Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2

Maria Perander; Rania Al-Mahdi; Thomas C. Jensen; Jennifer A. L. Nunn; Hanne Kildalsen; Bjarne Johansen; Mads Gabrielsen; Stephen M. Keyse; Ole-Morten Seternes

doi:10.1038/srep43471

Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2

Maria Perander, Rania Al-Mahdi, Thomas C. Jensen, Jennifer A. L. Nunn, Hanne Kildalsen, Bjarne Johansen, Mads Gabrielsen, Stephen M. Keyse, Ole-Morten Seternes (Lead / Corresponding author)

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Abstract

The atypical MAP kinases ERK3 and ERK4 are activated by phosphorylation of a serine residue lying within the activation loop signature sequence S-E-G. However, the regulation of ERK3 and ERK4 phosphorylation and activity is poorly understood. Here we report that the inducible nuclear dualspecificity MAP kinase phosphatase (MKP) DUSP2, a known regulator of the ERK and p38 MAPKs, is unique amongst the MKP family in being able to bind to both ERK3 and ERK4. This interaction is mediated by a conserved common docking (CD) domain within the carboxyl-terminal domains of ERK3 and ERK4 and the conserved kinase interaction motif (KIM) located within the non-catalytic amino terminus of DUSP2. This interaction is direct and results in the dephosphorylation of ERK3 and ERK4 and the stabilization of DUSP2. In the case of ERK4 its ability to stabilize DUSP2 requires its kinase activity. Finally, we demonstrate that expression of DUSP2 inhibits ERK3 and ERK4-mediated activation of its downstream substrate MK5. We conclude that the activity of DUSP2 is not restricted to the classical MAPK pathways and that DUSP2 can also regulate the atypical ERK3/4-MK5 signalling pathway in mammalian cells.

Original language	English
Article number	43471
Pages (from-to)	1-13
Number of pages	13
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/srep43471
Publication status	Published - 2 Mar 2017

Keywords

MAPK
DUSP phosphatases
cell signalling
protein kinases
dephoshorylation
protein-protein interaction

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10.1038/srep43471Licence: CC BY

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Final published version, 2.42 MBLicence: CC BY

Keyse, Stephen
- Cancer Research - Emeritus Professor
Person: Honorary

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title = "Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2",

abstract = "The atypical MAP kinases ERK3 and ERK4 are activated by phosphorylation of a serine residue lying within the activation loop signature sequence S-E-G. However, the regulation of ERK3 and ERK4 phosphorylation and activity is poorly understood. Here we report that the inducible nuclear dualspecificity MAP kinase phosphatase (MKP) DUSP2, a known regulator of the ERK and p38 MAPKs, is unique amongst the MKP family in being able to bind to both ERK3 and ERK4. This interaction is mediated by a conserved common docking (CD) domain within the carboxyl-terminal domains of ERK3 and ERK4 and the conserved kinase interaction motif (KIM) located within the non-catalytic amino terminus of DUSP2. This interaction is direct and results in the dephosphorylation of ERK3 and ERK4 and the stabilization of DUSP2. In the case of ERK4 its ability to stabilize DUSP2 requires its kinase activity. Finally, we demonstrate that expression of DUSP2 inhibits ERK3 and ERK4-mediated activation of its downstream substrate MK5. We conclude that the activity of DUSP2 is not restricted to the classical MAPK pathways and that DUSP2 can also regulate the atypical ERK3/4-MK5 signalling pathway in mammalian cells. ",

keywords = "MAPK, DUSP phosphatases, cell signalling, protein kinases, dephoshorylation, protein-protein interaction",

author = "Maria Perander and Rania Al-Mahdi and Jensen, {Thomas C.} and Nunn, {Jennifer A. L.} and Hanne Kildalsen and Bjarne Johansen and Mads Gabrielsen and Keyse, {Stephen M.} and Ole-Morten Seternes",

note = "We are grateful to Prof. Philip Cohen and the protein production and antibody purification teams [Division of Signal Transduction Therapy (DSTT), University of Dundee] co-coordinated by Hilary McLauchlan and James Hastie and Prof. Terje Johansen (University of Tromsoe) for antibodies. The work was supported by The National Programme for Research in Functional Genomics in Norway (FUGE) of The Research Council of Norway, the Norwegian Cancer Society, the Blix Family Foundation, Northern Norway Regional Health Authority/Helse Nord RHF and the Aakre foundation (to O.M.S). Research in the CR-UK Stress Response Laboratory is supported by Cancer Research UK Program Grant C8227/A12053 (to S. M. K.).",

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AU - Perander, Maria

AU - Al-Mahdi, Rania

AU - Jensen, Thomas C.

AU - Nunn, Jennifer A. L.

AU - Kildalsen, Hanne

AU - Johansen, Bjarne

AU - Gabrielsen, Mads

AU - Keyse, Stephen M.

AU - Seternes, Ole-Morten

N1 - We are grateful to Prof. Philip Cohen and the protein production and antibody purification teams [Division of Signal Transduction Therapy (DSTT), University of Dundee] co-coordinated by Hilary McLauchlan and James Hastie and Prof. Terje Johansen (University of Tromsoe) for antibodies. The work was supported by The National Programme for Research in Functional Genomics in Norway (FUGE) of The Research Council of Norway, the Norwegian Cancer Society, the Blix Family Foundation, Northern Norway Regional Health Authority/Helse Nord RHF and the Aakre foundation (to O.M.S). Research in the CR-UK Stress Response Laboratory is supported by Cancer Research UK Program Grant C8227/A12053 (to S. M. K.).

PY - 2017/3/2

Y1 - 2017/3/2

N2 - The atypical MAP kinases ERK3 and ERK4 are activated by phosphorylation of a serine residue lying within the activation loop signature sequence S-E-G. However, the regulation of ERK3 and ERK4 phosphorylation and activity is poorly understood. Here we report that the inducible nuclear dualspecificity MAP kinase phosphatase (MKP) DUSP2, a known regulator of the ERK and p38 MAPKs, is unique amongst the MKP family in being able to bind to both ERK3 and ERK4. This interaction is mediated by a conserved common docking (CD) domain within the carboxyl-terminal domains of ERK3 and ERK4 and the conserved kinase interaction motif (KIM) located within the non-catalytic amino terminus of DUSP2. This interaction is direct and results in the dephosphorylation of ERK3 and ERK4 and the stabilization of DUSP2. In the case of ERK4 its ability to stabilize DUSP2 requires its kinase activity. Finally, we demonstrate that expression of DUSP2 inhibits ERK3 and ERK4-mediated activation of its downstream substrate MK5. We conclude that the activity of DUSP2 is not restricted to the classical MAPK pathways and that DUSP2 can also regulate the atypical ERK3/4-MK5 signalling pathway in mammalian cells.

AB - The atypical MAP kinases ERK3 and ERK4 are activated by phosphorylation of a serine residue lying within the activation loop signature sequence S-E-G. However, the regulation of ERK3 and ERK4 phosphorylation and activity is poorly understood. Here we report that the inducible nuclear dualspecificity MAP kinase phosphatase (MKP) DUSP2, a known regulator of the ERK and p38 MAPKs, is unique amongst the MKP family in being able to bind to both ERK3 and ERK4. This interaction is mediated by a conserved common docking (CD) domain within the carboxyl-terminal domains of ERK3 and ERK4 and the conserved kinase interaction motif (KIM) located within the non-catalytic amino terminus of DUSP2. This interaction is direct and results in the dephosphorylation of ERK3 and ERK4 and the stabilization of DUSP2. In the case of ERK4 its ability to stabilize DUSP2 requires its kinase activity. Finally, we demonstrate that expression of DUSP2 inhibits ERK3 and ERK4-mediated activation of its downstream substrate MK5. We conclude that the activity of DUSP2 is not restricted to the classical MAPK pathways and that DUSP2 can also regulate the atypical ERK3/4-MK5 signalling pathway in mammalian cells.

KW - MAPK

KW - DUSP phosphatases

KW - cell signalling

KW - protein kinases

KW - dephoshorylation

KW - protein-protein interaction

U2 - 10.1038/srep43471

DO - 10.1038/srep43471

M3 - Article

C2 - 28252035

SN - 2045-2322

VL - 7

SP - 1

EP - 13

JO - Scientific Reports

JF - Scientific Reports

M1 - 43471

ER -

Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2

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Keyse, Stephen

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