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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)

Mitogen-activated protein (MAP) kinase is a serine/threonine kinase whose function is thought to be essential for the transduction of mitogenic signals. MAP kinase is activated by phosphorylation induced by a variety of extracellular stimuli, and its direct upstream activator has been identified. Using amphibian and mammalian systems, we show here that ras can activate MAP kinase and its activator. Injection of v-Ha-ras p21 into Xenopus immature oocytes activated both MAP kinase and maturation-promoting factor (MPF) activities. The activation of MAP kinase preceded that of MPF, demonstrating that ras activates MAP kinase in an MPF-independent pathway. Moreover, we found that the MAP kinase activator is also activated in ras-injected oocytes. Activation of MAP kinase and its activator occurred also when the v-Ki-ras gene was conditionally induced in rat fibroblastic 3Y1 cells. Furthermore, we observed that ras activated MAP kinase and its activator in a cell-free system prepared from Xenopus oocytes. Using an antibody against the Xenopus 45-kDa MAP kinase activator, we demonstrated that the 45-kDa activator molecule was activated by ras. These findings suggest that the MAP kinase activator/MAP kinase system may be the downstream components of ras signal transduction pathways.
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PMID:Activation of mitogen-activated protein kinase and its activator by ras in intact cells and in a cell-free system. 132 97

Thromboxane A2 stimulation of smooth muscle cells contributes to the development of vascular lesions after percutaneous transluminal coronary angioplasty. In view of this, we examined the signaling pathways stimulated by a thromboxane receptor agonist, U-46619, in cultures of rat aortic smooth muscle cells. Treatment of rat aortic smooth muscle cells with U-46619 induced cellular hypertrophy ([14C]leucine incorporation) without stimulating mitogenesis ([3H]thymidine incorporation). Analysis of signaling pathways elicited by U-46619 revealed enhanced tyrosine phosphorylation and increased enzymatic activity of mitogen-activated protein (MAP) kinase (Erk2). U-46619 also activated signaling proteins upstream of p21-ras, inducing tyrosine phosphorylation on Shc and complex formation between Shc and growth factor receptor binding protein-2 (GRB2). Exposure of cells to a stable prostacyclin analogue, ciprostene calcium, attenuated U-46619-induced cellular hypertrophy and MAP kinase activity. Ciprostene treatment elevated cellular cAMP and inhibited U-46619-induced tyrosine phosphorylation on Shc and Shc/GRB2 complex formation. These results demonstrate that stimulation of thromboxane A2 and prostacyclin receptors have opposing effects on smooth muscle cell hypertrophy and the signaling pathways associated with this process. We conclude that inhibition of Shc/GRB2 complex formation and MAP kinase activity by ciprostene may contribute to its ability to limit restenosis injury.
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PMID:Activation of thromboxane and prostacyclin receptors elicits opposing effects on vascular smooth muscle cell growth and mitogen-activated protein kinase signaling cascades. 747 20

Considerable effort has been devoted to identifying critical steps in mitogenic signal transduction pathways. Recently, the atypical PKC zeta isoform has attracted great interest since it has been reported to induce GVBD in Xenopus oocytes and transformation of NIH3T3 fibroblasts, two processes closely linked with the regulation of cell division. Furthermore, PKC zeta has been proposed as an essential effector for ras-p21 function and therefore may be an essential component of the signalling pathway(s) activated by mitogens. In this study we have analysed the responses induced in Xenopus oocytes after microinjection of purified recombinant PKC zeta protein. Microinjection of PKC zeta induced the early activation of MPF which precedes GVBD and also induced the activation of MAP kinase and S6 kinase II. The activation of MPF, MAP kinase and S6 kinase II by PKC zeta was sensitive to cycloheximide, while induction of GVBD was independent of protein synthesis. These results indicate that PKC zeta induces the activation of at least two pathways, only one of them leading to the activation of MAP kinase. By contrast, neither the induction of GVBD nor the activation of MPF, MAPK and S6 kinase II induced by the ras-p21 protein were dependent on protein synthesis. Thus, the comparison of these responses suggests that PKC zeta most likely does not mediate the ras-induced signal transduction pathway in Xenopus laevis oocytes.
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PMID:Evidence for different signalling pathways of PKC zeta and ras-p21 in Xenopus oocytes. 747 78

Ras p21 in the GTP-bound form was shown to act as an upstream activator for mitogen-activated protein (MAP) kinase kinase (MAPKK) and MAP kinase, and Raf-1 was reported to act as a MAPKK kinase. Further, physical association between Ras and Raf-1 was demonstrated. Here we have shown that incubation of Xenopus immature oocyte extracts with Ras enhances the ability of endogenous Raf-1 to activate MAPKK. Moreover, a dominant negative form of Raf-1 blocked the Ras-induced activation of MAPKK and MAP kinase in the extracts, but not the cyclin A-dependent activation of MAP kinase. When the extracts were depleted of 45-kDa MAPKK with polyclonal anti-MAPKK antibody, no activation of MAP kinase occurred even after incubation with Ras. These results suggest that Ras can activate the MAPKK kinase activity of Raf-1 in the extracts and that MAPKK is indispensable for the Ras-induced MAP kinase activation. It is well known that Ras can induce oocyte maturation when injected into immature Xenopus oocytes. Co-injection of Ras with an anti-MAPKK antibody that inhibits the MAPKK activity prevented the Ras-induced germinal vesicle breakdown, suggesting that MAPKK mediates, at least, one of cellular functions of Ras.
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PMID:Analysis of the Ras p21/mitogen-activated protein kinase signaling in vitro and in Xenopus oocytes. 780 37

Signal transduction induced by generations of second messengers from membrane phospholipids is a major regulatory mechanism in the control of cell proliferation. Indeed, oncogenic p21ras alters the intracellular levels of phospholipid metabolites in both mammalian cells and Xenopus oocytes. However, it is still controversial whether this alteration it is biologically significant. We have analyzed the ras-induced signal transduction pathway in Xenopus oocytes and have correlated its mechanism of activation with that of the three most relevant phospholipases (PLs). After microinjection, ras-p21 induces a rapid PLD activation followed by a late PLA2 activation. By contrast, phosphatidylcholine-specific PLC was not activated under similar conditions. When each of these PLs was studied for its ability to activate intracellular signalling kinases, all of them were found to activate maturation-promoting factor efficiently. However, only PLD was able to activate MAP kinase and S6 kinase II, a similar pattern to that induced by p21ras proteins. Thus, the comparison of activated enzymes after microinjection of p21ras or PLs indicated that only PLD microinjection mimetized p21ras signalling. Finally, inhibition of the endogenous PLD activity by neomycin substantially reduced the biological activity of p21ras. All these results suggest that PLD activation may constitute a relevant step in ras-induced germinal vesicle breakdown in Xenopus oocytes.
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PMID:Activation of intracellular kinases in Xenopus oocytes by p21ras and phospholipases: a comparative study. 782 25

Induction of mitosis in Xenopus laevis oocytes by hormones and the oncogenic ras-p21 protein has been shown to correlate with a cascade of phosphorylations of the Ser/Thr family of kinases. However, the exact hierarchy of enzymes and their mutual interdependency has not been fully elucidated yet. We have used the Xenopus laevis system to investigate the mechanism of activation of the Ser/Thr kinases cascade and their relationship. Comparison between progesterone-induced germinal vesicle breakdown (GVBD), a hallmark of mitosis in oocytes, to that triggered by ras-p21, revealed the existence of at least two independent mechanisms to activate the MAP kinase enzyme in vivo. While progesterone function is dependent of cdc2 protein kinase activity, ras-p21 is independent of this enzyme. However, both progesterone and ras-p21 converge at the MAP kinase level, and depletion of MAP kinase activity inhibits the GVBD and S6 kinase II activation induced by both progesterone and ras-p21. These results provides further evidence that MAP kinase is a critical step for regulation of the cell cycle in oocytes and a critical point where ras and progesterone signaling converge.
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PMID:Progesterone but not ras requires MPF for in vivo activation of MAPK and S6 KII: MAPK is an essential conexion point of both signaling pathways. 796 77

Raf-1, a serine/threonine kinase, is required for the mitogenic action of ras p21. It has been recently demonstrated that ras p21 directly associates with Raf-1. The C-terminal region of ras p21 is modified by farnesylation and carboxyl methylation. This modification is necessary for ras p21 function. To elucidate the role of post-translational modification of ras p21 in Raf-1 activation, we examined ras p21-dependent Raf-1 activity in baculovirus/Sf9 cells overexpressing Raf-1 and ras p21. Coexpression of Raf-1 with v-ras p21 in Sf9 cells stimulated the autophosphorylating activity of Raf-1. The activity of Raf-1, as assessed by its ability to activate extracellular signal-regulated kinase kinase (MEK) in vitro, was also increased when Raf-1 was coexpressed with v-ras p21. However, neither the autophosphorylating activity of Raf-1 nor its ability to activate MEK was stimulated by v-ras p21 mutants which are not post-translationally modified. Raf-1 formed a complex with v-ras p21 and the v-ras p21 mutants in Sf9 cells. These results indicate that the post-translational modification of ras p21 is necessary for Raf-1 activation but that the association of Raf-1 with ras p21 is not sufficient to activate Raf-1.
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PMID:The post-translational modification of ras p21 is important for Raf-1 activation. 805 Oct 91

Signal transduction pathways that respond to external signals through the MAP kinase family of protein kinases are involved in diverse responses in eukaryotic cells. MAP kinases are one element in a series of kinases that serve to connect the plasma membrane with cytoplasmic and nuclear events. MAP kinases have the unusual feature that their activation requires threonine and tyrosine phosphorylation carried out by a dual specificity protein kinase. Recent advances have shown that in two MAP kinase pathways (the mating response pathway in the fission yeast Schizosaccharomyces pombe, and receptor tyrosine kinase signalling), the small GTP binding protein ras p21 links membrane events to kinase pathway activation.
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PMID:MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. 819 45

Botulinum C3 exoenzyme was used to specifically ADP-ribosylate and inactivate rho p21, and the effects of rho p21 inactivation on lysophosphatidic acid (LPA)-induced tyrosine phosphorylation were examined in cultured Swiss 3T3 cells. LPA induced a rapid increase in the tyrosine phosphorylation of a number of proteins. Pretreatment of the cells with the C3 exoenzyme caused ADP-ribosylation of rho p21 in the cells and selectively attenuated the phosphorylation of several proteins, including p43 mitogen-activated protein kinase, p125 focal adhesion kinase, and two proteins of 72 and 88 kDa. C3 exoenzyme pretreatment did not block the initial phosphorylation and activation of mitogen-activated protein kinase but suppressed its subsequent rise. In contrast, the enzyme treatment inhibited the induction of phosphorylation of the 72- and 88-kDa proteins and suppressed the basal and LPA-induced tyrosine phosphorylation of p125 focal adhesion kinase. In addition, immunoprecipitation of cell lysates with an antibody directed against the 85-kDa subunit of phosphatidylinositol 3-kinase (PI 3-kinase) co-precipitated a tyrosine-phosphorylated band of 180 kDa. C3 exoenzyme pretreatment suppressed both the phosphorylation of this band and PI 3-kinase activation associated with LPA stimulation. These findings suggest that rho p21 works as a link between the LPA receptor signal and the subsequent tyrosine phosphorylation and PI 3-kinase activation in these cells.
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PMID:ADP-ribosylation of rho p21 inhibits lysophosphatidic acid-induced protein tyrosine phosphorylation and phosphatidylinositol 3-kinase activation in cultured Swiss 3T3 cells. 822 9

We describe a novel Triton-disrupted mammalian cell system wherein the pathways for activation of mitogen-activated protein (MAP) kinases (MAPKs) are capable of direct biochemical manipulation in vitro. MAPKs p42mapk and p44mapk are activated in signal transduction cascade(s) initiated by occupancy of plasma membrane receptors for peptide growth factors, hormones, and neurotransmitters. One likely activation pathway for MAPKs consists of sequential activations of c-ras, c-raf-1, and a protein-tyrosine/threonine kinase, MAP kinase kinase. Triton-disrupted cells retained capacity for activation of the pathway by both peptide growth factors and by addition of GTP-loaded p21 rasVal12. Incubation of disrupted cells with an antibody that neutralized the function of c-ras (Y13-259) abolished receptor-mediated stimulation of MAPK as did acute addition of 200 microM azatyrosine. Activation of the pathway was reconstituted in a cell-free system using high-speed supernatants generated from Triton-disrupted cells together with purified plasma membranes from parental cells and as a heterogeneous system using purified plasma membranes from v-ras-transformed cells. These systems will allow biochemical dissection in vitro of the interaction(s) between c-ras and the MAPK pathway in mammalian cells.
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PMID:Activation of the mitogen-activated protein kinase pathway in Triton X-100 disrupted NIH-3T3 cells by p21 ras and in vitro by plasma membranes from NIH 3T3 cells. 833 4


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