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Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2

Cadalbert, C. and Sloss, C.M. and Cunningham, M.M. and Al-Muteiri, M. and McIntire, A. and Shipley, J. and Plevin, R. (2009) Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2. Cellular Signalling, 22 (3). pp. 357-365. ISSN 0898-6568

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Abstract

MAP kinase phosphatase-2 (MKP-2) is a member of the family of dual specificity phosphatases that functions to inactivate the ERK and JNK MAP kinase signalling pathways. Here, we identify a novel human MKP-2 variant (MKP-2-S) lacking the MAP kinase binding site but retaining the phosphatase catalytic domain. Endogenous MKP-2-S transcripts and proteins were found in PC3 prostate and MDA-MB-231 breast cancer cells and also human prostate biopsies. Cellular transfection of MKP-2-S gave rise to a nuclear protein of 33 kDa which displayed phosphatase activity comparable to the formerly described long form of MKP-2 (MKP-2-L). Due to its lack of a kinase interacting motif (KIM), MKP-2-S did not bind to JNK or ERK; MKP-2-L bound ERK and to a lesser extent JNK. Protein turnover of adenoviral expressed MKP-2-S was accelerated relative to MKP-2-L, with a greater susceptibility to proteosomal-mediated degradation. MKP-2-S retained its ability to deactivate JNK in a similar manner as MKP-2-L and was an effective inhibitor of LPS-stimulated COX-2 induction. However, unlike MKP-2-L, MKP-2-S was unable to reverse serum-induced ERK activation or significantly inhibit endothelial cell proliferation. These findings reveal the occurrence of a novel splice variant of MKP-2 which is unable to bind ERK and may be significant in the dysregulation of MAP kinase activity in certain disease states, particularly in breast and prostate cancers.

Item type: Article
ID code: 26036
Keywords: map kinase phosphatase, map kinase, tyrosine kinase, pharmacology, Chemistry, Therapeutics. Pharmacology, Cell Biology
Subjects: Science > Chemistry
Medicine > Therapeutics. Pharmacology
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Related URLs:
    Depositing user: Strathprints Administrator
    Date Deposited: 23 Aug 2010 12:13
    Last modified: 05 Sep 2014 05:14
    URI: http://strathprints.strath.ac.uk/id/eprint/26036

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