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Proteomic analysis of ERK1/2-mediated human sickle red blood cell membrane protein phosphorylation.

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Date
2013-01-03
Authors
Soderblom, Erik J
Thompson, J Will
Schwartz, Evan A
Chiou, Edward
Dubois, Laura G
Moseley, M Arthur
Zennadi, Rahima
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Abstract
UNLABELLED: BACKGROUND: In sickle cell disease (SCD), the mitogen-activated protein kinase (MAPK) ERK1/2 is constitutively active and can be inducible by agonist-stimulation only in sickle but not in normal human red blood cells (RBCs). ERK1/2 is involved in activation of ICAM-4-mediated sickle RBC adhesion to the endothelium. However, other effects of the ERK1/2 activation in sickle RBCs leading to the complex SCD pathophysiology, such as alteration of RBC hemorheology are unknown. RESULTS: To further characterize global ERK1/2-induced changes in membrane protein phosphorylation within human RBCs, a label-free quantitative phosphoproteomic analysis was applied to sickle and normal RBC membrane ghosts pre-treated with U0126, a specific inhibitor of MEK1/2, the upstream kinase of ERK1/2, in the presence or absence of recombinant active ERK2. Across eight unique treatment groups, 375 phosphopeptides from 155 phosphoproteins were quantified with an average technical coefficient of variation in peak intensity of 19.8%. Sickle RBC treatment with U0126 decreased thirty-six phosphopeptides from twenty-one phosphoproteins involved in regulation of not only RBC shape, flexibility, cell morphology maintenance and adhesion, but also glucose and glutamate transport, cAMP production, degradation of misfolded proteins and receptor ubiquitination. Glycophorin A was the most affected protein in sickle RBCs by this ERK1/2 pathway, which contained 12 unique phosphorylated peptides, suggesting that in addition to its effect on sickle RBC adhesion, increased glycophorin A phosphorylation via the ERK1/2 pathway may also affect glycophorin A interactions with band 3, which could result in decreases in both anion transport by band 3 and band 3 trafficking. The abundance of twelve of the thirty-six phosphopeptides were subsequently increased in normal RBCs co-incubated with recombinant ERK2 and therefore represent specific MEK1/2 phospho-inhibitory targets mediated via ERK2. CONCLUSIONS: These findings expand upon the current model for the involvement of ERK1/2 signaling in RBCs. These findings also identify additional protein targets of this pathway other than the RBC adhesion molecule ICAM-4 and enhance the understanding of the mechanism of small molecule inhibitors of MEK/1/2/ERK1/2, which could be effective in ameliorating RBC hemorheology and adhesion, the hallmarks of SCD.
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Journal article
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https://hdl.handle.net/10161/11163
Published Version (Please cite this version)
10.1186/1559-0275-10-1
Publication Info
Soderblom, Erik J; Thompson, J Will; Schwartz, Evan A; Chiou, Edward; Dubois, Laura G; Moseley, M Arthur; & Zennadi, Rahima (2013). Proteomic analysis of ERK1/2-mediated human sickle red blood cell membrane protein phosphorylation. Clin Proteomics, 10(1). pp. 1. 10.1186/1559-0275-10-1. Retrieved from https://hdl.handle.net/10161/11163.
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Scholars@Duke

Moseley

Martin Arthur Moseley III

Adjunct Professor in the Department of Cell Biology
Soderblom

Erik James Soderblom

Associate Research Professor of Cell Biology
Director, Proteomics and Metabolomics Core Facility
Thompson

J. Will Thompson

Adjunct Assistant Professor in the Department of Pharmacology & Cancer Biology
Dr. Thompson's research focuses on the development and deployment of proteomics and metabolomics mass spectrometry techniques for the analysis of biological systems. He served as the Assistant Director of the Proteomics and Metabolomics Shared Resource in the Duke School of Medicine from 2007-2021. He currently maintains collaborations in metabolomics and proteomics research at Duke, and develops new tools for chemical analysis as a Princi
Zennadi

Rahima Zennadi

Associate Professor in Medicine
My research in Hematology addresses three areas of investigation: disorders associated with sickle cell disease pathophysiology, venous thrombosis/thromboembolism (VT/E) associated with aging, and cerebrovascular injury. In sickle cell disease, vaso-occlusion leads to serious life-threatening complications, including acute pain crises and irreversible organ damage.  Vaso-occlusion is caused largely by sickle red blood cell adhesion to the vascular endothelium.  Prevention of
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