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Published 9 June 2003. doi:10.1083/jcb.200211118
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© The Rockefeller University Press, 0021-9525/2003/6/933 $5.00
The Journal of Cell Biology, Volume 161, Number 5, 933-944

Article

Reactive oxygen species as essential mediators of cell adhesion

: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion



Paola Chiarugi1, Giovambattista Pani2, Elisa Giannoni1, Letizia Taddei1, Renata Colavitti2, Giovanni Raugei1, Mark Symons3, Silvia Borrello2, Tommaso Galeotti2 and Giampietro Ramponi1

1 Department of Biochemical Sciences, University of Florence, 50134 Florence, Italy
2 Institute of General Pathology, Catholic University Medical School, 00168 Rome, Italy
3 Laboratory of Molecular Oncology, Picower Institute for Medical Research, Manhasset, NY 10030

Address correspondence to Giampietro Ramponi, Dipartimento di Scienze Biochimiche, viale Morgagni 50, 50134 Firenze, Italy. Tel.: 39-055-413765. Fax: 39-055-4222725. E-mail: ramponi{at}scibio.unifi.it

Signal transduction by reactive oxygen species (ROS; "redox signaling") has recently come into focus in cellular biology studies. The signaling properties of ROS are largely due to the reversible oxidation of redox-sensitive target proteins, and especially of protein tyrosine phosphatases, whose activity is dependent on the redox state of a low pKa active site cysteine. A variety of mitogenic signals, including those released by receptor tyrosine kinase (RTKs) ligands and oncogenic H-Ras, involve as a critical downstream event the intracellular generation of ROS. Signaling by integrins is also essential for the growth of most cell types and is constantly integrated with growth factor signaling. We provide here evidence that intracellular ROS are generated after integrin engagement and that these oxidant intermediates are necessary for integrin signaling during fibroblast adhesion and spreading. Moreover, we propose a synergistic action of integrins and RTKs for redox signaling. Integrin-induced ROS are required to oxidize/inhibit the low molecular weight phosphotyrosine phosphatase, thereby preventing the enzyme from dephosphorylating and inactivating FAK. Accordingly, FAK phosphorylation and other downstream events, including MAPK phosphorylation, Src phosphorylation, focal adhesion formation, and cell spreading, are all significantly attenuated by inhibition of redox signaling. Hence, we have outlined a redox circuitry whereby, upon cell adhesion, oxidative inhibition of a protein tyrosine phosphatase promotes the phosphorylation/activation and the downstream signaling of FAK and, as a final event, cell adhesion and spreading onto fibronectin.

Key Words: reactive oxygen species; integrin-mediated cell adhesion; Rac; LMW-PTP; focal adhesion kinase

P. Chiarugi and G. Pani contributed equally to this work.

The online version of this article includes supplemental material.

* Abbreviations used in this paper: AA, arachidonic acid; BSO, butionine sulphoximide; DCA-DA, 2',7'-dichlorofluorescein diacetate; DPI, diphenyl iodide; FA, focal adhesion; 5'-F-IAA, 5'-iodoacetamidofluorescein; LMW-PTP, low molecular weight PTP; LOX, 5-lipoxygenase; NAC, N-acetyl-cysteine; NDGA, nordihydroguaiaretic acid; PNPP, p-paranitro phenyl-phosphase; PTP, phosphotyrosine protein phosphatase; ROS, reactive oxygen species; SHP, Src homology phosphatase.


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