MKP5, a new member of the MAP kinase phosphatase family, which selectively dephosphorylates stress-activated kinases

Abstract

Dual-speci®city protein tyrosine phosphatases are a burgeoning family of enzymes, some of which, the MKPs, are implicated in the regulation of mitogenactivated protein (MAP) kinases. MKPs have been shown to reverse the activation of the MAP kinases by hydrolyzing phosphothreonine and phosphotyrosine residues present in the substrates. Here we describe the characterization of a novel member of the MKP family, MKP5. The MKP5 gene, which maps to human chromosome 1q32, is expressed tissue-speci®cally as two transcripts of approximately 3.4 and 2.4 kb in human liver and skeletal muscle. When expressed in mammalian cells, MKP5 blocks the enzymatic activation of MAP kinases with the selectivity p38&JNK/ SAPK44ERK. Immunoprecipitation of endogenous MAP kinases by the catalytically inactive transfected MKP5 demonstrates that it preferentially binds to the p38 and JNK/SAPK kinases. These ®ndings suggest that the selectivity of this phosphatase may be determined at least in part at the level of substrate binding.

Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer

“…Another classifier gene of interest is dual-specificity phosphatase 10 (also called MAPK phosphatase-5 or MKP-5), which selectively dephosphorylates JNK and reduces its activity (38). The microarray data show that DSP-10/MKP-5 levels are reduced in PTEN-null tumors, suggesting that JNK activity may be increased in PTEN- null cancers.…”

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

“…A growing family of MAPK phosphatases (MKPs) exerts negative regulation of MAPK activities [62]. MKP5 has been shown to be able to deactivate all MAPK members, with some selectivity for the JNK/SAPK members [63,64]. Cr-induced activation of ERK, JNK and p38 pathways has been shown in a number of different cell lines, while the activation pattern is dependent on the dose/duration of the exposure [57,[65][66][67].…”

ATM-dependent activation of the gene encoding MAP kinase phosphatase 5 by radiomimetic DNA damage

“…Accordingly, MKP-5 physically interacted in vivo with members of the JNK and p38 subfamilies but not with ERK ( Figure 2c). Similar substrate speci®city of MKP-5 was also reported by others (Tanoue et al, 1999;Theodosiou et al, 1999). Of note, the JNK and p38 proteins are Control and A-T lymphoblastoid cell lines were treated with 80 ng/ml of NCS, and polyA + RNA was extracted at various time points after administration of the drug using a mRNA isolation system (Roche, Mannheim, Germany).…”

“…Antibodies were raised against the putative protein, it was expressed in bacterial and mammalian cells, and its activity was studied. While these experiments were in progress, the same protein was cloned independently by other laboratories and designated MKP-5 (Tanoue et al, 1999;Theodosiou et al, 1999). Brie¯y, our experiments demonstrated the phosphatase activity of recombinant MKP-5 (Figure 2a), which e ciently dephosphorylated in vitro activated JNK and p38 proteins, but not activated ERK (Figure 2b).…”