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Mol. Cell. Biol. 25 (15): 6391-6403

Copyright © 2005 by the American Society for Microbiology. All rights reserved.

Intracellular Reactive Oxygen Species Activate Src Tyrosine Kinase during Cell Adhesion and Anchorage-Dependent Cell Growth{dagger}

Elisa Giannoni,1 Francesca Buricchi,1 Giovanni Raugei,1,2 Giampietro Ramponi,1,2, and Paola Chiarugi1,2*

Department of Biochemical Sciences, University of Florence, V.le Morgagni 50, 50134 Florence, Italy,1 Center 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, Florence, Italy2

Received for publication 27 December 2004. Revision received 16 February 2005. Accepted for publication 4 May 2005.

Abstract: Src tyrosine kinases are central components of adhesive responses and are required for cell spreading onto the extracellular matrix. Among other intracellular messengers elicited by integrin ligation are reactive oxygen species, which act as synergistic mediators of cytoskeleton rearrangement and cell spreading. We report that after integrin ligation, the tyrosine kinase Src is oxidized and activated. Src displays an early activation phase, concurrent with focal adhesion formation and driven mainly by Tyr527 dephosphorylation, and a late phase, concomitant with reactive oxygen species production, cell spreading, and integrin-elicited kinase oxidation. In addition, our results suggest that reactive oxygen species are key mediators of in vitro and in vivo v-Src tumorigenic properties, as both antioxidant treatments and the oxidant-insensitive C245A and C487A Src mutants greatly decrease invasivity, serum-independent and anchorage-independent growth, and tumor onset. Therefore we propose that, in addition to the known phosphorylation/dephosphorylation circuitry, redox regulation of Src activity is required during both cell attachment to the extracellular matrix and tumorigenesis.

* Corresponding author. Mailing address: Dipartimento di Scienze Biochimiche, Viale Morgagni 50, 50134 Firenze, Italy. Phone: 39-055-4598343. Fax: 39-055-4498905. E-mail: paola.chiarugi{at}unifi.it.

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

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