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ERK-dependent signaling is key to many pathways through which extracellular signals are transduced into cell-fate decisions. One conundrum is the way in which disparate signals induce specific responses through a common, ERK-dependent kinase cascade. While studies have revealed intricate ways of controlling ERK signaling through spatiotemporal localization and phosphorylation dynamics, additional modes of ERK regulation undoubtedly remain to be discovered. We hypothesized that fine-tuning of ERK signaling could occur by cysteine oxidation. We report that ERK is actively and directly oxidized by signal-generated H2O2 during proliferative signaling, and that ERK oxidation occurs downstream of a variety of receptor classes tested in four cell lines. Furthermore, within the tested cell lines and proliferative signals, we observed that both activation loop-phosphorylated and non-phosphorylated ERK undergo sulfenylation in cells and that dynamics of ERK sulfenylation is dependent on the cell growth conditions prior to stimulation. We also tested the effect of endogenous ERK oxidation on kinase activity and report that phosphotransfer reactions are reversibly inhibited by oxidation by as much as 80 to 90%, underscoring the importance of considering this additional modification when assessing ERK activation in response to extracellular signals.

Background: Treatment of childhood atopic dermatitis (AD) is hindered by nonadherence, but caregiver reassurance may help overcome this hurdle. Objectives: To assess caregivers’ willingness to treat childhood AD with a corticosteroid when presented with clinical trial evidence, anecdote, or both. Methods: A total of 476 caregivers were recruited through a dermatology clinic and online crowdsourcing platform. Subjects were randomized to receive clinical trial evidence, anecdote, or both, using either the term “medication” or “topical steroid.” Additional caregivers were queried about their willingness to treat with the doctor’s recommendation or without knowledge of its safety information. Responses were recorded on a 10-point Likert scale. Results: Caregivers’ willingness to treat was higher in all information assignment groups compared to those not provided with safety information: clinical trial evidence of a “medication” ( P = .003; Cohen’s d = 0.83) or “topical steroid” ( P = .030; d = 0.55), anecdote of a “medication” ( P < .0001; d = 1.37) or “topical steroid” ( P < .0001; d = 0.85), both clinical trial evidence and anecdote of a “medication” ( P < .0001; d = 1.00) or “topical steroid” ( P = .000; d = 0.89), and simply the doctor’s recommendation ( P < .0001; d = 0.92). Significance was corrected for multiple comparisons to 0.0018. There were no differences between caregivers of children with and without AD ( P = .36). Conclusions: Providing anecdotal reassurance, even in the setting of reported high willingness to treat with the doctor’s recommendation, may be an effective strategy to improve caregivers’ perceptions of starting new medications.

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