Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2.
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 33kDa 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.
Mesh Terms:
Amino Acid Sequence, Binding Sites, Cell Line, Dual-Specificity Phosphatases, Extracellular Signal-Regulated MAP Kinases, HeLa Cells, Humans, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Phosphatases, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Protein Binding, Protein Isoforms, RNA Splicing, RNA, Small Interfering, Signal Transduction, p38 Mitogen-Activated Protein Kinases
Amino Acid Sequence, Binding Sites, Cell Line, Dual-Specificity Phosphatases, Extracellular Signal-Regulated MAP Kinases, HeLa Cells, Humans, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Phosphatases, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Protein Binding, Protein Isoforms, RNA Splicing, RNA, Small Interfering, Signal Transduction, p38 Mitogen-Activated Protein Kinases
Cell. Signal.
Date: Mar. 01, 2010
PubMed ID: 19843478
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