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

Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.
Molecular and Cellular Biochemistry (Impact Factor: 2.39). 05/2002; 233(1-2):107-17. DOI: 10.1023/A:1015502226940
Source: PubMed


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.

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    • "However, MKP1 transcriptional induction occurs after physiological levels of NMDA receptor activation (Davis et al. 2000), where there is probably no Rsk2 activation (Rakhit et al. 2005), so this mechanism maybe unlikely to explain the feedback action of Rsk2. Equally, we note that MKP1 contains a consensus Rsk phosphorylation site (R-X-X-S) at S334, conserved from rodents to humans, within the MKP1 Cterminal domain – a region that regulates its phosphatase activity (Hutter et al. 2002). It could be speculated that Rsk2- mediated phosphorylation at this site might enhance MKP1 function and thereby suppress subsequent Erk activity. "
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