The carboxyl-terminal domains of MKP-1 and MKP-2 have inhibitory effects on their phosphatase activity

Mol Cell Biochem. 2002 Apr;233(1-2):107-17. doi: 10.1023/a:1015502226940.


Both the mitogen-activated protein kinase (MAPK) phosphatases MKP-1 and MKP-2 exert important feedback control of MAPK-mediated signaling events. The function of MKP-1 and MKP-2 is regulated via complex mechanisms, ranging from increased transcription of the MKP-1 and MKP-2 genes to post-translational catalytic activation of MKP-1 and MKP-2 proteins upon binding to their substrate MAPKs. In addition, MKP-1 stability increases upon ERK-dependent phosphorylation of two serine residues in its C-terminus. The C-terminal regions of MKP-1 and MKP-2, but not those of other MKPs, are homologous. To investigate the role of this domain, we have deleted the C-terminal tails from MKP-1 and MKP-2 and examined the effect of these deletions on their enzymatic activity. C-terminally truncated MKP-1 and MKP-2 exhibited, both in vivo and in vitro, substantially greater phosphatase activity towards their substrate MAPKs than did the full-length counterparts. However, C-terminal truncations did not significantly change either their substrate affinity, or their substrate-mediated catalytic activation. Basal phosphatase activity of the truncated proteins was also significantly higher than that of the wild-type counterparts. Collectively, these results suggest that the C-terminal domain may potentially play a role in the regulation of MKP-1 and MKP-2.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Catalytic Domain
  • Cell Cycle Proteins*
  • Dual Specificity Phosphatase 1
  • Gene Deletion
  • Glutathione Transferase / metabolism
  • Immediate-Early Proteins / metabolism*
  • In Vitro Techniques
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / immunology
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / immunology
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Sequence Data
  • Nitrophenols / metabolism
  • Organophosphorus Compounds / metabolism
  • Phosphoprotein Phosphatases*
  • Phosphorylation
  • Plasmids
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Transcription Factor AP-1 / pharmacology
  • Transcription, Genetic
  • Tumor Cells, Cultured / metabolism*


  • Cell Cycle Proteins
  • Immediate-Early Proteins
  • Nitrophenols
  • Organophosphorus Compounds
  • Recombinant Fusion Proteins
  • Transcription Factor AP-1
  • nitrophenylphosphate
  • Glutathione Transferase
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • Dual Specificity Phosphatase 1
  • Protein Tyrosine Phosphatases