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 dual-specificity 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.
authors.affiliation: Department of Medical Biology, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Maria
authors.initials: M
authors.lastname: Perander
authors.affiliation: Department of Pharmacy UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Rania
authors.initials: R
authors.lastname: Al-Mahdi
authors.affiliation: Department of Pharmacy UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Jensen
authors.affiliation: Department of Pharmacy UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Jennifer A L
authors.initials: JA
authors.lastname: Nunn
authors.affiliation: Department of Pharmacy UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Hanne
authors.initials: H
authors.lastname: Kildalsen
authors.affiliation: Department of Pharmacy UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Johansen
authors.affiliation: Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, James Arrot Drive, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Mads
authors.initials: M
authors.lastname: Gabrielsen
authors.affiliation: Stress Response Laboratory, Division of Cancer Research, Jacqui Wood Cancer Centre, James Arrot Drive, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Keyse
authors.affiliation: Department of Pharmacy UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Ole-Morten
authors.initials: OM
authors.lastname: Seternes
mesh_terms: D000818:Animals; D016367:Baculoviridae / Q000235:genetics / Q000378:metabolism; D054641:Dual Specificity Phosphatase 2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D019169:Jurkat Cells; D048053:Mitogen-Activated Protein Kinase 6 / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D018411:Spodoptera
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048053:Mitogen-Activated Protein Kinase 6; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2