Disruption of two putative nuclear localization sequences is required for cytosolic localization of mitogen-activated protein kinase phosphatase-2

Callum M. Sloss, Laurence Cadalbert, Stephen G. Finn, Stephen J. Fuller, Robin Plevin

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

MAP kinase phosphatase-2 (MKP-2) is a member of a family of dual specificity phosphatases (DSPs) that function in both the cytosol and nucleus to inactivate the MAP kinases. The mechanism that controls the subcellular distribution of these proteins is currently unclear. In this study, we have used site-directed mutagenesis to remove two novel nuclear localization sequences, NLS-1 and -2, either alone or in combination (DNLS). Loss of NLS-1 or NLS-2 alone did not alter the nuclear targeting of MKP-2 but mutation of both resulted in MKP-2 being retained within the cytosol. Furthermore, whilst expression of WT-MKP-2, NLS-1 or NLS-2 reduced both sorbitol- or UV-stimulated nuclear c-Jun N-terminal kinase (JNK) activity in HEK293 cells, this effect was absent in cells expressing DNLS-MKP-2. Similarly, transient transfection of WT-MKP-2, NLS-1 or NLS-2, but not DNLS-MKP-2 was able to substantially reduce agonist-stimulated ANF reporter activity in rat cardiac myocytes. Taken together, these results indicate that whilst both novel NLS participate in the nuclear localization of MKP-2, the expression of either sequence is sufficient to retain nuclear targeting.

Original languageEnglish
Pages (from-to)709-716
Number of pages8
JournalCellular Signalling
Volume17
Issue number6
DOIs
Publication statusPublished - Jun 2005

Keywords

  • MAP kinase
  • MKP
  • NLS
  • nuclear localization
  • dual-specificity phosphatases
  • mitogen-activated protein knase phosphatases
  • stress activated protein kinase

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