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)

The immunosuppressant rapamycin inhibited proliferation of the H4IIEC hepatoma cell line. Rapamycin, but not its structural analog FK506, also inhibited the basal and insulin-stimulated activity of the p70 ribosomal protein S6 kinase. By contrast, insulin stimulation of the p85 Rsk S6 kinase and mitogen-activated protein (MAP) kinase activity were unaffected by drug. Rapamycin treatment of COS cells transfected with recombinant p70 S6 kinase completely inhibited the appearance of the hyperphosphorylated form of p70 S6 kinase concomitant with the inhibition of enzyme activity toward 40S subunits. Thus, rapamycin inhibits a signal transduction element that is necessary for the activation of p70 S6 kinase and mitogenesis but unnecessary for activation of p85 Rsk S6 kinase or MAP kinase.
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PMID:Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. 138 Jan 82

We have investigated the signalling pathways involved in the stimulation of glycogen and fatty acid synthesis by insulin in rat fat cells using wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, which blocks activation of p70 ribosomal S6 protein kinase (p70S6K). Insulin produced a decrease in the activity of glycogen synthase kinase-3 which is likely to be important in the observed stimulation of glycogen synthase. Both of these actions were found to be sensitive to inhibition by wortmannin. Activation of three processes is involved in the stimulation of fatty acid synthesis from glucose by insulin, namely glucose uptake, acetyl-CoA carboxylase and pyruvate dehydrogenase. Whereas wortmannin largely abolished the effects of insulin on glucose utilization and acetyl-CoA carboxylase activity, it was without effect on the stimulation of pyruvate dehydrogenase. Although epidermal growth factor stimulated mitogen-activated protein kinase to a greater extent than insulin, it was unable to mimic the effect of insulin on glycogen synthase, glycogen synthase kinase-3, glucose utilization, acetyl-CoA carboxylase or pyruvate dehydrogenase. Rapamycin also failed to have any appreciable effect on stimulation of these parameters by insulin, although it did block the effect of insulin on p70S6K. We conclude that the activity of phosphatidylinositol 3-kinase is required for the effects of insulin on glycogen synthesis, glucose uptake and acetyl-Co-AN carboxylase, but is not involved in signalling to pyruvate dehydrogenase. Activation of mitogen-activated protein kinase or p70S6K, however, does not appear to be sufficient to bring about the stimulation of fatty acid or glycogen synthesis. Altogether is seems likely that at least four distinct signalling pathways are involved in the effects of insulin on rat fat cells.
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PMID:Multiple signalling pathways involved in the stimulation of fatty acid and glycogen synthesis by insulin in rat epididymal fat cells. 748 1

It has been suggested that phosphorylation of a 40S ribosomal protein, S6, regulates protein synthesis. Two distinct families of S6 kinase have been identified, the rsk-encoded 85- to 92-kD S6 kinase (RSK) and the 70- or 85-kD S6 kinase (p70S6K). We have previously shown that hypertrophic stimuli, such as angiotensin II (Ang II), rapidly activate RSK in cardiac myocytes. However, RSK and p70S6K are regulated by distinct mechanisms, and p70S6K, but not RSK, is the physiological S6 kinase in vivo in other cell types. Using cultured neonatal rat ventricular myocytes, we examined whether Ang II activates p70S6K and investigated the effect of rapamycin, a potent yet indirect inhibitor of p70S6K, on the Ang II-induced hypertrophic response. Immunoblot analyses indicate that cardiac myocytes express the 70- and 85-kD forms of p70s6K. Ang II caused a rapid and sustained activation of p70S6K through the type I Ang II receptor. Rapamycin inhibited Ang II-induced activation of p70S6K in a dose-dependent manner, with an IC50 of 0.14 ng/mL (0.15 nmol/L). Rapamycin did not inhibit Ang II-induced activation of tyrosine kinase, mitogen-activated protein kinase, RSK, and protein kinase C. The effect of rapamycin is unlikely to be mediated by its effect on p34cdc2 and p33cdk2 because Ang II did not activate these cell cycle-dependent kinases in cardiac myocytes. In contrast, a dose-dependent inhibition of p70S6K by rapamycin is very closely correlated with its inhibition of the Ang II-induced increase in protein synthesis. Interestingly, rapamycin did not affect the Ang II-induced activation of specific gene expression, including the immediate-early gene c-fos and fetal type genes, such as atrial natriuretic factor and skeletal alpha-actin. Moreover, rapamycin did not suppress Ang II-induced phenotypic changes at the protein level, such as increased atrial natriuretic factor secretion, expression of beta-myosin heavy chain, and organization of actin into sarcomeric units. These results indicate that p70S6K is activated by Ang II and that a rapamycin-sensitive signaling mechanism, most likely p70S6K, plays an essential role in the Ang II-induced increase in overall protein synthesis but not in Ang II-induced specific phenotypic changes in cardiac myocytes.
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PMID:Rapamycin selectively inhibits angiotensin II-induced increase in protein synthesis in cardiac myocytes in vitro. Potential role of 70-kD S6 kinase in angiotensin II-induced cardiac hypertrophy. 758 15

PHAS-I levels increased 8-fold as 3T3-L1 fibroblasts differentiated into adipocytes and acquired sensitivity to insulin. Insulin increased PHAS-I protein (3.3-fold after 2 days), the rate of PHAS-I synthesis (3-fold after 1 h), and the half-life of the protein (from 1.5 to 2.5 days). Insulin also increased the phosphorylation of PHAS-I and promoted dissociation of the PHAS-I eukaryotic initiation factor-4E (eIF-4E) complex, effects that were maximal within 10 min. With recombinant [H6]PHAS-I as substrate, mitogen-activated protein (MAP) kinase was the only insulin-stimulated PHAS-I kinase detected after fractionation of extracts by Mono Q chromatography; however, MAP kinase did not readily phosphorylate [H6]PHAS-I when the [H6]PHAS-I.eIF-4E complex was the substrate. Thus, while MAP kinase may phosphorylate free PHAS-I, it is not sufficient to dissociate the complex. Moreover, rapamycin attenuated the stimulation of PHAS-I phosphorylation by insulin and markedly inhibited dissociation of PHAS-I.eIF-4E, without decreasing MAP kinase activity. Rapamycin abolished the effects of insulin on increasing phosphorylation of ribosomal protein S6 and on activating p70S6K. The MAP kinase kinase inhibitor, PD 098059, markedly decreased MAP kinase activation by insulin, but it did not change PHAS-I phosphorylation or the association of PHAS-I with eIF-4E. In summary, insulin increases the expression of PHAS-I and promotes phosphorylation of multiple sites in the protein via multiple transduction pathways, one of which is rapamycin-sensitive and independent of MAP kinase. Rapamycin may inhibit translation initiation by increasing PHAS-I binding to eIF-4E.
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PMID:Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin-sensitive and mitogen-activated protein kinase-independent pathway. 762 82

The metabolic and mitogenic actions of insulin have been proposed to be mediated by cellular serine/threonine kinases such as the ribosomal protein S6 kinases pp70-S6 (pp70-S6 kinase) and pp90rsk and the erk-encoded mitogen-activated protein kinases (pp42mapk and pp44mapk). Rapamycin completely blocked activation of pp70-S6 kinase by insulin in 3T3-L1 adipocytes, but did not inhibit insulin-stimulated glucose transport, translocation of GLUT4 to the cell surface, or activation of pp90rsk or pp44mapk by insulin. Concordant with the inhibition of kinase activity, rapamycin prevented the insulin-induced decrease in mobility of pp70-S6 kinase visualized by SDS-polyacrylamide gel electrophoresis, reflecting a reduction in the hormone-stimulated phosphorylation of the enzyme. The structurally related macrolide, FK506, had no effect on pp70-S6 kinase or hexose uptake. These data demonstrate that rapamycin blocks insulin activation of pp70-S6 kinase in 3T3-L1 adipocytes and that pp70-S6 kinase is not required in the signaling pathway leading to insulin-stimulated glucose transport.
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PMID:Dissociation of pp70 ribosomal protein S6 kinase from insulin-stimulated glucose transport in 3T3-L1 adipocytes. 767 6

Lactogens [prolactin (Prl) and growth hormone] stimulate phosphorylation of the 40S ribosomal protein, S6, in Nb2 cells by mechanisms that do not involve participation of cAMP or protein kinase A, protein kinase C, or cGMP-dependent protein kinase. However, inhibition of tyrosine kinase (TK) abrogates Prl-mediated macromolecular biosynthesis. Inasmuch as lactogen signaling may involve sequential activation of protein kinases, the effect of Prl on the well-characterized mitogen-activated protein kinase (MAPK) and S6 kinase (S6K), the enzyme responsible for S6 phosphorylation in vivo, and their relationship to Nb2 macromolecular biosynthesis and mitogenesis were investigated. The results show that MAPK stimulation is transient (peak activity, 30 min) and precedes that of S6K, which reaches a maximum at 1.5-2 h, and slowly returns towards control levels at 6 h. Both staurosporine which inhibits GH receptor-associated kinase (JAK2) and genistein (GEN), an inhibitor of membrane-associated and cytoplasmic TKs, abrogate Prl-stimulated TK, MAPK, and S6K. Rapamycin (RAP), a specific inhibitor of p70S6K, completely blocks S6K but does not affect TK and MAPK. TK and MAPK activity correlates with Prl-stimulated anabolism, i.e., protein and DNA synthesis and mitogenesis. Thus, concentrations of STR and GEN which abrogate TK and MAPK inhibit anabolism virtually 100%. However, RAP, which inhibits S6K (ca. 100%) but not TK or MAPK, only delays Prl-mediated anabolism. These results indicate that Prl signaling in Nb2 cells involves a protein kinase cascade and that regulation of receptor-associated kinase, TK, and MAPK correlates with anabolism. The role of S6K (and S6 phosphorylation) appears to be ancillary.
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PMID:Stimulation of receptor-associated kinase, tyrosine kinase, and MAP kinase is required for prolactin-mediated macromolecular biosynthesis and mitogenesis in Nb2 lymphoma. 784 Jun 14

Independent of its ability to block translation, anisomycin intrinsically initiates intracellular signals and immediate-early gene induction [L. C. Mahadevan and D. R. Edwards, Nature (London) 349:747-749, 1991]. Here, we characterize further its action as a potent, selective signalling agonist. In-gel kinase assays show that epidermal growth factor (EGF) transiently activates five kinases: the mitogen-activated protein (MAP) kinases ERK-1 and -2, and three others, p45, p55, and p80. Anisomycin, at inhibitory and subinhibitory concentrations, does not activate ERK-1 and -2 but elicits strong sustained activation of p45 and p55, which are unique in being serine kinases whose detection is enhanced with poly-Glu/Tyr or poly-Glu/Phe copolymerized in these gels. Translational arrest using emetine or puromycin does not activate p45 and p55 but does prolong EGF-stimulated ERK-1 and -2 activation. Rapamycin, which blocks anisomycin-stimulated p70/85S6k activation without affecting nuclear responses, has no effect on p45 or p55 kinase. p45 and p55 are activable by okadaic acid or UV irradiation, and both kinases phosphorylate the c-Jun NH2-terminal peptide 1-79, putatively placing them within c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) subfamily of MAP kinases. Thus, the EGF- and anisomycin-activated kinases p45 and p55 are strongly implicated in signalling to c-fos and c-jun, whereas the MAP kinases ERK-1 and -2 are not essential for this process.
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PMID:Anisomycin-activated protein kinases p45 and p55 but not mitogen-activated protein kinases ERK-1 and -2 are implicated in the induction of c-fos and c-jun. 793 49

We have previously shown that insulin causes inactivation of glycogen synthase kinase-3 (GSK-3) in Chinese hamster ovary cells over-expressing the human insulin receptor (CHO.T cells). We now show that serum and phorbol ester also cause rapid inactivation of GSK-3, both in CHO.T cells and in the nontransfected parental cell line, CHO.K1 cells. Rapamycin was without effect on the inactivation of GSK-3 by insulin, serum or phorbol ester, indicating that the p70 S6 kinase pathway is not involved. In contrast, wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, blocked the effects of both insulin and serum on GSK-3 activity, and also substantially reduced the activation of both p90 S6 kinase (by insulin) and mitogen-activated protein (MAP) kinase (by insulin and serum). These findings imply (i) that GSK-3 activity is regulated by a cascade involving MAP kinase and p90 S6 kinase and (ii) that wortmannin affects an early step in the MAP kinase pathway. One can infer from this that GSK-3 may be an important regulatory enzyme for the control of several biosynthetic pathways, key enzymes in which are regulated by GSK-3-mediated phosphorylation. Wortmannin had a smaller effect on the activation of MAP kinase by phorbol ester, indicating that phorbol esters may stimulate MAP kinase by a different or additional mechanism to that employed by insulin or serum. Wortmannin had very little effect on the inactivation of GSK-3 by phorbol ester: possible reasons for this are discussed.
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PMID:Wortmannin inhibits the effects of insulin and serum on the activities of glycogen synthase kinase-3 and mitogen-activated protein kinase. 794 34

Glycogen synthase kinase-3 (GSK3) is inactivated in vitro by p70 S6 kinase or MAP kinase-activated protein kinase-1 beta (MAPKAP kinase-1 beta; also known as Rsk-2). Here we show that GSK3 isoforms are inhibited by 40% within minutes after stimulation of the rat skeletal-muscle cell line L6 with insulin-like growth factor-1 (IGF-1) or insulin. GSK3 was similarly inhibited in rabbit skeletal muscle after an intravenous injection of insulin. Inhibition resulted from increased phosphorylation of GSK3, probably at a serine/threonine residue(s), because it was reversed by incubation with protein phosphatase-2A. Rapamycin blocked the activation of p70 S6 kinase by IGF-1 in L6 cells, but had no effect on the inhibition of GSK3 or the activation of MAPKAP kinase-1 beta. In contrast, wortmannin, a potent inhibitor of PtdIns 3-kinase, prevented the inactivation of GSK3 and the activation of MAPKAP kinase-1 beta and p70 S6 kinase by IGF-1 or insulin. Wortmannin also blocked the activation of p74raf-1. MAP kinase kinase and p42 MAP kinase, but not the formation of GTP-Ras by IGF-1. The results suggest that the stimulation of glycogen synthase by insulin/IGF-1 in skeletal muscle involves the MAP-KAP kinase-1-catalysed inhibition of GSK3, as well as the previously described activation of the glycogen-associated form of protein phosphatase-1.
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PMID:The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. 794 42

Rapamycin (RAP) has recently been shown to inhibit the phosphorylation and activity of p70 S6 kinase (p70s6k). In interleukin (IL)-2-induced cell activation of the human IL-2-dependent T-cell line, Kit225, RAP inhibited p70s6k phosphorylation and activation, but not the activation of MAP kinase, p90 S6 kinase (p90rsk), early tyrosine kinases, or the transcription of the c-fos and c-myc genes. Cell cycle progression induced by IL-2 was arrested by RAP prior to p110Rb phosphorylation and the major increase in total RNA synthesis, both of which were initiated around 6 h after addition of IL-2 and 9 h before the beginning of DNA synthesis. Interestingly, RAP could not inhibit DNA synthesis if addition of the drug was delayed for 6 h after addition of IL-2, despite the fact that even at this time, RAP rapidly induced the accumulation of the dephosphorylated form of p70s6k and that p70s6k was inactivated within 1 h of RAP addition. Furthermore, when RAP was added to continuously growing Kit225 cells, cell proliferation was maintained for at least two additional cell cycles, in the absence of apparent p70s6k activity. These results indicate that 1) among the earliest detectable signals after IL-2 treatment, RAP selectively inhibits p70s6k activation, 2) RAP inactivates p70s6k regardless of the stage of the cell cycle in which the drug is added, 3) RAP blocks resting T-cells from entering the cell cycle, but does not directly arrest cell cycle progression once cells have entered the cycle, and 4) inactivation of p70s6k does not cause immediate arrest of cell cycle progression once cells have entered the cycle.
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PMID:Failure of rapamycin to block proliferation once resting cells have entered the cell cycle despite inactivation of p70 S6 kinase. 838 70


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