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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have provided suggestive evidence for an interaction between ras activation and signalling pathways involved in agonist-stimulated arachidonic acid release in a variety of cell systems. In order to clarify this interaction, we have measured epidermal growth factor (EGF)-stimulated arachidonic acid release in rat-1 fibroblasts transfected with the N-17 dominant negative mutation of ras. Cells transfected with the N-17 ras mutant, display a markedly attenuated arachidonic acid-release response to EGF, compared to sham-transfected and non-transfected cells. In contrast, the response to phorbol myristate acetate (PMA) was not attenuated in the N-17-mutant expressing cells. No differences were detected between sham-transfected and N-17 mutant expressing cells in levels of immunodetectable EGF receptor, cytosolic phospholipase A2 or mitogen-activated protein (MAP) kinase. Attenuation of EGF-stimulated arachidonic acid release in the N-17 mutant expressing cells, was accompanied by a marked diminution in EGF-stimulated tyrosine phosphorylation of MAP kinase. We conclude that the signalling pathway involved in epidermal growth factor-stimulated arachidonic acid release is similar to the signalling pathway for mitogenic responses to epidermal growth factor and requires ras activation, likely followed by a downstream cascade of kinases eventuating in MAP kinase activation.
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PMID:RAS is required for epidermal growth factor-stimulated arachidonic acid release in rat-1 fibroblasts. 824 28

Rap1 is a small Ras-related GTPase which when over-expressed is able to revert transformation by Ki-Ras. We have investigated the role of Rap1 in regulating 'normal' Ras function by studying the activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2 by two fundamentally different growth factors, epidermal growth factor (EGF) and 1-oleoyl-lyso-phosphatidic acid (LPA). Conditional expression of RasN17 (a dominant-negative mutant) in Rat-1 cells inhibited activation of MAP kinases by EGF and also LPA, the first time a defined G-protein-coupled receptor mitogen has been shown to require Ras to exert its effects. Conditional or constitutive expression of even low levels of RapV12 (a mutant insensitive to Rap-GAP) attenuated activation of MAP kinases by EGF and LPA, but did not interfere with growth factor-stimulated increases in Ras-GTP, indicating that signalling from receptors to Ras was not impaired. Inhibition of Ras-mediated signalling with either RasN17 or RapV12 attenuated DNA synthesis by EGF and LPA. We conclude that receptor tyrosine kinases and G-protein-coupled receptors use Ras as a common step in signalling to MAP kinases and that Rap-GTP (RapV12) at physiological levels interferes with downstream signalling from Ras to MAP kinases in vivo.
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PMID:RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts. 825 74

During development of the Caenorhabditis elegans hermaphrodite, the gonadal anchor cell induces nearby Pn.p cells to adopt vulval fates. The response to this signal is mediated by a receptor tyrosine kinase signal transduction pathway that has been remarkably well conserved during metazoan evolution. Because mitogen-activated protein (MAP) kinases are activated by receptor tyrosine kinase pathways in vertebrate cells, we hypothesized that C. elegans MAP kinase homologs may play a role in vulval induction. Two C. elegans MAP kinase genes, mpk-1 and mpk-2 (mpk, MAP kinase), were cloned using degenerate oligonucleotide primers and PCR amplification; in parallel, genes involved in vulval induction were identified by screening for mutations that suppress the vulval defects caused by an activated let-60 ras gene. One such suppressor mutation is an allele of mpk-1. We used a new type of mosaic analysis to show that mpk-1 acts cell autonomously in the Pn.p cells. Our results show that mpk-1 plays an important functional role as an activator in ras-mediated cell signaling in vivo.
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PMID:A MAP kinase homolog, mpk-1, is involved in ras-mediated induction of vulval cell fates in Caenorhabditis elegans. 829 36

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

The point-mutated active form of ras p21 is known to activate mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) in intact mammalian cells and Xenopus oocytes, although the direct target molecule of ras p21 remains to be identified. To elucidate the role of the post-translational processing of ras p21 for the MAP kinase activation, we established the cell-free system in which ras p21 activated MAP kinase. The guanosine 5'-(3-O-thio)triphosphate (GTP gamma S) bound form of post-translationally processed Ki-ras 4B p21 activated MAP kinase in the cytosol fraction of Xenopus oocytes, but the GTP gamma S bound form of post-translationally unprocessed Ki-ras 4B p21 or the GDP bound form of processed or unprocessed Ki-ras 4B p21 was far less effective. The GTP gamma S bound form of processed Ki-ras 4B p21 activated recombinant ERK2 in the presence of the cytosol fraction of Xenopus oocytes, but the unprocessed protein was far less effective. These results provide a complete biochemical assay for ras p21 to activate MAP kinase in a cell-free system and indicate that all the elements downstream of ras p21 necessary for the MAP kinase activation are cytosolic and that the post-translational processing of ras p21 is important for the MAP kinase activation.
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PMID:The post-translational processing of ras p21 is critical for its stimulation of mitogen-activated protein kinase. 838 17

To identify the direct target molecule of ras p21 in higher eukaryotes, we have recently developed the cell-free system in which ras p21 activates mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK). In this cell-free system, the guanosine 5'-[gamma-thio]triphosphate- bound form of Ki-ras p21, but not the GDP-bound form, activates endogenous Xenopus MAP kinase as well as recombinant ERK2 in the presence of the cytosol fraction of Xenopus oocytes. We separated two protein factors from the cytosol fraction of Xenopus oocytes by column chromatography: one was the inactive form of MAP kinase kinase and the other was a factor tentatively named ras p21-dependent ERK-kinase stimulator (REKS). The former and latter showed M(r) values of approximately 45,000 and 150,000-200,000, respectively, as estimated by gel filtration. Both factors were necessary for Ki-ras p21-dependent activation of MAP kinase/ERK2. These results indicate that an additional protein factor (REKS) is essential for Ki-ras p21 to activate MAP kinase through MAP kinase kinase.
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PMID:A protein factor for ras p21-dependent activation of mitogen-activated protein (MAP) kinase through MAP kinase kinase. 838 39

NF-IL6, a member of the basic leucine zipper (bZIP) family transcription factors, is involved in expression of inducible genes involved in immune and inflammatory responses. We observed that coexpression of oncogenic p21ras stimulated the transactivating activity of NF-IL6 and induced phosphorylation of Thr-235 located just N-terminal to the DNA binding domain of NF-IL6. Recently, mitogen-activated protein (MAP) kinases have been shown to be implicated in the cellular response to activated ras. Purified MAP kinases specifically phosphorylated Thr-235 of NF-IL6 in vitro. Mutation of Thr-235 abolished the ras-dependent activation of NF-IL6. From these results, we conclude that NF-IL6 is regulated through phosphorylation by MAP kinases in response to activated ras.
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PMID:Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. 838 17

Virtually all mitogens lead to the rapid activation of one or more mitogen-activated protein (MAP) kinases. In almost all cases, mitogen-activated surface signaling complexes transmit an essential signal via ras on to a protein kinase cascade that involves the serine/threonine kinase raf. Raf appears to be a MAP kinase kinase kinase, activating MAP kinase kinase which, in turn, activates MAP kinase. Among the targets of MAP kinase are other kinases, nuclear transcription factors and other proteins with roles in cell cycle activation. Both G0-arrested somatic cells and G2-arrested oocytes use many of the same signaling mechanisms to break cell cycle arrest; this is a useful concept in light of newly developed cell-free systems from quiescent oocytes that can be used to study signal transduction in vitro.
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PMID:MAP kinase and the activation of quiescent cells. 838 66

Rap1 small GTP-binding protein has the same amino acid sequence at its effector domain as that of Ras. Rap1 has been shown to antagonize the Ras functions, such as the Ras-induced transformation of NIH 3T3 cells and the Ras-induced activation of the c-Raf-1 protein kinase-dependent mitogen-activated protein (MAP) kinase cascade in Rat-1 cells, whereas we have shown that Rap1 as well as Ras stimulates DNA synthesis in Swiss 3T3 cells. We have established a cell-free assay system in which Ras activates bovine brain B-Raf protein kinase. Here we have used this assay system and examined the effect of Rap1 on the B-Raf activity to phosphorylate recombinant MAP kinase kinase (MEK). Recombinant Rap1B stimulated the activity of B-Raf, which was partially purified from bovine brain and immunoprecipitated by an anti-B-Raf antibody. The GTP-bound form was active, but the GDP-bound form was inactive. The fully post-translationally lipid-modified form was active, but the unmodified form was nearly inactive. The maximum B-Raf activity stimulated by Rap1B was nearly the same as that stimulated by Ki-Ras. Rap1B enhanced the Ki-Ras-stimulated B-Raf activity in an additive manner. These results indicate that not only Ras but also Rap1 is involved in the activation of the B-Raf-dependent MAP kinase cascade.
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PMID:Activation of brain B-Raf protein kinase by Rap1B small GTP-binding protein. 857 7

Desensitization of p21(ras) after stimulation of cells by growth factors and phorbol 12-myristate 13-acetate (PMA) correlates with hyperphosphorylation of the guanine nucleotide exchange factor Son-of-sevenless (Sos) and its dissociation from the adaptor protein Grb2 (Cherniack, A., Klarlund, J. K., Conway, B. R., and Czech, M. P. (1995) J. Biol. Chem. 270, 1485-1488). To test the role of the Raf/mitogen-activated protein (MAP) kinase pathway, we utilized cells expressing a chimera composed of the catalytic domain of p74Raf-1 and the hormone binding domain of the estradiol receptor (DeltaRaf-1:ER). Estradiol markedly stimulated DeltaRaf-1:ER and the downstream MEK and MAP kinases in these cells as well as Sos phosphorylation. However, the dissociation of Grb2 from Sos observed in response to PMA was not apparent upon DeltaRaf-1:ER activation. Furthermore, stimulation of DeltaRaf-1:ER did not impair GTP loading of p21(ras) in response to platelet-derived growth factor or epidermal growth factor. We conclude that activation of the Raf/MAP kinase pathway alone in these cells is insufficient to cause disassembly of Sos from Grb2 or to interrupt the ability of Sos to catalyze activation of p21(ras).
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PMID:Role of the Raf/mitogen-activated protein kinase pathway in p21ras desensitization. 866 95


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