Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2
详细信息 查看全文
- 作者：Laurence C. Cadalbert ; Callum M. Sloss ; Margaret R. Cunningham ; Mashael Al-Mutairi ; Alan McIntire ; Janet Shipley ; Robin Plevin
- 关键词：MAP kinase phosphatase ; MAP kinase ; JNK ; ERK ; MKP-2 ; DUSP4 ; MKP ; DUSP ; Tyrosine kinase
- 刊名：Cellular Signalling
- 出版年：2010
- 出版时间：March 2010
- 年：2010
- 卷：22
- 期：3
- 页码：357-365
- 全文大小：1400 K
文摘
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.