Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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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)

We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERK1), which appears to play a pivotal role in converting tyrosine phosphorylation into the serine/threonine phosphorylations that regulate downstream events. We now describe cloning and characterization of two ERK1-related kinases, ERK2 and ERK3, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKs are activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine phosphorylation to activate serine/threonine phosphorylation cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals.
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PMID:ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. 203 90

The prototype mitogen-activated protein (MAP) kinase module is a three-kinase cascade consisting of the MAP kinase, extracellular signal-regulated protein kinase (ERK) 1 or ERK2, the MAP/ERK kinase (MEK) MEK1 or MEK2, and the MEK kinase, Raf-1 or B-Raf. This and other MAP kinase modules are thought to be critical signal transducers in major cellular events including proliferation, differentiation, and stress responses. To identify novel mammalian MAP kinase modules, polymerase chain reaction was used to isolate a new MEK family member, MEK5, from the rat. MEK5 is more closely related to MEK1 and MEK2 than to the other known mammalian MEKs, MKK3 and MKK4. MEK5 is thought to lie in an uncharacterized MAP kinase pathway, because MEK5 does not phosphorylate the ERK/MAP kinase family members ERK1, ERK2, ERK3, JNK/SAPK, or p38/HOG1, nor will Raf-1, c-Mos, or MEKK1 highly phosphorylate it. Alternative splicing results in a 50-kDa alpha and a 40-kDa beta isoform of MEK5. MEK5 beta is ubiquitously distributed and primarily cytosolic. MEK5 alpha is expressed most highly in liver and brain and is particulate. The 23 amino acids encoded by the 5' exon in the larger alpha isoform are similar to a sequence found in certain proteins believed to associate with the actin cytoskeleton; this alternatively spliced modular domain may lead to the differential subcellular localization of MEK5 alpha.
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PMID:Isolation of MEK5 and differential expression of alternatively spliced forms. 749 18

The molecular mechanism underlying the cAMP inhibition of nuclear activation events in T lymphocytes is unknown. Recently, the activation of fibroblasts and muscle cells are shown to be antagonized by cAMP through the inhibition of mitogen-activated protein (MAP) kinases signaling pathway. Whether a similar antagonism may account for the late inhibitory effect of cAMP in T cell was examined. Surprisingly, extracellular signal regulated kinase 2 (ERK1, ERK2, and ERK3) of MAP kinase were poorly inhibited by cAMP. High concentration of cAMP also only weakly antagonized Raf-1 in T cells. The resistance of ERK and Raf-1 to cAMP clearly distinguishes T cells from fibroblasts. In contrast, another MAP kinase homologue c-Jun N-terminal kinase (JNK) was inhibited by cAMP in good correlation with that of IL-2 suppression. Moreover, JNK was antagonized by a delayed kinetics which is characteristic of cAMP inhibition. Despite that both ERK and JNK are essential for T cell activation, selective inhibition by cAMP further supports the specific role of JNK in T cell activation.
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PMID:c-Jun N-terminal kinase but not mitogen-activated protein kinase is sensitive to cAMP inhibition in T lymphocytes. 762 20

The present study revealed that the pineal gland expressed basic fibroblast growth factor (bFGF) and FGF-receptor 1 (FGFR1/flg), suggesting that bFGF in the pineal gland acts in an autocrine or paracrine manner, which is mediated by FGFR1/flg. The present study also examined gene expression of the extracellular signal-regulated kinase (ERK) family (ERK1-3) which may be intracellular signal mediators of growth factors. ERK1 [mitogen-activated protein kinase (MAP-kinase)] was strongly expressed throughout the pineal gland, while expression of ERK2 and ERK3 was not found. These findings suggest the presence of a signal pathway from bFGF to ERK1 via FGFR1/flg in the pineal gland.
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PMID:Growth factors and extracellular signal-regulated kinases (mitogen-activated protein kinase) in the rat pineal gland. 812 4

The extracellular signal-regulated kinases ERK1 and ERK2 are 43- and 41-kd enzymes activated by many extracellular cues. They lie within a protein kinase cascade that is used to achieve many cellular responses. In addition to the wide variety of regulatory contexts in which they are activated, they phosphorylate important regulatory proteins, including receptors, transcription factors, cytoskeletal proteins, and other protein kinases. Thus, the stimulation of this kinase cascade is thought to have a pleiotropic action. ERK1 and ERK2 are controlled by phosphorylation on threonine and tyrosine. To understand the regulatory mechanisms, wild-type and mutant ERKs were expressed in bacteria and phosphorylated with MEK, the enzyme that is upstream of ERKs. Wild-type proteins could be activated 500- to 1,000-fold in vitro by MEK. ERK3, an enzyme of 62 kd and only 50% identical to ERK1 and ERK2 in the catalytic core, was also phosphorylated by MEK in vitro. This suggests that all three of these enzymes are targets of common signaling pathways.
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PMID:Regulation and properties of extracellular signal-regulated protein kinases 1, 2, and 3. 830 37

The ERK3 cDNA predicts a protein of 62,000 in size with a C-terminal domain that extends 180 amino acids beyond the conserved core of ERK family protein kinases. Immunoblotting with antibodies raised to recombinant protein and to peptides from the catalytic core and three regions of the C-terminal tail revealed that ERK3 is the expected size and is ubiquitously expressed in a variety of cell lines and tissues. ERK3, unlike the MAP kinases ERK1 and ERK2, is localized in the nucleus in exponentially growing, quiescent, and growth factor-stimulated cells. If the 180 amino acids at its C terminus are deleted, the resulting ERK3 fragment of 45 kDa is still found primarily in the nucleus, indicating that the C terminus is not required for its localization. Recombinant ERK3 expressed in mammalian cells or in bacteria is a protein kinase, as deduced from its capacity to autophosphorylate. Mutation of a conserved residue (Asp171) expected to be involved in catalysis eliminated autophosphorylation. Ser189 of ERK3, which corresponds to Thr183, one of the activating phosphorylation sites of ERK2, is autophosphorylated in vitro and phosphorylated in vivo. Despite marked similarities to ERK1 and ERK2, ERK3 does not phosphorylate typical MAP kinase substrates, indicating that it has distinct functions.
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PMID:ERK3 is a constitutively nuclear protein kinase. 862 39

In a prior study, we have shown that stable transfection of expression plasmids for protein kinases C beta 1 (PKC beta 1) or PKC beta 2 into differentiated colon cancer cells led to elevated levels of PKC beta 1 or PKC beta 2 protein and PKC beta kinase activities in the transfectants, without altering PKC alpha levels. PKC gamma is not found in these cells, so the major modulation was in PKC beta. PKC beta transfectant cells exhibited blocked differentiation, increased growth rate in athymic mice, and restoration of the basic fibroblast growth factor response pathway. In this study, we have extended the analysis of these PKC beta transfectants to the mitogen-activated protein kinase ERK3. Analysis of cell lysates on the mitogen-activated protein kinase substrate myelin basic protein by in gel kinase assay showed increased activity at 63 kDa, the size of ERK3, in each of two PKC beta 1 and each of two PKC beta 2 transfectants compared with the vector control transfectant. ERK3 was expressed at equal abundance in PKC beta 1, PKC beta 2, and control transfectant cells as demonstrated by Western blotting and by immunoprecipitation with anti-ERK3 monoclonal antibody. However, a > 10-fold increase in ERK3 activity in each PKC beta transfectant was shown by immunoprecipitation with anti-ERK3 monoclonal antibody followed by either immune complex kinase assay or by in gel kinase assay. Thus, while overexpression of transfected PKC beta does not lead to overexpression of ERK3, it does lead to constitutive activation of ERK3. A causal link between PKC beta overexpression and ERK3 activation was established because 12-O-tetradecanoylphorbol-13-acetate treatment down-regulated both PKC and ERK3 activities in both PKC beta 1 transfectants. ERK3 activity was found in nuclear and membrane fractions in each PKC beta transfectant, in contrast to controls, perhaps accounting for constitutive activation of ERK3 in cells with elevated levels of PKC beta 1 or PKC beta 2.
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PMID:Increased expression of protein kinase C beta activates ERK3. 862 98

A novel protein kinase activity present in nuclear and cytosolic extracts has been identified and partially purified as a consequence of its tight binding to and phosphorylation of the extracellular signal-regulated protein kinase (ERK) 3. This novel protein kinase is inactivated by treatment with phosphoprotein phosphatase 2A. The ERK3 protein kinase was immunologically distinct from mitogen-activated protein (MAP) kinase/ERK kinases (MEK) 1 and 2 which phosphorylate the ERK3-related MAP kinases ERK1 and ERK2. This ERK3 kinase phosphorylated a single site on ERK3, Ser189, comparable to Thr183, one of the two activating phosphorylation sites of ERK2. To test the specificity of the ERK3 kinase, mutants of ERK3 and ERK2 were made in which the phosphorylated residues were exchanged. The double mutant S189T,G191Y ERK3, in which the phosphorylated residues from ERK2 replaced the comparable residues in ERK3, was phosphorylated by the ERK3 kinase but only on threonine. The ERK3 kinase did not phosphorylate ERK2 or ERK2 mutants. These findings indicate that although the ERK3 kinase is highly specific for ERK3, it does not recognize tyrosine, a feature that distinguishes it from MEKs that phosphorylate other ERK/MAP kinase family members.
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PMID:Characterization of a protein kinase that phosphorylates serine 189 of the mitogen-activated protein kinase homolog ERK3. 866 49

Using a combination of screening, RACE, and RT-PCR, we have isolated a new rat brain cDNA, we refer to as rMNK2, that showed strong homology to known MAP-kinases. The deduced amino acid sequence of rMNK2 indicated that it is the rat homolog of human p63(mapk), showing 94.5% identity. rMNK2 showed 77% homology with rat ERK3 and its human homolog p97(mapk), and 43% homology with both rat genes rMNK1(ERK1) and ERK2, within the kinase domain. This suggest that rMNK2 and ERK3 belong to a separate subfamily within the rat MAP-kinase multigene family. The most interesting difference lies in subdomain VIII, where this new subfamily contain a SEG/SPR motif instead of the TEY/APE found in the ERK subfamily, the TPY/APE found in the JNK/SAPK subfamily or the TGY/APE found in the p38/RK subfamily. The human homologs of ERK3 and rMNK2 (p97(mapk) and p63(mapk)) also show this significant change. Expression of rMNK2 has been detected in brain and to a lesser extent in lung by reverse transcription/PCR (RT-PCR). In situ hybridization of rat brain slices demonstrated a restricted expression of rMNK2 in the choroid plexus and hippocampus. This is interesting because the human homolog p63(mapk) maps to 18q12-21, a region that might be implicated in manic-depressive illness.
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PMID:Isolation of a cDNA encoding the rat MAP-kinase homolog of human p63mapk. 887 88

To examine the specificity of MEKs for MAP kinase family members, we determined the abilities of several MEK isoforms to phosphorylate mutants of the MAP kinase ERK2 and the related kinase ERK3 which are modified in the phosphorylation loop. The ERK2 mutants included mutations of the two phosphorylation sites, mutations of the acidic residue between these two sites, and mutations that shorten the length of this loop. All mutants were tested for phosphorylation by six mammalian MEKs and compared with several wild type MAP kinases. MEK1 and MEK2 phosphorylate a majority of the ERK2 mutants. MEK2 but not MEK1 will phosphorylate ERK3. Alteration of the residue between the two phosphorylation sites neither dramatically affected the activity of MEK1 and MEK2 toward ERK2 nor conferred recognition by other MEKs. Likewise, reduction of the length of the phosphorylation loop only partially reduces recognition by MEK1 and MEK2 but does not promote recognition by other MEKs. Thus other yet to be identified factors must contribute to the specificity of MEK recognition of MAP kinases.
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PMID:Contributions of the mitogen-activated protein (MAP) kinase backbone and phosphorylation loop to MEK specificity. 893 8


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