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Activity independent regulation of Vaccinia-Related Kinase 1 (VRK1) by Mitogen Activated Kinase Phosphatase 2 (MKP2)

Title
Activity independent regulation of Vaccinia-Related Kinase 1 (VRK1) by Mitogen Activated Kinase Phosphatase 2 (MKP2)
Authors
정민우
Date Issued
2013
Publisher
포항공과대학교
Abstract
Cells organize their DNA by forming chromatins composed of core histones and DNA. The different levels of DNA organization can be controlled by post-translational modification of histone tails
acetylation, methylation, ADP-ribosylation, ubiquitination and phosphorylation. The phosphorylations of histone H3 at the threonine 3 and serine 10 residues are crucial for chromosome condensation and cell cycle progression during mitosis. Despite the importance of the histone H3 phosphorylation in the cell cycle progression, the regulatory mechanisms are still unclear and only a few proteins are discovered for mitotic histone H3 kinase or phosphatase including Haspin, Aurora kinase B, and Vaccinia-related kinase 1(VRK1). VRK proteins are a class of mammalian Ser/Thr kinase enzymes those have similarity to the B1R Ser/Thr kinase protein of vaccinia virus. Since the VRKs had found in 1997, their in vivo functions and structures are still remained as enigmas. VRK1 is highly expressed in proliferating tissues and is known to phosphorylate transcription factors like p53, Activating transcription factor 2 (ATF2), c-Jun in vitro and Barrier-to-autointegration factor-1 (BAF-1) in C. elegans. Previously, our group discovered VRK1 as a novel mitotic histone H3 kinase phosphorylating Thr3 and Ser10 to condense chromatin and cause cell cycle progression. Therefore, I tried to identify binding partners of VRK1 to find the regulatory proteins of VRK1 for the first step. I could successfully identify Mitogen-activated protein kinase phosphatase 2 (MKP2) as a novel binding partner of VRK1. The main action of MKP2 is dephosphorylating the Mitogen-activated protein kinases (MAPKs) like Extracelluar signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. The possibility that MKP2 regulates VRK1 function on histone H3 phosphorylation has been tested. MKP2 specifically blocked VRK1-mediated phosphorylation of histone H3 regardless of its phosphatase activity. However, MKP2 failed to directly act on phosphorylated histone H3, implying that blockage of histone H3 phosphorylation is due to inhibition of VRK1 by MKP2. I also discovered that MKP2 overexpression caused a decrease in histone H3 phosphorylation and inhibition of cell cycle progression. The MKP2 expression and interaction to histone H3 with VRK1 were increased following the cell cycle progression G1 phase to G2/M phase. Furthermore, the knock-down of MKP2 showed the increased phosphorylation of histone H3 in G2/M phase arrested cells. Together, these results demonstrate that MKP2 negatively regulates VRK1 activity on histone H3 phosphorylation and is involved in control of the cell cycle.
URI
http://postech.dcollection.net/jsp/common/DcLoOrgPer.jsp?sItemId=000001560770
http://oasis.postech.ac.kr/handle/2014.oak/1862
Article Type
Thesis
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