generation during Integrin-Mediated Cell Adhesion ^,

Queen's University Cancer Research Institute, Division of Cancer Biology and Genetics, Kingston, Ontario K7L 3N6,¹ Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6,² Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada³

Received 15 September 2006/ Returned for modification 16 November 2006/ Accepted 15 June 2007

The molecular details linking integrin engagement to downstream cortactin (Ctn) tyrosine phosphorylation are largely unknown. In this report, we show for the first time that Fer and Ctn are potently tyrosine phosphorylated in response to hydrogen peroxide (H₂O₂) in a variety of cell types. Working with catalytically inactive fer and src/yes/fyn-deficient murine embryonic fibroblasts (fer^DR/DR and syf MEF, respectively), we observed that H₂O₂-induced Ctn tyrosine phosphorylation is primarily dependent on Fer but not Src family kinase (SFK) activity. We also demonstrated for the first time that Fer is activated by fibronectin engagement and, in concert with SFKs, mediates Ctn tyrosine phosphorylation in integrin signaling pathways. Reactive oxygen species (ROS) scavengers or the NADPH oxidase inhibitor, diphenylene iodonium, attenuated integrin-induced Fer and Ctn tyrosine phosphorylation. Taken together, these findings provide novel genetic evidence that a ROS-Fer signaling arm contributes to SFK-mediated Ctn tyrosine phosphorylation in integrin signaling. Lastly, a migration defect in fer^DR/DR MEF suggests that integrin signaling through the ROS-Fer-Ctn signaling arm may be linked to mechanisms governing cell motility. These data demonstrate for the first time an oxidative link between integrin adhesion and an actin-binding protein involved in actin polymerization.

Published ahead of print on 2 July 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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