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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ERK7, a member of the mitogen-activated protein kinase family, has a carboxyl-terminal tail that is required for ERK7 activation, cellular localization, and its ability to inhibit DNA synthesis. To identify proteins that interact with ERK7, we utilized a yeast two-hybrid screen with the COOH-terminal tail of ERK7 as bait and isolated the cDNA for a novel protein termed CLIC3. The interaction between CLIC3 and ERK7 in mammalian cells was confirmed by co-immunoprecipitation. CLIC3 has significant homology to human intracellular chloride channels 1 (NCC27/CLIC1) and 2 and bovine kidney chloride channel p64. Like NCC27/CLIC1, CLIC3 is predominantly localized in the nucleus and stimulates chloride conductance when expressed in cells. Taken together, these results suggest that CLIC3 is a new member of the human CLIC family. The observed interaction between CLIC3 and ERK7 is the first demonstration of a stable complex between a protein that activates chloride ion transport and a member of the mitogen-activated protein kinase family of signal transducers. The specific association of CLIC3 with the COOH-terminal tail of ERK7 suggests that CLIC3 may play a role in the regulation of cell growth.
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PMID:Molecular cloning and characterization of a mitogen-activated protein kinase-associated intracellular chloride channel. 988 May 41

The ERKs are a subfamily of the MAPKs that have been implicated in cell growth and differentiation. By using the rat ERK7 cDNA to screen a human multiple tissue cDNA library, we identified a new member of the ERK family, ERK8, that shares 69% amino acid sequence identity with ERK7. Northern analysis demonstrates that ERK8 is present in a number of tissues with maximal expression in the lung and kidney. Fluorescence in situ hybridization localized the ERK8 gene to chromosome 8, band q24.3. Expression of ERK8 in COS cells and bacteria indicates that, in contrast to constitutively active ERK7, ERK8 has minimal basal kinase activity and a unique substrate profile. ERK8, which contains two SH3-binding motifs in its C-terminal region, associates with the c-Src SH3 domain in vitro and co-immunoprecipitates with c-Src in vivo. Co-transfection with either v-Src or a constitutively active c-Src increases ERK8 activation indicating that ERK8 can be activated downstream of c-Src. ERK8 is also activated following serum stimulation, and the extent of this activation is reduced by pretreatment with the specific Src family inhibitor PP2. The ERK8 activation by serum or Src was not affected by the MEK inhibitor U0126 indicating that activation of ERK8 does not require MEK1, MEK2, or MEK5. Although most closely related to ERK7, the relatively low sequence identity, minimal basal activity, and different substrate profile identify ERK8 as a distinct member of the MAPK family that is activated by an Src-dependent signaling pathway.
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PMID:ERK8, a new member of the mitogen-activated protein kinase family. 1187 70

ERK7 is a unique member of the extracellular signal-regulated kinase (ERK) subfamily of MAP kinases. Although ERK7 shares a TEY motif in the activation loop of the kinase, it displays constitutive activation, nuclear localization, and growth inhibitory properties that are regulated by its C-terminal domain. Because ERK7 is expressed at low levels compared with ERK2 and its activity is dependent upon its expression level, we investigated the mechanism by which ERK7 expression is regulated. We now show that ERK7 expression is regulated by ubiquitination and rapid proteosomal turnover. Furthermore, both the kinase domain and the C-terminal tail are independently degraded at a rate comparable with that of the intact protein. Analysis of a series of chimeras between ERK2 and ERK7 reveal that the N-terminal 20 amino acids of the kinase domain are a primary determinant of ERK7 degradation. Fusion of the N-terminal 20 amino acids is both necessary and sufficient to cause proteolytic degradation of both ERK2 and green fluorescent protein. Finally, ERK7 is stabilized by an N-terminal mutant of Cullin-1 suggesting that ERK7 is ubiquitinated by the Skip1-Cullin-F box complex. These results indicate that ERK7 is a highly regulated enzyme whose cellular expression and kinase activation level is tightly controlled by the ubiquitin-proteosome pathway.
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PMID:ERK7 expression and kinase activity is regulated by the ubiquitin-proteosome pathway. 1503 83

A gene encoding mitogen-activated protein kinase (MAPK) from the human enteric parasite, Entamoeba histolytica has been identified. Sequence analyses of the polymerase chain reaction (PCR) and reverse transcription PCR (RT-PCR) products reveal that the EhMAPK gene is intronless and encodes a protein of 352 amino acids. EhMAPK shows significant homology with other MAPKs and contains the 11 subdomains including the invariant residues characteristic of serine/threonine protein kinases. The MAPK signature residues and motifs are also present in EhMAPK. The atomic model of EhMAPK built with rat ERK2 as template exhibits the conservation of all major secondary structural features. However, a deletion in close proximity to the dual phosphorylation/activation site is of particular interest as it may have functional implications. Phylogenetic analysis indicates that EhMAPK is tightly clustered with Giardia intestinalis ERK2 and Dictyostelium discoideum ERK2. Detailed sequence analysis and phylogenetic study aided us to postulate that EhMAPK belongs to the extracellular signal-regulated kinase (ERK) family. Although EhMAPK bears good homology and phylogenetic closeness with human ERK8 and rat ERK7, sequence analysis indicates that they may be functionally different. The significant differences such as the deletions in the vicinity of the phosphorylation lip, variations in the P+1 specificity pocket, presence of additional acidic amino acids in the common docking domain provide a ground for postulations that activators and substrates for EhMAPK may be to some extent divergent from that of the ERKs of the mammalian host. Although functional characterization of EhMAPK remains to be done, this is the first study of any member of the MAPK signaling system in this organism.
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PMID:Identification, structure, and phylogenetic relationships of a mitogen-activated protein kinase homologue from the parasitic protist Entamoeba histolytica. 1571 29

ERK8 (extracellular-signal-regulated protein kinase 8) expressed in Escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the Thr-Glu-Tyr motif. Dephosphorylation of the threonine residue by PP2A (protein serine/threonine phosphatase 2A) decreased ERK8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by PTP1B (protein tyrosine phosphatase 1B) decreased activity by only 15-20%. Wild-type ERK8 expressed in HEK-293 cells was over 100-fold less active than the enzyme expressed in bacteria or insect cells, but activity could be increased by exposure to hydrogen peroxide, by incubation with the protein serine/threonine phosphatase inhibitor okadaic acid, or more weakly by osmotic shock. In unstimulated cells, ERK8 was monophosphorylated at Tyr-177, and exposure to hydrogen peroxide induced the appearance of ERK8 that was dually phosphorylated at both Thr-175 and Tyr-177. IGF-1 (insulin-like growth factor 1), EGF (epidermal growth factor), PMA or anisomycin had little effect on activity. In HEK-293 cells, phosphorylation of the Thr-Glu-Tyr motif of ERK8 was prevented by Ro 318220, a potent inhibitor of ERK8 in vitro. The catalytically inactive mutants ERK8[D154A] and ERK8[K42A] were not phosphorylated in HEK-293 cells or E. coli, whether or not the cells had been incubated with protein phosphatase inhibitors or exposed to hydrogen peroxide. Our results suggest that the activity of ERK8 in transfected HEK-293 cells depends on the relative rates of ERK8 autophosphorylation and dephosphorylation by one or more members of the PPP family of protein serine/threonine phosphatases. The major residue in myelin basic protein phosphorylated by ERK8 (Ser-126) was distinct from that phosphorylated by ERK2 (Thr-97), demonstrating that, although ERK8 is a proline-directed protein kinase, its specificity is distinct from ERK1/ERK2.
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PMID:Characterization of the reversible phosphorylation and activation of ERK8. 1633 13

Mitogen-activated protein (MAP) kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation, and apoptosis. Extracellular signal-regulated kinase 8 (Erk8) is a large MAP kinase whose activity is controlled by serum and the c-Src non-receptor tyrosine kinase. Here, we show that RET/PTC3, an activated form of the RET proto-oncogene, was able to activate Erk8, and we demonstrate that such MAP kinase participated in RET/PTC3-dependent stimulation of the c-jun promoter. By using RET/PTC3 molecules mutated in specific tyrosine autophosphorylation sites, we characterized Tyr(981), a known binding site for c-Src, as a major determinant of RET/PTC3-induced Erk8 activation, although, surprisingly, the underlying mechanism did not strictly depend on the activity of Src. In contrast, we present evidence that RET/PTC3 acts on Erk8 through Tyr(981)-mediated activation of c-Abl. Furthermore, we localized the region responsible for the modulation of Erk8 activity by the RET/PTC3 and Abl oncogenes in the Erk8 C-terminal domain. Altogether, these results support a role for Erk8 as a novel effector of RET/PTC3 and, therefore, RET biological functions.
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PMID:Activation of the Erk8 mitogen-activated protein (MAP) kinase by RET/PTC3, a constitutively active form of the RET proto-oncogene. 1648 22

All eukaryotes express mitogen-activated protein kinases (MAPKs) that govern diverse cellular processes including proliferation, differentiation, and survival. Even though these proteins are highly conserved throughout nature, MAPKs from closely related species often possess distinct signature sequences, making them well suited as drug discovery targets. Based on the central amino acid in the TXY dual phosphorylation loop, mammalian MAPKs are classified as extracellular signal-regulated kinases (ERKs), c-Jun amino-terminal kinases (JNKs), or p38 stress-response MAPKs. The presence of MAPKs in nonmetazoan eukaryotes suggests significant evolutionary conservation of these important signalling pathways. We recently cloned a novel stress-response MAPK gene (tgMAPK1) from Toxoplasma gondii, an obligate intracellular human parasite that can cause life-threatening infections in immunocompromised patients, and we now present data on a second T. gondii MAPK gene (tgMAPK2) that we cloned. We show that tgMAPK1 and tgMAPK2 are members of two distinct and previously unknown protozoan MAPK subfamilies that we have named pzMAPKl/pzMAPK3 and pzMAPK2. Our phylogenetic analysis of a collection of protozoan and metazoan MAPK genes in relation to ERK8-like genes demonstrates that an ERK8-like family, which includes the pzMAPK2 subfamily, is represented across a large variety of eukaryotic kingdoms and is evolutionarily very distant from other MAPK families.
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PMID:Toxoplasma gondii expresses two mitogen-activated protein kinase genes that represent distinct protozoan subfamilies. 1716 Jun 47

Mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that play a central role in transducing extracellular cues into a variety of intracellular responses ranging from lineage specification to cell division and adaptation. Fourteen MAP kinase genes have been identified in the human genome, which define 7 distinct MAP kinase signaling pathways. MAP kinases can be classified into conventional or atypical enzymes, based on their ability to get phosphorylated and activated by members of the MAP kinase kinase (MAPKK)/MEK family. Conventional MAP kinases comprise ERK1/ERK2, p38s, JNKs, and ERK5, which are all substrates of MAPKKs. Atypical MAP kinases include ERK3/ERK4, NLK and ERK7. Much less is known about the regulation, substrate specificity and physiological functions of atypical MAP kinases.
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PMID:Atypical mitogen-activated protein kinases: structure, regulation and functions. 1716 75

Mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs including embryogenesis, proliferation, differentiation and apoptosis based on cues derived from the cell surface and the metabolic state and environment of the cell. In mammals, there are more than a dozen MAPK genes. The best known are the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK(1-3)) and p38(alpha, beta, gamma and delta) families. ERK3, ERK5 and ERK7 are other MAPKs that have distinct regulation and functions. MAPK cascades consist of a core of three protein kinases. Despite the apparently simple architecture of this pathway, these enzymes are capable of responding to a bewildering number of stimuli to produce exquisitely specific cellular outcomes. These responses depend on the kinetics of their activation and inactivation, the subcellular localization of the kinases, the complexes in which they act, and the availability of substrates. Fine-tuning of cascade activity can occur through modulatory inputs to cascade component from the primary kinases to the scaffolding accessory proteins. Here, we describe some of the properties of the three major MAPK pathways and discuss how these properties govern pathway regulation and activity.
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PMID:Differential regulation and properties of MAPKs. 1749 9

Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a moderately potent and poorly selective inhibitor of protein kinase CK2, one of the most pleiotropic serine/threonine protein kinases, implicated in neoplasia and in other global diseases. By virtual screening of the MMS (Molecular Modeling Section) database, we have now identified quinalizarin (1,2,5,8-tetrahydroxyanthraquinone) as an inhibitor of CK2 that is more potent and selective than emodin. CK2 inhibition by quinalizarin is competitive with respect to ATP, with a Ki value of approx. 50 nM. Tested at 1 microM concentration on a panel of 75 protein kinases, quinalizarin drastically inhibits only CK2, with a promiscuity score (11.1), which is the lowest ever reported so far for a CK2 inhibitor. Especially remarkable is the ability of quinalizarin to discriminate between CK2 and a number of kinases, notably DYRK1a (dual-specificity tyrosine-phosphorylated and -regulated kinase), PIM (provirus integration site for Moloney murine leukaemia virus) 1, 2 and 3, HIPK2 (homeodomain-interacting protein kinase-2), MNK1 [MAPK (mitogen-activated protein kinase)-interacting kinase 1], ERK8 (extracellular-signal-regulated kinase 8) and PKD1 (protein kinase D 1), which conversely tend to be inhibited as drastically as CK2 by commercially available CK2 inhibitors. The determination of the crystal structure of a complex between quinalizarin and CK2alpha subunit highlights the relevance of polar interactions in stabilizing the binding, an unusual characteristic for a CK2 inhibitor, and disclose other structural features which may account for the narrow selectivity of this compound. Tested on Jurkat cells, quinalizarin proved able to inhibit endogenous CK2 and to induce apoptosis more efficiently than the commonly used CK2 inhibitors TBB (4,5,6,7-tetrabromo-1H-benzotriazole) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole).
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PMID:Quinalizarin as a potent, selective and cell-permeable inhibitor of protein kinase CK2. 1943 57


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