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)

Nuclear factor kappaB (NF-kappaB) is a eukaryotic member of the Rel family of transcription factors whose biological activity is post-translationally regulated by its assembly with various ankyrin-rich cytoplasmic inhibitors, including IkappaBalpha. Expression of NF-kappaB in the nucleus occurs after signal-induced phosphorylation, ubiquitination, and proteasome-mediated degradation of IkappaBalpha. The induced proteolysis of IkappaBalpha unmasks the nuclear localization signal within NF-kappaB, allowing its rapid migration into the nucleus, where it activates the transcription of many target genes. At present, the identity of the IkappaBalpha kinase(s) that triggers the first step in IkappaBalpha degradation remains unknown. We have investigated the potential function of the 90-kDa ribosomal S6 kinase, or pp90(rsk), as a signal-inducible IkappaBalpha kinase. pp90(rsk) lies downstream of mitogen-activated protein (MAP) kinase in the well characterized Ras-Raf-MEK-MAP kinase pathway that is induced by various growth factors and phorbol ester. We now show that pp90(rsk), but not pp70(S6K) or MAP kinase, phosphorylates the regulatory N terminus of IkappaBalpha principally on serine 32 and triggers effective IkappaBalpha degradation in vitro. When co-expressed in vivo in COS cells, IkappaBalpha and pp90(rsk) readily assemble into a complex that is immunoprecipitated with antibodies specific for either partner. While phorbol 12-myristate 13-acetate produced rapid activation of pp90(rsk), in vivo, other potent NF-kappaB inducers, including tumor necrosis factor alpha and the Tax transactivator of human T-cell lymphotrophic virus, type I, failed to activate pp90(rsk). These data suggest that more than a single IkappaBalpha kinase exists within the cell and that these IkappaBalpha kinases are differentially activated by different NF-kappaB inducers.
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PMID:The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IkappaBalpha and stimulates its degradation in vitro. 926 Nov 39

We examined the signal transduction pathway for the development of cardiac hypertrophy induced by high blood pressure. The activities of Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK), MAP kinases (MAPKs) and 90-kDa ribosomal S6 kinase (p90rsk) was examined by passively stretching neonatal rat cardiomyocytes in vitro. Mechanical stretch activated these protein kinases transiently and sequentially: the maximal activation of Raf-1, MAPKK, MAPKs and p90rsk was observed at 2 minutes, 5 minutes, 8 minutes and 10 approximately 30 minutes, respectively. Both angiotensin II (AngII) and endothelin-1 (ET-1) were constitutively secreted from cultured cardiomyocytes, and a significant increase in the concentration was recognized in the culture medium of cardiomyocytes within 10 minutes after stretch. ET-1 mRNA levels were also increased in cardiomyocytes at 30 minutes after stretch. Moreover, ET-1 and AngII synergistically activated Raf-1 and MAPKs in cultured cardiomyocytes. In conclusion, mechanical stretch stimulates secretion and production of AngII and ET-1 in cultured cardiomyocytes, and both vasoconstrictive peptides may play an important role in mechanical stress (high blood pressure)-induced cardiac hypertrophy.
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PMID:[Molecular mechanism of cardiac hypertrophy and dysfunction]. 928 12

We examined the possibility that the alpha6A and alpha6B cytoplasmic domain variants of the alpha6beta1 integrin differentially activate p42 and p44 mitogen-activated protein (MAP) kinases. P388D1 macrophages that express equivalent surface levels of either the alpha6Abeta1 or alpha6Bbeta1 integrin were used to examine this issue. Adhesion to laminin-1 mediated by the alpha6Abeta1 integrin triggered activation of a substantial fraction of total p42 and p44 MAP kinases as assessed using a mobility shift assay, immunoblot analysis with a phosphospecific MAP kinase antibody, and an immune complex kinase assay. In contrast, ligation of the alpha6Bbeta1 integrin did not trigger significant MAP kinase activation. These data were confirmed by antibody clustering of the alpha6beta1 integrins. Both the alpha6Abeta1 and alpha6Bbeta1 integrins were capable of activating the p70 ribosomal S6 kinase and this activation, unlike MAP kinase activation, is dependent on phosphoinositide 3-OH kinase. Activation of MAP kinase by alpha6beta1 requires both Ras and protein kinase C activity. A functional correlate for differential activation of MAP kinase was provided by the findings that the alpha6Abeta1 transfectants migrated significantly better on laminin than the alpha6Bbeta1 transfectants and this migration was dependent on MAP kinase activity based on the use of the MAP kinase kinase (MEK1) inhibitor PD98059. Our findings demonstrate that the alpha6beta1 integrin can activate MAP kinase, that this activation is regulated by the cytoplasmic domain of the alpha6 subunit, and that it relates to alpha6beta1-mediated migration.
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PMID:Regulation of mitogen-activated protein kinase activation by the cytoplasmic domain of the alpha6 integrin subunit. 948 28

The mitogen-activated protein (MAP) kinase signaling pathways are believed to act as critical signal transducers between stress stimuli and transcriptional responses in mammalian cells. However, it is not known whether these signaling cascades also participate in the response to injury in human tissues. To determine whether injury to the vastus lateralis muscle activates MAP kinase signaling in human subjects, two needle biopsies or open muscle biopsies were taken from the same incision site 30-60 min apart. The muscle biopsy procedures resulted in striking increases in dual phosphorylation of the extracellular-regulated kinases (ERK1 and ERK2) and in activity of the downstream substrate, the p90 ribosomal S6 kinase. Raf-1 kinase and MAP kinase kinase, upstream activators of ERK, were also markedly stimulated in all subjects. In addition, c-Jun NH2-terminal kinase and p38 kinase, components of two parallel MAP kinase pathways, were activated following muscle injury. The stimulation of the three MAP kinase cascades was present only in the immediate vicinity of the injury, a finding consistent with a local rather than systemic activation of these signaling cascades in response to injury. These data demonstrate that muscle injury induces the stimulation of the three MAP kinase cascades in human skeletal muscle, suggesting a physiological relevance of these protein kinases in the immediate response to tissue injury and possibly in the initiation of wound healing.
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PMID:Extracellular-regulated protein kinase cascades are activated in response to injury in human skeletal muscle. 968 10

Little is known about the regulation of the mitogen-activated protein (MAP) kinase signaling cascades by hormonal stimulation in vivo. The extracellular signal-regulated kinase (ERK) and the c-jun kinase (JNK) are two MAP kinase signaling pathways that could play a role in the cellular response to hormones such as insulin and epinephrine. We studied the effects of insulin (20 U/rat) and epinephrine (25 microg/100 g body wt) injected in vivo on ERK and JNK signaling in skeletal muscle from Sprague-Dawley rats. Insulin significantly increased ERK phosphorylation and the activity of its downstream substrate, the p90 ribosomal S6 kinase 2 (RSK2), by 1.4-fold, but it had no effect on JNK activity. In contrast, epinephrine had no effect on ERK phosphorylation or RSK2 activity, but it increased JNK activity by twofold, an effect that was inhibited by the presence of combined alpha and beta blockade. Furthermore, the phosphorylation of both p46 and p55 isoforms of JNK, measured by phosphospecific antibody, was increased severalfold. The activity and phosphorylation of MAP kinase kinase (MKK)-4, an upstream regulator of JNK, was unchanged by epinephrine. Incubation of isolated soleus muscles in vitro with epinephrine (10(-5) mol/l) also increased JNK activity by twofold. These data are the first to demonstrate that epinephrine can increase JNK activity. Insulin and epinephrine have different effects on MAP kinase signaling pathways in skeletal muscle, which may be one of the underlying molecular mechanisms through which these hormones regulate opposing metabolic functions.
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PMID:Epinephrine and insulin stimulate different mitogen-activated protein kinase signaling pathways in rat skeletal muscle. 975 91

Xenopus laevis oocytes undergo an increase in intracellular pH (pHi) from 7.2 to 7.7 due to the up-regulation of Na+/H+ antiporters in their plasma membrane during oocyte meiotic maturation. Up-regulation of Na+/H+ exchangers (NHE) found in other cell systems appears to be controlled, in some cases, by direct phosphorylation of the exchanger. A number of active protein kinases can be found in maturing Xenopus oocytes. These include, c-mos kinase, Raf-1 kinase, mitogen-activated kinase kinase (MAPKK), MAPK, ribosomal S6 kinase (RSK), and histone H-1 kinase. Our previous study indicated that c-mos kinase, was involved in regulating the increase in oocyte pHi. In the current study, we show that when mRNA coding for a constitutively active form of Raf-1 kinase (delta N-Raf-1) was microinjected into oocytes, the protein product induced an increase in oocyte pHi. On the contrary, the injection of mRNA coding for wild-type Raf-1 (WT-Raf-1) or a kinase-deficient form of Raf-1 (KD-Raf-1) had no effect on the recipient oocyte pHi. 8-Br-cAMP and forskolin blocked the increase in pHi during oocyte meiotic maturation, but had no effect on the Raf-1-induced increase in oocyte pHi. Studies using antisense c-mos oligos demonstrated that Raf-1 was not working via a feedback loop to endogenous c-mos mRNA within the recipient oocytes. Experiments using the selective MAPKK inhibitor, PD 98059, indicated that the Raf-1 effect on oocyte pHi was not mediated by the downstream kinase, MAPKK. Therefore, Raf-1 appears to act independently of c-mos kinase in a pathway, not involving MAPKK, leading to the up-regulation of the Na+/H+ antiporters in Xenopus oocytes.
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PMID:Raf-1 kinase, a potential regulator of intracellular pH in Xenopus oocytes. 992 73

Bradykinin (BK) has a direct hypertrophic effect on rat ventricular cardiomyocytes (VCM) as defined by an increase in protein synthesis and an increase in atrial natriuretic peptide mRNA and secretion. In the current study, we have examined the dependence of BK-induced protein synthesis on activation of 90-kDa ribosomal S6 kinase (p90(rsk)) and 70-kDa S6 kinase (p70(S6K)). Both of these kinases possess the ability to phosphorylate the ribosomal protein S6, which plays an important role in initiating mRNA translation. Stimulation of adult VCM with 10 microM BK increased p90(rsk) activity by 2.5 +/- 0.3-fold and increased p70(S6K) activity by 2.0 +/- 0.3-fold. p90(rsk) is a terminal kinase in the mitogen-activated protein (MAP) kinase pathway. Inhibition of MAP kinase kinase activation by Raf in the MAP kinase pathway with PD-098059 (25 microM) blocked BK-stimulated activation of p90(rsk) by 70% and unexpectedly blocked p70(S6K) by 72%. Rapamycin inhibited BK-stimulated p70(S6K) activity by 93% but had no effect on p90(rsk) activation by BK. Inhibition of the MAP kinase pathway and p70(S6K) with PD-098059 was paralleled by changes in protein synthesis. BK (10 microM) increased [3H]phenylalanine incorporation by 27 +/- 3 and 39 +/- 6% in cultured adult and neonatal VCM, respectively. Treatment with PD-098059 or rapamycin abolished the increase in protein synthesis stimulated by BK. These results suggest that 1) BK activates p70(S6K) and p90(rsk); 2) although both p70(S6K) and p90(rsk) have the potential to phosphorylate the ribosomal S6 protein, p70(S6K) and not p90(rsk) is the predominant kinase involved in increasing protein synthesis by BK; and 3) p70(S6K) activation is dependent on stimulation of the MAP kinase pathway at a point distal to Raf.
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PMID:Bradykinin-stimulated protein synthesis by myocytes is dependent on the MAP kinase pathway and p70(S6K). 1019 67

Intracellular signaling pathways that mediate survival of prostate carcinoma (PCa) cells are poorly understood. We examined the potential role of the phosphatidylinositol 3' kinase (PI3K) pathway as a mediator of cell survival in LNCaP human PCa cells, which express a variety of properties characteristic of human prostate cancer. LNCaP cell cultures rapidly became apoptotic when treated with the specific PI3K inhibitors, wortmannin and LY294002. In contrast, apoptosis was not induced when the cells were treated with: (a) rapamycin, an inhibitor of the ribosomal S6 kinase pp70S6K, which acts downstream of PI3K; (b) PD98059, a specific inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (Erk/MAPK) kinase (MEK); or (c) the antiandrogen, Casodex; or when the cells were cultured under androgen-depleted conditions. Apoptosis induced by PI3K inhibition was attenuated by: (a) dihydrotestosterone; or (b) the ErbB1 activating ligands [epidermal growth factor (EGF), transforming growth factor alpha, or heparin-binding EGF-like growth factor]. In response to ErbB1 activation by ligand, the p85 regulatory subunit of PI3K associated specifically with ErbB3 but not detectably with ErbB1. The anti-apoptotic effect of ErbB1 activation was significantly reduced when cells were treated simultaneously with wortmannin and PD98059. These data indicate that survival signals can be evoked in LNCaP cells by several distinct pathways and can be triggered by nuclear and cell-surface receptors. Constitutive signaling through the PI3K pathway is required to prevent cell death in LNCaP, whereas activation of the Erk/MAPK and androgen response pathways is not obligatory for cell survival. These results also show that survival signals, as distinguished from mitogenic signals, can be evoked in PCa cells by ErbB1 ligands known to be synthesized within the human prostate.
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PMID:The phosphatidylinositol 3'-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. 1038 51

Reactive oxygen species and growth factors stimulate similar intracellular signal transduction events including activation of Src kinase family members and extracellular signal-regulated kinases (ERK1/2). A potentially important downstream effector of Src and ERK1/2 is p90 ribosomal S6 kinase (p90RSK), which plays an important role in cell growth by activating several transcription factors as well as the Na(+)/H(+) exchanger. In the present study, we determined whether H(2)O(2) activates p90RSK to gain insight into signal transduction mechanisms activated by reactive oxygen species. H(2)O(2) (200 microM) stimulated ERK1/2 and p90RSK activity in lymphocytes, endothelial cells, and fibroblasts. The MEK-1 inhibitor, PD98059 (30 microM), inhibited H(2)O(2)-mediated activation of ERK1/2 but not of p90RSK. An essential role for Fyn and Ras in p90RSK activation was suggested by five findings. 1) The tyrosine kinase inhibitor, herbimycin A, and the specific Src kinase family inhibitor, PP1, blocked p90RSK activation by H(2)O(2) in a concentration-dependent manner. 2) p90RSK activation by H(2)O(2) was significantly reduced in fibroblasts derived from transgenic mice deficient in Fyn, but not c-Src. 3) H(2)O(2) rapidly activated Ras (peak at 2-5 min), which preceded p90RSK activation (peak at 20 min). 4) Dominant negative Ras completely blocked H(2)O(2)-induced activation of p90RSK. 5) In Fyn-/- fibroblasts, activation of Ras by H(2)O(2) was significantly attenuated. These results show essential roles for Fyn and Ras in H(2)O(2)-mediated activation of p90RSK and establish redox-sensitive regulation of Ras and p90RSK as a new function for Fyn.
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PMID:Reactive oxygen species activate p90 ribosomal S6 kinase via Fyn and Ras. 1063 70

We showed that the rat Na(+)/P(i) cotransporter-1 (RNaPi-1) gene was regulated by insulin and glucose in rat hepatocytes. The aim of this work was to elucidate signaling pathways of insulin-mediated metabolic regulation of the RNaPi-1 gene in H4IIE cells. Insulin increased RNaPi-1 mRNA abundance in the presence of glucose and decreased RNaPi-1 mRNA in the absence of glucose, clearly establishing an involvement of metabolic signals for insulin-induced upregulation of the RNaPi-1 gene. Pyruvate and insulin increased RNaPi-1 expression but downregulated L-pyruvate kinase, indicating the existence of gene-specific metabolic signals. Although fructose, glycerol, and lactate could support insulin-induced upregulation of the RNaPi-1 gene, compounds entering metabolism beyond pyruvate oxidation, such as acetate and citrate, could not, suggesting that RNaPi-1-specific metabolic signals are generated at or above pyruvate oxidation. Wortmannin, LY-294002, and rapamycin abolished the insulin effect on the RNaPi-1 gene, whereas expression of dominant negative Asn(17) Ras and mitogen-activating protein kinase (MAPK) kinase (MEK) inhibitor PD-98059 exhibited no effect. Thus we herein propose that metabolic regulation of RNaPi-1 expression by insulin is mediated through the phosphatidylinositol 3-kinase/p70 ribosomal S6 kinase pathways, but not the Ras/MAPK pathway.
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PMID:Metabolic regulation of Na(+)/P(i)-cotransporter-1 gene expression in H4IIE cells. 1075 Nov 98


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