Oxidative stress generated by the production of reactive oxygen species (ROS) is recognized as an underlying cause of various inflammatory diseases. While ROS are known to produce deleterious effects, it is increasingly accepted that ROS-induced post-translational modifications of proteins can also play a physiological role in cell signaling. One such modification is the oxidation of cysteine residues in receptor proteins, which affects their activity. 

Results and Discussion

Drosophila epithelia have been used to understand how damage can promote tissue repair and regeneration. The activation of apoptosis to induce damage results in a burst of ROS production that ultimately activates the MAP kinases JNK and p38. These kinases act upstream of Wnt signaling and cytokines, promoting regenerative growth. The kinase ASK1 can act as a link between ROS and the regenerative response. Among the kinases that operate upstream of JNK and p38, ASK1 is particularly sensitive to oxidative stressors.

Additionally, oxidative stress can modify the reduced thiol groups of TNF receptors, promoting ligand-independent signaling of some TNF receptors. The kinase activity of ASK1 is also stimulated by TNF signaling via members of the TNF Receptor-Associated Factor (TRAF) family of adaptor proteins. Upon activation of TNF receptors, TRAFs interact with ASK1, facilitating the transduction of the signal to ASK1 and thereby modulating its activity.

ASK1 can also sense nutrient availability, and this activity is ROS-dependent. The insulin pathway, through its PI3K/Akt signaling kinases, is necessary for ASK1 to activate p38. The PI3K/Akt signaling is also sensitive to ROS.

In summary, we propose a model in which ASK1 functions as a molecular hub that integrates several ROS-dependent signals required for the onset of regeneration.