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

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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 1873-3913 (https://doi.org/10.1016/j.cellsig.2009.10.002)

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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.

ORCID iDs

Cadalbert, C., Sloss, C.M., Cunningham, M.M., Al-Muteiri, M., McIntire, A., Shipley, J. and Plevin, R. ORCID logoORCID: https://orcid.org/0000-0002-7849-1220;
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