Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen-activated protein (MAP) kinase phosphatases constitute a growing family of dual specificity phosphatases thought to play a role in the dephosphorylation and inactivation of MAP kinases and are therefore likely to be important in the regulation of diverse cellular processes such as proliferation, differentiation, and apoptosis. For this reason it has been suggested that MAP kinase phosphatases may be tumor suppressors. We have determined the chromosomal locations of three human dual specificity phosphatase genes by fluorescence in situ hybridization and radiation hybrid mapping. The genes were localized to three different chromosomes, MKP2 (DUSP4) to 8p11-p12, MKP3 (DUSP6) to 12q22-q23, and MKPX (DUSP7) to 3p21. This will allow the potential roles of these genes in disease processes to be evaluated.
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PMID:Chromosomal localization of three human dual specificity phosphatase genes (DUSP4, DUSP6, and DUSP7). 920 28

MAPK (MAP kinase) phosphatase 3 (DUSP6/MKP3) is a cytosolic MKP (MAPK phosphatase) that regulates negatively ERK1/2 downstream to growth factor or apoptotic signaling. Transcription of DUSP6 gene is activated through the ERK1/2 pathway, which constitutes a feedback regulatory loop of ERK1/2 activation. However, the regulation of the function of the DUSP6/MKP3 protein is poorly known. MKP3 possesses a linker region between its N-terminal MAPK-binding domain and its C-terminal catalytic domain, which is conserved in the related MKPs DUSP7/MKPX and DUSP9/MKP4. In MKP3, the interdomain linker region contains a secondary ERK1/2 binding motif and an active nuclear export sequence. Here, we report that MKP3 protein levels are decreased in cells upon apoptotic stimulation in a caspase-dependent manner, and we identify a novel MKP3 regulatory mechanism mediated by the pro-apoptotic protease caspase-3, which involves the MKP3 interdomain linker region. Active caspase-3 targeted the linker region of MKP3 at several residues, rendering N-terminal and C-terminal MKP3 fragments that contain specific arrangements of nuclear export sequence and ERK1/2 interaction motifs. MKP3 caspase-3-generated fragments displayed differential properties to regulate ERK1/2 nuclear/cytosolic localization and activity. Our results indicate that caspase-3 cleavage of MKP3 down-regulates MKP3 full length and renders active MKP3 fragments, which may participate in novel regulatory pathways controlling the subcellular localization and activation of ERK1/2 during apoptosis.
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PMID:Caspase-3 cleavage of DUSP6/MKP3 at the interdomain region generates active MKP3 fragments that regulate ERK1/2 subcellular localization and function. 2250 24