Reactive oxygen species as essential mediators of cell adhesion

Abstract

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.

Activation of SRC Tyrosine Kinases in Response to ICAM-1 Ligation in Pulmonary Microvascular Endothelial Cells

“…One of the identified downstream targets of ROS is tyrosine phosphatases. ROS cause oxidation of cysteine residues in the tyrosine phosphatase catalytic domain to form a disulfide bond, resulting in the inactivation of tyrosine phosphatases (37)(38)(39)(40)(41). Whether inactivation of tyrosine phosphatases is one of the underlying mechanisms whereby xanthine oxidase-dependent ROS production mediates activation of SRC tyrosine kinases remains to be determined.…”

T cell tyrosine phosphorylation response to transient redox stress

“…Several reports have also demonstrated that ROS mediate leukocytes' recruitment to wounded areas [47][48][49][50]. It has been shown that the Lyn kinase is activated by wound-generated H 2 O 2, inducing the chemotactic movement of leukocytes [51].…”

Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS)

“…Racdependent redox signals have an established role not only in cell proliferation and survival (Joneson and BarSagi, 1998;Bedogni et al, 2003), but also in adhesion, detachment and shape changes, secretion of metalloproteases and epithelial-mesenchimal transition (Kheradmand et al, 1998;Werner and Werb, 2002;Chiarugi et al, 2003;Radisky et al, 2005), all responses integral to the invasive and metastatic behavior of malignant cells; activation of the Rac-ROS cascade by c-Met therefore appears to be biologically plausible. Interestingly, a redox-sensitive component has been recently identified in the signaling pathway triggered by plexins (Ventura and Pelicci, 2002), a family of molecules known to associate and cooperate with c-Met during invasive growth .…”

“…In fact, several PTPs have been previously reported to associate with the HGF/SF receptors (VillaMoruzzi et al, 1998;Maroun et al, 2000;Palka et al, 2003) and to modulate its downstream signaling pathways. Moreover, preliminary evidence suggests physical association between c-Met and the low molecular weight protein tyrosine phoshatase (LMW-PTP; data not shown), an enzyme exquisitely sensitive to redox modulation by growth factors and integrins (Chiarugi et al, 2003;Nimnual et al, 2003), and able to restrain ligand-dependent activation of MAP kinases (Chiarugi et al, 2003).…”

“…The Rac/ ROS signaling module has been convincingly shown to contribute to mitogenic signaling by PDGF (Sundaresan et al, 1995), EGF (Bae et al, 1997;Pani et al, 2000), and VEGF (Colavitti et al, 2002) receptors and by oncogenic H-Ras (Irani et al, 1997;Liu et al, 2001), and to have a role in the antiapoptotic cascade downstream of neurotrophin receptors (Bedogni et al, 2003). Moreover, this signaling cassette is robustly activated by integrins upon cell-matrix interaction (Chiarugi et al, 2003;Nimnual et al, 2003) and is necessary for optimal focal adhesion assembly and for cell spreading of NIH-3T3 cells. In the current model, many of the above effects are mediated, at least in part, by the inhibitory effect of oxidant species on protein tyrosine phophatases on duty for restraining both the strength and the duration of growth factor and integrin signaling (Xu et al, 2002).…”