ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation

Ka-Won Noh; Jihyun Park; Eun Hye Joo; Eun Kyung Lee; Eun Young Choi; Myung-Soo Kang

doi:10.18632/oncotarget.8177

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Research Papers:

ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation

Ka-Won Noh, Jihyun Park, Eun Hye Joo, Eun Kyung Lee, Eun Young Choi and Myung-Soo Kang _

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Oncotarget. 2016; 7:25507-25515. https://doi.org/10.18632/oncotarget.8177

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Abstract

Ka-Won Noh1,*, Jihyun Park1,*, Eun Hye Joo1,*, Eun Kyung Lee1, Eun Young Choi3, Myung-Soo Kang1,2,3

1Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea

2Samsung Biomedical Research Institute (SBRI), Samsung Medical Center and Sungkyunkwan University, Seoul, Korea

3BioMembrane Plasticity Research Center (MPRC), Seoul National University College of Medicine, Jongno-gu, Seoul, Korea

*These authors have contributed equally to this work

Correspondence to:

Myung-Soo Kang, e-mail: [email protected], [email protected]

Keywords: Epstein-Barr virus, EBNA1, ERK, phosphorylation, inhibitor

Received: November 19, 2015 Accepted: February 29, 2016 Published: March 18, 2016

ABSTRACT

Functional inhibition of Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) can cause the death of EBV infected cells. In this study, a bioinformatics tool predicted the existence of putative extracellular signal-regulated kinase (ERK) docking and substrate consensus sites on EBNA1, suggesting that ERK2 could bind to and phosphorylate EBNA1. In accordance, ERK2 was found to phosphorylate EBNA1 serine 383 in a reaction suppressed by H20 (a structural congener of the ERK inhibitor), U0126 (an inhibitor of MEK kinase), and mutations at substrate (S383A) or putative ERK docking sites. Wild-type (S383) and phosphomimetic (S383D) EBNA1 demonstrated comparable transactivation function, which was suppressed by H20 or U0126. In contrast, non-phosphorylated EBNA1 mutants displayed significantly impaired transactivation activity. ERK2 knock-down by siRNA, or treatment with U0126 or H20 repressed EBNA1-dependent transactivation.Collectively, these data indicate that blocking ERK2-directed phosphorylation can suppress EBNA1-transactivation function in latent EBV-infected cells, validating ERK2 as a drug target for EBV-associated disorders.

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Research Papers:

ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation

Abstract