Editors' ChoiceBiochemistry

New connections: Redox regulation of kinases

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Science Signaling  21 Jul 2020:
Vol. 13, Issue 641, eabd8558
DOI: 10.1126/scisignal.abd8558

Several studies glean insight into how kinases are structurally regulated by reversible oxidation.

Reactive oxygen species (ROS) are a normal byproduct of cellular respiration and metabolism, but disturbances in the reduction-oxidation balance (redox state) in cells can cause oxidative stress and altered cell signaling that contribute to various pathologies. Redox signaling is mediated, in part, through modification of cysteine residues in proteins. In the Archives, Byrne et al. and Shrestha et al. together showed that an activation loop cysteine, Cys290, was evolutionarily conserved across the eukaryotic kinome and enabled redox regulation of kinase activity. Byrne et al. found that the function of various mitotic kinases, such as Aurora A, was inhibited by ROS-associated agents and facilitated by reducing agents. Shrestha et al. found that conserved cysteines within the diabetes-associated metabolic kinase FN3K acted as a redox-regulated switch that altered its functional oligomerization and, consequently, the broader cellular redox status. In this issue of Science Signaling, Lim et al. focused on Aurora A. Because its activity promotes cell division, targeting Aurora A is of interest for treating cancer patients. Upon screening for Cys-binding compounds that inhibited the kinase, the authors then explored how such adducts affected the conformation and, consequently, the activation of Aurora A. One of these compounds, Coenzyme A, resulted in two dimerized structures—one in which the conserved Cys290 was CoAlated and the activation (autophosphorylation) site was in an “open” conformation, and a second that lacked CoAlation but was in an “active” conformation. These structures suggest that CoAlation may promote Aurora A activation by generating an intermediate structure that facilitates its autophosphorylation. Thus, compounds that block CoAlation may inhibit Aurora A in tumors. Although the three studies are consistent in showing that redox modification of kinases underscores their function in broad and critical cellular processes, differences among the studies reveal that such regulation is not straightforward.Adding to the complexity are the findings from Behring et al., further back in the Archives of 2020. There, the authors found not only that ligand binding–induced activation of the growth factor receptor EGFR stimulated the generation of localized ROS, which oxidizes cysteines in proteins of the EGFR pathway, but also that EGFR-mediated phosphorylation of these proteins altered their conformation such that ROS-target cysteines became accessible—and susceptible—to redox regulation. These cysteines were buried and inaccessible in the absence of EGF. These findings indicate that redox regulation of proteins is not solely conditioned upon intracellular redox status, but also upon protein activation status. Thus, altogether the functional effects of oxidative stress on kinase signaling appear to be dependent on spatiotemporal factors as well as interdependent with phosphorylation. Further exploration of this previously underappreciated posttranslational modification is likely to create landmark shifts in our understanding of cellular biology, physiology, and the clinical implications thereof.

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