Electronic versions


  • Robin J Dickinson
    University of Dundee
  • Laurent Delavaine
    University of Dundee
  • Rocío Cejudo-Marín
    Centro de Investigación Príncipe Felipe, Malaga
  • Graeme Stewart
    University of Dundee
  • Christopher J Staples
    University of Dundee
  • Mark P Didmon
    University of Dundee
  • Antonio Garcia Trinidad
    Universidad de Valladolid
  • Andrés Alonso
    Universidad de Valladolid
  • Rafael Pulido
    Centro de Investigación Príncipe Felipe, Malaga
  • Stephen M Keyse
    University of Dundee

MAP kinase phosphatase 4 (DUSP9/MKP-4) plays an essential role during placental development and is one of a subfamily of three closely related cytoplasmic dual-specificity MAPK phosphatases, which includes the ERK-specific enzymes DUSP6/MKP-3 and DUSP7/MKP-X. However, unlike DUSP6/MKP-3, DUSP9/MKP-4 also inactivates the p38α MAP kinase both in vitro and in vivo. Here we demonstrate that inactivation of both ERK1/2 and p38α by DUSP9/MKP-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. Furthermore, DUSP9/MKP-4 is unique among these cytoplasmic MKPs in containing a conserved PKA consensus phosphorylation site (55)RRXSer-58 immediately adjacent to the kinase interaction motif. DUSP9/MKP-4 is phosphorylated on Ser-58 by PKA in vitro, and phosphorylation abrogates the binding of DUSP9/MKP-4 to both ERK2 and p38α MAP kinases. In addition, although mutation of Ser-58 to either alanine or glutamic acid does not affect the intrinsic catalytic activity of DUSP9/MKP-4, phospho-mimetic (Ser-58 to Glu) substitution inhibits both the interaction of DUSP9/MKP-4 with ERK2 and p38α in vivo and its ability to dephosphorylate and inactivate these MAP kinases. Finally, the use of a phospho-specific antibody demonstrates that endogenous DUSP9/MKP-4 is phosphorylated on Ser-58 in response to the PKA agonist forskolin and is also modified in placental tissue. We conclude that DUSP9/MKP-4 is a bona fide target of PKA signaling and that attenuation of DUSP9/MKP-4 function can mediate cross-talk between the PKA pathway and MAPK signaling through both ERK1/2 and p38α in vivo.


  • Amino Acid Motifs, Animals, COS Cells, Catalysis, Catalytic Domain, Cercopithecus aethiops, Cyclic AMP-Dependent Protein Kinases, Dual-Specificity Phosphatases, Humans, Mice, Mitogen-Activated Protein Kinase Phosphatases, Phosphorylation, Recombinant Proteins, Signal Transduction, p38 Mitogen-Activated Protein Kinases, Journal Article, Research Support, Non-U.S. Gov't
Original languageEnglish
Pages (from-to)38018-26
Number of pages9
JournalJournal of Biological Chemistry
Issue number44
Publication statusPublished - 4 Nov 2011
Externally publishedYes
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