Document Type
Article
Publication Date
10-20-2023
Department
Department of Computer Science
Abstract
Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are dysregulated in many pervasive diseases. Recently, we discovered that ERK1/2 is oxidized by signal-generated hydrogen peroxide in various cell types. Since the putative sites of oxidation lie within or near ERK1/2’s ligand-binding surfaces, we investigated how oxidation of ERK2 regulates interactions with the model substrates Sub-D and Sub-F. These studies revealed that ERK2 undergoes sulfenylation at C159 on its D-recruitment site surface and that this modification modulates ERK2 activity differentially between substrates. Integrated biochemical, computational, and mutational analyses suggest a plausible mechanism for peroxide-dependent changes in ERK2-substrate interactions. Interestingly, oxidation decreased ERK2’s affinity for some D-site ligands while increasing its affinity for others. Finally, oxidation by signal-generated peroxide enhanced ERK1/2’s ability to phosphorylate ribosomal S6 kinase A1 (RSK1) in HeLa cells. Together, these studies lay the foundation for examining crosstalk between redox- and phosphorylation-dependent signaling at the level of kinase-substrate selection.
Publication Title
iScience
Recommended Citation
Postiglione, A.,
Adams, L.,
Ekhator, E.,
Odelade, A.,
Patwardhan, S.,
Chaudhari, M.,
Pardue, A.,
Kumari, A.,
LeFever, W.,
Tornow, O.,
Kaoud, T.,
Neiswinger, J.,
Jeong, J.,
Parsonage, D.,
Nelson, K.,
KC, D.,
Furdui, C.,
Zhu, H.,
Wommack, A.,
Dalby, K.,
Dong, M.,
Poole, L.,
Keyes, J.,
&
Newman, R.
(2023).
Hydrogen peroxide-dependent oxidation of ERK2 within its D-recruitment site alters its substrate selection.
iScience,
26(10).
http://doi.org/10.1016/j.isci.2023.107817
Retrieved from: https://digitalcommons.mtu.edu/michigantech-p2/100
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Version
Publisher's PDF
Publisher's Statement
© 2023 The Authors. Publisher’s version of record: https://doi.org/10.1016/j.isci.2023.107817