Mitogen-activated protein kinase phosphatase 2 regulates histone H3 phosphorylation via interaction with vaccinia-related kinase 1

Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate MAP kinase signaling. However, MKP2 functions are still largely unknown. In this study, we showed that MKP2 could regulate histone H3 phosphorylation under oxidative stress conditions. We found that MKP2 inhibited histone H3 phosphorylation by suppressing vaccinia-related kinase 1 (VRK1) activity. Moreover, this regulation was dependent on the selective interaction with VRK1, regardless of its phosphatase activity. The interaction between MKP2 and VRK1 mainly occurred in the chromatin, where histones are abundant. We also observed that the protein level of MKP2 and its interaction with histone H3 increased from G1 to M phase during the cell cycle, which is similar to the VRK1 profile. Furthermore, MKP2 specifically regulated the VRK1-mediated histone H3 phosphorylation at M phase. Taken together, these data suggest a novel function of MKP2 as a negative regulator of VRK1-mediated histone H3 phosphorylation.

Download Full-text

Genomic instability and histone H3 phosphorylation induction by the Ras-mitogen activated protein kinase pathway in pancreatic cancer cells

International Journal of Cancer ◽

10.1002/ijc.23959 ◽

2009 ◽

Vol 124 (3) ◽

pp. 562-567 ◽

Cited By ~ 11

Author(s):

Paula S. Espino ◽

Susan Pritchard ◽

Henry H.Q. Heng ◽

James R. Davie

Keyword(s):

Pancreatic Cancer ◽

Protein Kinase ◽

Genomic Instability ◽

Histone H3 ◽

Mitogen Activated Protein Kinase ◽

Pancreatic Cancer Cells ◽

H3 Phosphorylation ◽

Mitogen Activated Protein ◽

Histone H3 Phosphorylation ◽

Kinase Pathway

Download Full-text

Mitogen-Activated Protein Kinase Cascade-Mediated Histone H3 Phosphorylation Is Critical for Telomerase Reverse Transcriptase Expression/Telomerase Activation Induced by Proliferation

Molecular and Cellular Biology ◽

10.1128/mcb.26.1.230-237.2006 ◽

2006 ◽

Vol 26 (1) ◽

pp. 230-237 ◽

Cited By ~ 43

Author(s):

Zheng Ge ◽

Cheng Liu ◽

Magnus Björkholm ◽

Astrid Gruber ◽

Dawei Xu

Keyword(s):

T Cells ◽

Protein Kinase ◽

Histone H3 ◽

Telomerase Activity ◽

Mitogen Activated Protein Kinase ◽

Telomerase Reverse Transcriptase ◽

Htert Expression ◽

H3 Phosphorylation ◽

Mitogen Activated Protein ◽

Normal Human

ABSTRACT Telomerase activity and telomerase reverse transcriptase (hTERT), the key component of the telomerase complex, are tightly proliferation regulated in normal and malignant cells both in vitro and in vivo; however, underlying mechanisms are unclear. In the present study, we identified mitogen-activated protein kinase (MAPK) cascade-mediated histone H3 ser10 phosphorylation to be a molecular link between proliferation and induction of hTERT/telomerase activity. In normal human T lymphocytes and fibroblasts, growth or stress stimuli known to drive H3 phosphorylation through the MAPK signaling induce hTERT expression and/or telomerase activity that was preceded by phosphorylated histone H3 (ser10) at the hTERT promoter. Blockade of the MAPK-triggered H3 phosphorylation significantly abrogates hTERT induction and ser10 phosphorylation at this promoter. However, H3 ser10 phosphorylation alone resulted in low, transient hTERT induction, as seen in fibroblasts, whereas H3 phosphorylation followed by its acetylation at lys14 robustly trans-activated the hTERT gene accompanying constitutive telomerase activity in normal and malignant T cells. H3 acetylation without phosphorylation similarly exerted weak effects on hTERT expression. These results define H3 phosphorylation as a key to hTERT transactivation induced by proliferation and reveal a fundamental mechanism for telomerase regulation in both normal human cells and transformed T cells.

Download Full-text

Atf1 Is a Target of the Mitogen-activated Protein Kinase Pmk1 and Regulates Cell Integrity in Fission Yeast

Molecular Biology of the Cell ◽

10.1091/mbc.e07-03-0282 ◽

2007 ◽

Vol 18 (12) ◽

pp. 4794-4802 ◽

Cited By ~ 40

Author(s):

Hirofumi Takada ◽

Masayuki Nishimura ◽

Yuta Asayama ◽

Yoshiaki Mannse ◽

Shunji Ishiwata ◽

...

Keyword(s):

Protein Kinase ◽

Fission Yeast ◽

Mapk Pathway ◽

Mapk Signaling ◽

Negative Regulator ◽

Mitogen Activated Protein Kinase ◽

Mrna Levels ◽

Cell Integrity ◽

Dual Specificity ◽

Mitogen Activated Protein

In fission yeast, knockout of the calcineurin gene resulted in hypersensitivity to Cl−, and the overexpression of pmp1+ encoding a dual-specificity phosphatase for Pmk1 mitogen-activated protein kinase (MAPK) or the knockout of the components of the Pmk1 pathway complemented the Cl− hypersensitivity of calcineurin deletion. Here, we showed that the overexpression of ptc1+ and ptc3+, both encoding type 2C protein phosphatase (PP2C), previously known to inactivate the Wis1–Spc1–Atf1 stress-activated MAPK signaling pathway, suppressed the Cl− hypersensitivity of calcineurin deletion. We also demonstrated that the mRNA levels of these two PP2Cs and pyp2+, another negative regulator of Spc1, are dependent on Pmk1. Notably, the deletion of Atf1, but not that of Spc1, displayed hypersensitivity to the cell wall-damaging agents and also suppressed the Cl− hypersensitivity of calcineurin deletion, both of which are characteristic phenotypes shared by the mutation of the components of the Pmk1 MAPK pathway. Moreover, micafungin treatment induced Pmk1 hyperactivation that resulted in Atf1 hyperphosphorylation. Together, our results suggest that PP2C is involved in a negative feedback loop of the Pmk1 signaling, and results also demonstrate that Atf1 is a key component of the cell integrity signaling downstream of Pmk1 MAPK.

Download Full-text

Dual-specificity phosphatases regulate mitogen-activated protein kinase signaling in adipocytes in response to inflammatory stress

Cellular Signalling ◽

10.1016/j.cellsig.2018.10.011 ◽

2019 ◽

Vol 53 ◽

pp. 234-245 ◽

Cited By ~ 5

Author(s):

Bradley S. Ferguson ◽

Heesun Nam ◽

Ron F. Morrison

Keyword(s):

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Kinase Signaling ◽

Inflammatory Stress ◽

Dual Specificity ◽

Mitogen Activated Protein ◽

Dual Specificity Phosphatases ◽

Protein Kinase Signaling

Download Full-text

Dual Specificity Mitogen-Activated Protein Kinase Kinase 4

10.32388/y89j9z ◽

2020 ◽

Author(s):

Keyword(s):

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Dual Specificity ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

Download Full-text

Protein kinase A acts at multiple points to inhibit Xenopus oocyte maturation

Molecular and Cellular Biology ◽

10.1128/mcb.14.7.4419-4426.1994 ◽

1994 ◽

Vol 14 (7) ◽

pp. 4419-4426

Author(s):

W Matten ◽

I Daar ◽

G F Vande Woude

Keyword(s):

Protein Kinase ◽

Xenopus Oocytes ◽

Negative Regulator ◽

Mitogen Activated Protein Kinase ◽

Mobility Shift ◽

Dependent Protein Kinase ◽

Multiple Points ◽

Mitogen Activated Protein ◽

Dependent Protein ◽

Phosphatase Activation

In Xenopus oocytes, initiation of maturation is dependent on reduction of cyclic AMP-dependent protein kinase (PKA) activity and the synthesis of the mos proto-oncogene product. Mos is required during meiosis I for the activation of both maturation-promoting factor (MPF) and mitogen-activated protein kinase (MAPK). Here we show that injection of the catalytic subunit of PKA (PKAc) prevented progesterone-induced synthesis of endogenous Mos as well as downstream MPF and MAPK activation. However, PKAc did not prevent injected soluble Mos product from activating MAPK. While MAPK is activated during Mos-PKAc coinjection, attendant MPF activation is blocked. Additionally, PKAc caused a potent block in the electrophoretic mobility shift of cdc25 that is associated with phosphatase activation. This inhibition of cdc25 activity was not reversed by progesterone, Mos, or MPF. We conclude that PKAc acts as a negative regulator at several points in meiotic maturation by preventing both Mos translation and MPF activation.

Download Full-text

Two human cDNAs, including a homolog of Arabidopsis FUS6 (COP11), suppress G-protein- and mitogen-activated protein kinase-mediated signal transduction in yeast and mammalian cells.

Molecular and Cellular Biology ◽

10.1128/mcb.16.12.6698 ◽

1996 ◽

Vol 16 (12) ◽

pp. 6698-6706 ◽

Cited By ~ 81

Author(s):

B H Spain ◽

K S Bowdish ◽

A R Pacal ◽

S F Staub ◽

D Koo ◽

...

Keyword(s):

Signal Transduction ◽

Protein Kinase ◽

G Protein ◽

Mammalian Cells ◽

Enhanced Recovery ◽

Negative Regulator ◽

Mitogen Activated Protein Kinase ◽

Striking Similarity ◽

Protein Subunit ◽

Mitogen Activated Protein

We have isolated two novel human cDNAs, gps1-1 and gps2, that suppress lethal G-protein subunit-activating mutations in the pheromone response pathway of the yeast Saccharomyces cerevisiae. Suppression of other pathway-activating events was examined. In wild-type cells, expression of either gps1-1 or gps2 led to enhanced recovery from cell cycle arrest induced by pheromone. Sequence analysis indicated that gps1-1 contains only the carboxy-terminal half of the gps1 coding sequence. The predicted gene product of gps1 has striking similarity to the protein encoded by the Arabidopsis FUS6 (COP11) gene, a negative regulator of light-mediated signal transduction that is known to be essential for normal development. A chimeric construct containing gps1 and FUS6 sequences also suppressed the yeast pheromone pathway, indicating functional conservation between these human and plant genes. In addition, when overexpressed in mammalian cells, gps1 or gps2 potently suppressed a RAS- and mitogen-activated protein kinase-mediated signal and interfered with JNK activity, suggesting that signal repression is part of their normal function. For gps1, these results are consistent with the proposed function of FUS6 (COP11) as a signal transduction repressor in plants.

Download Full-text