Endogenous, regulatory cysteine sulfenylation of ERK kinases in response to proliferative signals

Jeremiah D. Keyes, Derek Parsonage, Rama D. Yammani, Le Ann C. Rogers, Chelsea Kesty, Cristina M. Furdui, Kimberly J. Nelson, Leslie B. Poole

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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 80–90%, underscoring the importance of considering this additional modification when assessing ERK activation in response to extracellular signals.

Original languageEnglish (US)
Pages (from-to)534-543
Number of pages10
JournalFree Radical Biology and Medicine
Volume112
DOIs
StatePublished - Nov 2017

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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