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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice lacking expression of the p66 isoform of the ShcA adaptor protein (p66(ShcA)) are less susceptible to oxidative stress and have an extended life span. Specifically, phosphorylation of p66(ShcA) at serine 36 is critical for the cell death response elicited by oxidative damage. We sought to identify the kinase(s) responsible for this phosphorylation. Utilizing the SH-SY5Y human neuroblastoma cell model, it is demonstrated that p66(ShcA) is phosphorylated on serine/threonine residues in response to UV irradiation. Both c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinases are activated by UV irradiation, and we show that both are capable of phosphorylating serine 36 of p66(ShcA) in vitro. However, treatment of cells with a multiple lineage kinase inhibitor, CEP-1347, that blocks UV-induced JNK activation, but not p38, phosphatidylinositol 3-kinase, or MEK1 inhibitors, prevented p66(ShcA) phosphorylation in SH-SY5Y cells. Consistent with this finding, transfected activated JNK1, but not the kinase-dead JNK1, leads to phosphorylation of serine 36 of p66(ShcA) in Chinese hamster ovary cells. In conclusion, JNKs are the kinases that phosphorylate serine 36 of p66(ShcA) in response to UV irradiation in SH-SY5Y cells, and blocking p66(ShcA) phosphorylation by intervening in the JNK pathway may prevent cellular damage due to light-induced oxidative stress.
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PMID:c-Jun N-terminal kinase specifically phosphorylates p66ShcA at serine 36 in response to ultraviolet irradiation. 1160 89

The protein kinase Raf is an important signaling protein. Raf activation is initiated by an interaction with GTP-bound Ras, and Raf functions in signal transmission by phosphorylating and activating a mitogen-activated protein (MAP) kinase kinase named MEK. We identified 13 mutations in the Caenorhabditis elegans lin-45 raf gene by screening for hermaphrodites with abnormal vulval formation or germline function. Weak, intermediate, and strong loss-of-function or null mutations were isolated. The phenotype caused by the most severe mutations demonstrates that lin-45 is essential for larval viability, fertility, and the induction of vulval cell fates. The lin-45(null) phenotype is similar to the mek-2(null) and mpk-1(null) phenotypes, indicating that LIN-45, MEK-2, and MPK-1 ERK MAP kinase function in a predominantly linear signaling pathway. The lin-45 alleles include three missense mutations that affect the Ras-binding domain, three missense mutations that affect the protein kinase domain, two missense mutations that affect the C-terminal 14-3-3 binding domain, three nonsense mutations, and one small deletion. The analysis of the missense mutations indicates that Ras binding, 14-3-3-binding, and protein kinase activity are necessary for full Raf function and suggests that a 14-3-3 protein positively regulates Raf-mediated signaling during C. elegans development.
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PMID:Caenorhabditis elegans lin-45 raf is essential for larval viability, fertility and the induction of vulval cell fates. 1186 55

Components of the transforming growth factor-beta and mitogen-activated protein kinase pathways interact in controlling cell growth and differentiation. We show that phosphorylation of Smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (ERK1) increases the amount of Smad2 protein and leads to enhanced transcriptional activity. Epidermal growth factor increased phosphorylation of Smad2 in COS7 cells, and Smad2-dependent transcription in a mink lung epithelial cell line, L17, was enhanced by co-transfection of a constitutively active MEK1. In addition, transfection of Smad2 mutants lacking ERK sites resulted in reduced transcription, whereas mutants that mimicked ERK phosphorylation stimulated transcription. The amount of Smad2 protein was increased by transfection with a constitutively active MEK1 and reduced by co-transfection with the ERK phosphatase, HVH2. The elevation of Smad2 protein levels was because of increased half-life and resulted in increased complex formation with Smad4. A site of ERK-dependent phosphorylation on Smad2 was located to Thr(8), a site that overlaps with the calmodulin binding region. We show that calmodulin inhibits Smad2 phosphorylation by ERK1, and overexpressing calmodulin, or stimulating calmodulin activity with ionomycin, reduces Smad2 levels. These findings suggest that the ERK pathway positively regulates Smad2 signaling by phosphorylating Smad2 and that negative regulation of Smad2 signaling by calmodulin is achieved in part by inhibiting this phosphorylation.
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PMID:Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. 1219 95

Rat embryo fibroblasts (REF) transformed with the complementing E1A and cHa-ras oncogenes show a down-regulation of the c-fos early response gene, which is transcribed with the participation of Elk-1. The role of Elk-1 was studied with constructs coding for the full-length factor or its N- or C-terminal fragment fused with Gal. The trans-activating effect of each construct on the Gal4-Luc reporter plasmid was estimated in contransfected REF52 and E1A + cHa-ras cells stimulated with serum or treated with sodium butyrate, a histone deacetylase inhibitor. In E1A + cHa-ras cells, serum activated the expression of C-terminal Gal-Elk(206-428) but not that of full-length Gal-Elk(1-428). The serum-induced activation of Gal-Elk(206-428) was suppressed by PD98059, a MEK/ERK inhibitor, and enhanced by SB203580, an inhibitor of the p38-kinase cascade. It was assumed that p38 negatively affects the MEK/ERK cascade, which plays the major role in the Elk-1 activation in response to serum. Sodium butyrate enhanced the Gal-Elk(1-428) activity both in serum-stimulated and in starving E1A - cHa-ras cells, suggesting a high activity of Elk-1-phosphorylating kinases in the latter. The butyrate-mediated activation of Gal-Elk(206-428) and Gal-Elk(1-428) was suppressed by PD98059 and, therefore, depended on the MEK/ERK cascade. Thus, Elk-1 acted not only as a positive, but also as a negative transcription regulator. Possibly, to suppress transcription, Elk-1 binds with histone deacetylases and thereby contributes to the inactive chromatin state in E1A + cHa-ras cells.
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PMID:[Transformation with the E1A + cHa-ras oncogenes enhances the trans-repressor function of the Elk-1 transcription factor]. 1239 46

Phosphorylation of linker histone H1(S)-3 (previously named H1b) and core histone H3 is elevated in mouse fibroblasts transformed with oncogenes or constitutively active mitogen-activated protein kinase (MAPK) kinase (MEK). H1(S)-3 phosphorylation is the only histone modification known to be dependent upon transcription and replication. Our results show that the increased amounts of phosphorylated H1(S)-3 in the oncogene Ha-ras-transformed mouse fibroblasts was a consequence of an elevated Cdk2 activity rather than the reduced activity of a H1 phosphatase, which our studies suggest is PP1. Induction of oncogenic ras expression results in an increase in H1(S)-3 and H3 phosphorylation. However, in contrast to the phosphorylation of H3, which occurred immediately following the onset of Ras expression, there was a lag of several hours before H1(S)-3 phosphorylation levels increased. We found that there was a transient increase in the levels of p21(cip1), which inhibited the H1 kinase activity of Cdk2. Cdk2 activity and H1(S)-3 phosphorylated levels increased after p21(cip1) levels declined. Our studies suggest that persistent activation of the Ras-MAPK signal transduction pathway in oncogene-transformed cells results in deregulated activity of kinases phosphorylating H3 and H1(S)-3 associated with transcribed genes. The chromatin remodelling actions of these modified histones may result in aberrant gene expression.
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PMID:Histone H1(S)-3 phosphorylation in Ha-ras oncogene-transformed mouse fibroblasts. 1246 60

Mitogen-activated protein kinase (MAPK) cascades control gene expression patterns in response to extracellular stimuli. MAPK/ERK (extracellular-signal-regulated kinase) kinases (MEKs) activate MAPKs by phosphorylating them; activated MAPKs, in turn, phosphorylate target transcription factors, and are deactivated by phosphatases. One mechanism for maintaining signal specificity and efficiency is the interaction of MAPKs with their substrates and regulators through high-affinity docking sites. In the present study, we show that peptides corresponding to the MAPK-docking sites of MEK1, MEK2, Ste7, Elk-1 and MAPK phosphatase (MKP)-2 potently inhibit MEK2 phosphorylation of ERK2, ERK2 phosphorylation of Elk-1, and MKP-1 dephosphorylation of ERK2. Each peptide inhibited multiple reactions; for example, the MEK2 peptide inhibited not only MEK2, but also ERK2 and MKP-1. In addition, these docking-site peptides inhibited MEK2-ERK2 binding. The MAPK-docking site of MEK1 also potently stimulated ERK2-mediated phosphorylation of a target site on the same peptide. Control peptides with mutations of conserved basic and hydrophobic residues of the MAPK-docking site consensus lacked biological activity. We conclude that MEKs, MKPs and the Elk-1 transcription factor compete for binding to the same region of ERK2 via protein-protein interactions that are crucial for kinase/phosphatase activity.
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PMID:Docking sites on mitogen-activated protein kinase (MAPK) kinases, MAPK phosphatases and the Elk-1 transcription factor compete for MAPK binding and are crucial for enzymic activity. 1252 72

The MAP Kinase pathway is a key signalling mechanism that regulates many cellular functions such as cell growth, transformation and apoptosis. One of the essential components of this pathway is the serine/threonine kinase, Raf. Raf (MAPKK kinase, MAPKKK) relays the extracellular signal from the receptor/Ras complex to a cascade of cytosolic kinases by phosphorylating and activating MAPK/ERK kinase (MEK; MAPK kinase, MAPKK) that phosphorylates and activates extracellular signal regulated kinase (ERK; mitogen-activated protein kinase, MAPK), which phosphorylates various cytoplasmic and nuclear proteins. Regulation of both Ras and Raf is crucial in the proper maintenance of cell growth as oncogenic mutations in these genes lead to high transforming activity. Ras is mutated in 30% of all human cancers and B-Raf is mutated in 60% of malignant melanomas. The mechanisms that regulate the small GTPase Ras as well as the downstream kinases MEK and extracellular signal regulated kinase (ERK) are well understood. However, the regulation of Raf is complex and involves the integration of other signalling pathways as well as intramolecular interactions, phosphorylation, dephosphorylation and protein-protein interactions. From studies using mammalian isoforms of Raf, as well as C. elegans lin45-Raf, common patterns and unique differences of regulation have emerged. This review will summarize recent findings on the regulation of Raf kinase.
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PMID:Mechanisms of regulating the Raf kinase family. 1263 9

Transcriptional regulation of downstream gene expression by thyroid hormone (T(3)) is mediated by the thyroid hormone receptor (TR). T(3) binding induces a complicated transition, where TR converts from a transcriptional repressor into a transcriptional activator and instigates downstream gene transcription. Binding of T(3) to TR also induces the degradation of TR, resulting in desensitization of the cells to further T(3) treatment. It has been shown that phosphorylation of TR plays a critical role in its activity and stability after T(3) binding. However, the kinases in control of phosphorylating TR in the nucleus have not been identified. In this study we demonstrate that MAPKs are possible candidates responsible for the nuclear phosphorylation of TR. Suppression of MAPKs with specific inhibitors repressed TR transcriptional activity and antagonized okadeic acid-induced TR transcriptional activity potentiation. Overexpression of the MAPK activator, MKK6, and its constitutively active mutant, MKK6EE, significantly increased TR activity and protected TR from degradation. Involvement of the 26S ubiquitin proteasome in hormone binding-induced TR degradation was also examined. We found that MAPKs enhanced the DNA binding affinity of TR. Our results suggest that MAPKs are the major kinases responsible for the nuclear phosphorylation of TR and are critical factors modulating the transcriptional activity and protein stability of TR subsequent to ligand binding.
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PMID:Mitogen-activated protein kinases potentiate thyroid hormone receptor transcriptional activity by stabilizing its protein. 1263 24

The proteasome is a multisubunit proteolytic enzyme comprising activator complexes bound to the 20 S catalytic core. The functions of the proteasomal activator (PA) 700 in ubiquitin/ATP-dependent protein degradation and of the PA28 alpha/beta activators in antigen presentation are well defined. However, the function of a third PA, PA28 gamma, remains elusive. We now show that mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase kinase 3 (MEKK3), a MAPK kinase kinase (MAPKKK) involved in MAPK kinase 7 (MKK7)-c-Jun N-terminal kinase ('JNK') and MKK6-p38 signalling, can bind PA28 gamma but not PA28 alpha. In contrast, B-Raf, a MAPKKK specific for the MAPK/ERK kinase ('MEK')-ERK module, binds PA28 gamma and alpha. The PA28 gamma-binding domain of MEKK3 is located within its N-terminal regulatory domain (amino acids 1-178). Expression of MEKK3 in Cos-7 cells led to an increase in endogenous and co-expressed PA28 gamma protein levels, whereas kinase-deficient MEKK3 had no effect on PA28 gamma expression. Furthermore, in vitro assays indicated that PA28 gamma was a MEKK3 substrate. MEKK3 represents the first protein kinase capable of binding and phosphorylating a PA, and provides a potential mechanism to link stress-activated protein kinase signalling with the PA28 gamma-dependent proteasome.
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PMID:MEKK3 interacts with the PA28 gamma regulatory subunit of the proteasome. 1265 Jun 40

Mixed lineage kinases (MLKs) are a family of serine/threonine kinases that function in the SAPK signaling cascade. MLKs activate JNK/SAPK in vivo by directly phosphorylating and activating the JNK kinase SEK-1 (MKK4 and -7). Importantly, the MLK member MLK3/SPRK has been shown recently to be a direct target of ceramide and tumor necrosis factor-alpha (TNF-alpha) and to mediate the TNF-alpha and ceramide-induced JNK activation in Jurkat cells. Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells. Surprisingly, this induction of MEK phosphorylation does not result in ERK activation in vivo. Rather, in cells expressing active MLK3, ERK becomes resistant to activation by growth factors and mitogens. This restriction in ERK activation requires MLK3 kinase activity, is independent of Raf activation, and is reversed by JNK pathway inhibition either at the level of SEK-1, JNK, or Jun. These results demonstrate that sustained JNK activation uncouples ERK activation from MEK in a manner requiring Jun-mediated gene transcription. This in turn points to the existence of a negative cross-talk relationship between the stress-activated JNK pathway and the mitogen-activated ERK pathway. Thus, our findings imply that some of the biological functions of JNK activators, such as TNF-alpha and ceramide, may be attributed to their ability to block cell responses to growth and survival factors acting through the ERK/MAPK pathway.
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PMID:Cross-talk between JNK/SAPK and ERK/MAPK pathways: sustained activation of JNK blocks ERK activation by mitogenic factors. 1273 96


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