Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Five putative dual specificity protein phosphatases (DSPs), designated LMW-DSP1, -DSP4, -DSP6, -DSP10, and -DSP11, were cloned with a combination of RT-PCR and cDNA library screening strategies. Sequencing analysis revealed that all lacked the cdc25 homology domain that is conserved in most known DSPs/MAP kinase phosphatases (MKPs). LMW-DSP1 exhibited the highest similarity to plant DSPs. LMW-DSP4 exhibited the highest similarity to human YVH1 and rat GKAP, but its C-terminal region was much shorter than that of the human and rat clones. LMW-DSP6 was found to be identical to recently cloned TMDP, and LMW-DSP11 seemed to be a mouse ortholog of human VHR. LMW-DSP10 was found to have a DSP catalytic-like domain, but the critical cysteine residue for catalytic activity was missing. Recombinant LMW-DSP1, -DSP6, and -DSP11 exhibited obvious and strong activity against an artificial low molecular substrate, para-nitrophenyl phosphate (pNPP). Recombinant LMW-DSP4 exhibited slight but significant activity, whereas no activity was detected for LMW-DSP10. The phosphatase activity of the recombinant LMW-DSPs was inhibited by orthovanadate but not sodium fluoride. However, none of the DSPs could dephosphorylate MAP kinases such as ERK1, p38, and SAPK/JNK in transiently transfected COS7 cells under the conditions used. Northern blot analysis revealed that LMW-DSP1, -DSP6, -DSP10, and -DSP11 were specifically expressed in testis, while LMW-DSP4 was broadly expressed. The testis-specific expression and apparent absence of dephosphorylation action on MAP kinases suggest that LMW-DSP1, -DSP6, -DSP10, and -DSP11 play specific roles in testis. Taken together, it is conceivable that a distinct class of low molecular mass DSPs is present and plays a role in dephosphorylating unknown molecules other than MAP kinases.
 ...
PMID:A growing family of dual specificity phosphatases with low molecular masses. 1143 89

The JNK group (for c-Jun N-terminal kinase) of mitogen-activated protein kinases (MAP kinases) is activated in cells in response to environmental stress and cytokines. Activation of JNK is the result of dual phosphorylation by specific upstream kinases which phosphorylate the TxY motif. Much less is known concerning the down-regulation by protein phosphatases. Here, we demonstrate that the tyrosine-specific and constitutively-expressed phosphatase VHR (for VH1-Related) down-regulates the JNK signaling pathway at the level of JNK dephosphorylation. VHR was shown to efficiently dephosphorylate JNK and to form a tight complex with activated JNK when the catalytically-inactive C124S VHR mutant was employed as an in vivo substrate trap. Utilizing an in vitro assay, the transcription factor c-Jun specifically inhibited the ability of VHR to dephosphorylate JNK, likely by sterically blocking access to the phosphorylation sites when JNK and c-Jun form a complex. c-Jun has no effect on the ability of VHR to inactivate the ERK MAP kinases or to hydrolyze artificial substrates. The c-Jun inhibition results are discussed in terms of the resistant-nature of JNK dephosphorylation in cellular extracts and in terms of a general model in which VHR may be a general MAP kinase phosphatase whose specificity and activity are dictated by the presence of MAP kinase-associated proteins that inhibit dephosphorylation.
 ...
PMID:Dual-specificity protein tyrosine phosphatase VHR down-regulates c-Jun N-terminal kinase (JNK). 1197 Nov 92

Protein tyrosine phosphatases dephosphorylate tyrosine residues of proteins, whereas, dual specificity phosphatases (DUSPs) are a subgroup of protein tyrosine phosphatases that dephosphorylate not only Tyr(P) residue, but also the Ser(P) and Thr(P) residues of proteins. The DUSPs are linked to the regulation of many cellular functions and signaling pathways. Though many cellular targets of DUSPs are known, the relationship between catalytic activity and substrate specificity is poorly defined. We investigated the interactions of peptide substrates with select DUSPs of four types: MAP kinases (DUSP1 and DUSP7), atypical (DUSP3, DUSP14, DUSP22 and DUSP27), viral (variola VH1), and Cdc25 (A-C). Phosphatase recognition sites were experimentally determined by measuring dephosphorylation of 6,218 microarrayed Tyr(P) peptides representing confirmed and theoretical phosphorylation motifs from the cellular proteome. A broad continuum of dephosphorylation was observed across the microarrayed peptide substrates for all phosphatases, suggesting a complex relationship between substrate sequence recognition and optimal activity. Further analysis of peptide dephosphorylation by hierarchical clustering indicated that DUSPs could be organized by substrate sequence motifs, and peptide-specificities by phylogenetic relationships among the catalytic domains. The most highly dephosphorylated peptides represented proteins from 29 cell-signaling pathways, greatly expanding the list of potential targets of DUSPs. These newly identified DUSP substrates will be important for examining structure-activity relationships with physiologically relevant targets.
...
PMID:Phosphotyrosine Substrate Sequence Motifs for Dual Specificity Phosphatases. 2630 45