Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion.
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.
Chiarugi
Paola
P
Department of Biochemical Sciences, University of Florence, Italy.
Pani
Giovambattista
G
Giannoni
Elisa
E
Taddei
Letizia
L
Colavitti
Renata
R
Raugei
Giovanni
G
Symons
Mark
M
Borrello
Silvia
S
Galeotti
Tommaso
T
Ramponi
Giampietro
G
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002462:Cell Membrane / Q000201:enzymology*; D005057:Eukaryotic Cells / Q000166:cytology / Q000201:enzymology*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008970:Molecular Weight; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D005353:Fibronectins; D016023:Integrins; D017382:Reactive Oxygen Species; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases; D020830:rac1 GTP-Binding Protein