1. ¹Department of Biochemical Sciences, University of Florence, Florence, Italy
2. ²Center for Research, Transfer and High Education 'Study at Molecular and Clinical Level of Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies', University of Florence, Florence, Italy

Correspondence: P Chiarugi, Dipartimento di Scienze Biochimiche, University of Florence, Viale Morgagni 50, Florence 50134, Italy. Tel: +39 055 459 8343; Fax: +39 055 459 8905; E-mail: paola.chiarugi@unifi.it

Received 25 September 2007; Revised 17 December 2007; Accepted 7 January 2008; Published online 8 February 2008.

Abstract

Proper attachment to the extracellular matrix (ECM) is essential for cell survival. The loss of integrin-mediated cell–ECM contact results in an apoptotic process termed anoikis. However, mechanisms involved in regulation of cell survival are poorly understood and mediators responsible for anoikis have not been well characterized. Here, we demonstrate that reactive oxygen species (ROS) produced through the involvement of the small GTPase Rac-1 upon integrin engagement exert a mandatory role in transducing a pro-survival signal that ensures that cells escape from anoikis. In particular, we show that ROS are responsible for the redox-mediated activation of Src that trans-phosphorylates epidermal growth factor receptor (EGFR) in a ligand-independent manner. The redox-dependent phosphorylation of EGFR activates both extracellular signal-regulated protein kinase and Akt downstream signalling pathways, culminating in degradation of the pro-apoptotic protein Bim. Hence, our results shed new light on the mechanism granting the adhesion-dependent antiapoptotic effect, highlighting a fundamental role of ROS-mediated Src regulation in ensuring anoikis protection.