title: The carboxyl-terminal domains of MKP-1 and MKP-2 have inhibitory effects on their phosphatase activity.
abstract: 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.
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hutter
authors.forename: Peili
authors.initials: P
authors.lastname: Chen
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.forename: Janice
authors.initials: J
authors.lastname: Barnes
authors.forename: Yusen
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D020134:Catalytic Domain; D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D009596:Nitrophenols / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D010957:Plasmids; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D018808:Transcription Factor AP-1 / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; C008644:nitrophenylphosphate; D005982:Glutathione Transferase; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases