Authors

Anthony E. Postiglione, North Carolina Agricultural and Technical State University
Laquaundra L. Adams, North Carolina Agricultural and Technical State University
Ese S. Ekhator, North Carolina Agricultural and Technical State University
Anuoluwapo E. Odelade, North Carolina Agricultural and Technical State University
Supriya Patwardhan, North Carolina Agricultural and Technical State University
Meenal Chaudhari, North Carolina Agricultural and Technical State University
Avery S. Pardue, North Carolina Agricultural and Technical State University
Anjali Kumari, North Carolina Agricultural and Technical State University
William A. LeFever, High Point University
Olivia P. Tornow, High Point University
Tamer S. Kaoud, The University of Texas at Austin
Johnathan Neiswinger, Johns Hopkins School of Medicine
Jun Seop Jeong, North Carolina Agricultural and Technical State University
Derek Parsonage, Wake Forest University School of Medicine
Kimberly J. Nelson, Wake Forest University School of Medicine
Dukka KC, Michigan Technological UniversityFollow
Cristina M. Furdui, Wake Forest University School of Medicine
Heng Zhu, Johns Hopkins School of Medicine
Andrew J. Wommack, High Point University
Kevin N. Dalby, The University of Texas at Austin
Ming Dong, North Carolina Agricultural and Technical State University
Leslie B. Poole, Wake Forest University School of Medicine
Jeremiah D. Keyes, Wake Forest University School of Medicine
Robert H. Newman, North Carolina Agricultural and Technical State University

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.

Publisher's Statement

© 2023 The Authors. Publisher’s version of record: https://doi.org/10.1016/j.isci.2023.107817

Publication Title

iScience

Version

Publisher's PDF

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