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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)

Proteins of the ras family of oncogenes have been implicated in signal transduction pathways initiated by protein kinase C (PKC) and by tyrosine kinase oncogenes and receptors, but the role that ras plays in these diverse signalling systems is poorly defined. The activity of ras proteins has been shown to be controlled in part by a cellular protein, GAP (GTPase-activating protein), that negatively regulates p21c-ras by enhancing its intrinsic GTPase activity. Thus, overexpression of GAP provides a tool for determining the step(s) in signal transduction dependent on p21c-ras activity. In this paper, we report that overexpression of GAP blocks the phorbol ester (tetradecanoyl phorbol acetate [TPA])-induced activation of p42 mitogen-activated protein kinase (p42mapk), c-fos expression, and DNA synthesis. GAP overexpression did not block responses to serum or fluoroaluminate. Moreover, not all biochemical events elicited by TPA were affected by GAP overexpression, as increased glucose uptake and phosphorylation of MARCKS, a major PKC substrate, occurred normally. Reduction of GAP expression to near normal levels restored the ability of the cells to activate p42mapk in response to TPA. These findings suggest that ras and GAP together play a key role in a PKC-dependent signal transduction pathway which leads to p42mapk activation and cell proliferation.
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PMID:Regulation of tetradecanoyl phorbol acetate-induced responses in NIH 3T3 cells by GAP, the GTPase-activating protein associated with p21c-ras. 154 25

Although signaling by the epidermal growth factor (EGF) receptor is thought to be dependent on receptor tyrosine kinase activity, it is clear that mitogen-activated protein (MAP) kinase can be activated by receptors lacking kinase activity. Since analysis of the signaling pathways used by kinase-defective receptors could reveal otherwise masked capabilities, we examined in detail the tyrosine phosphorylations and enzymes of the MAP kinase pathway induced by kinase-defective EGF receptors. Following EGF stimulation of B82L cells expressing a kinase-defective EGF receptor mutant (K721M), we found that ERK2 and ERK1 MAP kinases, as well as MEK1 and MEK2 were all activated, and SHC became prominently tyrosine-phosphorylated. By contrast, kinase-defective receptors failed to induce detectable phosphorylations of GAP (GTPase-activating protein), p62, JAK1, or p91STAT1, all of which were robustly phosphorylated by wild-type receptors. These data demonstrate that kinase-defective receptors induce several protein tyrosine phosphorylations, but that these represent only a subset of those seen with wild-type receptors. This suggests that kinase-defective receptors activate a heterologous tyrosine kinase with a specificity different from the EGF receptor. We found that kinase-defective receptors induced ErbB2/c-Neu enzymatic activation and ErbB2/c-Neu binding to SHC at a level even greater than that induced by wild-type receptors. Thus, heterodimerization with and activation of endogenous ErbB2/c-Neu is a possible mechanism by which kinase-defective receptors stimulate the MAP kinase pathway.
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PMID:An incomplete program of cellular tyrosine phosphorylations induced by kinase-defective epidermal growth factor receptors. 753 32

Activated versions of ras and mos oncogenes subvert the signal transduction pathway by mimicking transducers at the plasma membrane and cytosol respectively. Radicicol (UCS1006), an antifungal antibiotic, had the ability to suppress transformation by ras and mos oncogenes in a rapid, reversible and dose-dependent manner. UCS1006 inhibited MAP kinase activity (both ERK1 and ERK2) in untransformed as well as ras and mos transformed cells. However, ERK2 but not ERK1 activity was constitutively elevated in ras and mos transformed cells used in this study. In addition, a 62 kDa (kilodalton) phosphoprotein was identified whose tyrosine phosphorylation was inhibited by UCS1006, in both ras and mos transformed cells. This 62 kDa phosphoprotein, which was found to be heavily phosphorylated on tyrosine residues only in the ras and mos transformed cells but not in untransformed NIH3T3 cells, was identical to the previously described GAP-associated tyrosine phosphoprotein, p62, that is the major target for phosphorylation in cells transformed by tyrosine kinase oncogenes. These results suggest that agents such as radicicol can suppress transformation by diverse oncogenes such as src, ras and mos at least in part by inhibiting the function of key signal transduction intermediates such as MAP kinase and GAP-associated p62.
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PMID:Suppression of RAS and MOS transformation by radicicol. 762 24

Pleckstrin homology (PH) domains are 90-110 amino acid regions of protein sequence homology that are found in a variety of proteins involved in signal transduction and growth control. We have previously reported that the PH domains of several proteins, including beta ARK1, PLC gamma, IRS-1, Ras-GRF, and Ras-GAP, expressed as glutathione S-transferase fusion proteins, can reversibly bind purified bovine brain G beta gamma subunits in vitro with varying affinity. To determine whether PH domain peptides would behave as antagonists of G beta gamma subunit-mediated signal transduction in intact cells, plasmid minigene constructs encoding these PH domains were prepared, which permit transient cellular expression of the peptides. Pertussis toxin-sensitive, G beta gamma subunit-mediated inositol phosphate (IP) production was significantly inhibited in COS-7 cells transiently coexpressing the alpha 2-C10 adrenergic receptor (AR) and each of the PH domain peptides. Pertussis toxin-insensitive, Gq alpha subunit-mediated IP production via coexpressed M1 muscarinic acetylcholine receptor (M1 AChR) was attenuated only by the PLC gamma PH domain peptide, suggesting that the inhibitory effect of most of the PH domain peptides was G beta gamma subunit-specific. Stimulation of the mitogen-activated protein (MAP) kinase pathway by Gi-coupled receptors in COS-7 cells has been reported to require activation of p21ras and to be independent of protein kinase C. Since several proteins involved in activation contain PH domains, the effect of PH domain peptide expression on alpha 2-C10 AR-mediated p21ras-GTP exchange and MAP kinase activation as well as direct G beta gamma subunit-mediated activation of MAP kinase was determined. In each assay, coexpression of the PH domain peptides resulted in significant inhibition. Increasing G beta gamma subunit expression surmounted PH domain peptide-mediated inhibition of MAP kinase activation. These data suggest that the PH domain peptides behave as specific antagonists of G beta gamma-mediated signaling in intact cells and that interactions between PH domains and G beta gamma subunits or structurally related proteins may play a role in the activation of mitogenic signaling pathways by G protein-coupled receptors.
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PMID:Effect of cellular expression of pleckstrin homology domains on Gi-coupled receptor signaling. 776 89

The yeast (Saccharomyces cerevisiae) pheromone response pathway is one of the best understood eukaryotic signal transduction pathways. Nonetheless, it is likely that components and regulators of the pathway remain to be identified. We have employed three approaches to learn about interactions among known pathway components and to identify new components. First, the two-hybrid system of Fields and Song revealed that STE5, a protein of unknown biochemical function, interacts with each member of the MAP kinase cascade. One interpretation of this finding is that STE5 facilitates interactions between members of the cascade and thereby makes signal transmission more efficient. Second, genetic studies have identified new gene functions that appear to be involved in pheromone response. One of these is homologous to RHO-GAP proteins, an observation that suggests that a RHO protein (members of the RAS super-family) is part of the response pathway. A second gene function, FAR3, appears to be required only for a specific facet of pheromone response, arrest of the mitotic cell division cycle in G1.
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PMID:The yeast pheromone response pathway: new insights into signal transmission. 787 99

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

We have begun characterizing the signal transduction pathways used by the c-met receptor in cells in which ligand (HGF-SF) stimulates motogenesis in the absence of mitogenesis. Primary targets (within 10-15 minutes) were identified as PI-3 kinase, GAP, PLC gamma, src, and MAP kinase, substrates which are also activated upon growth factor activation of mitogenic receptor systems. Following HGF-SF treatment, the 85 kD subunit of PI-3 kinase is phosphorylated on tyrosine and PI-3 kinase activity rapidly associates with the c-met receptor. A number of these substrates are implicated in cytoskeletal rearrangements and may be important in the motogenic response to the factor. We have also identified a number of colon carcinoma lines which express unamplified levels of constitutively tyrosine phosphorylated c-met protein. In these and other (gastric) cell lines which express amplified levels of activated receptor protein, we have determined that receptor activation is not due to the autocrine production of ligand.
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PMID:Signal transduction in c-met mediated motogenesis. 838 Jul 34

RalGDS family members (ralGDS and RGL) interact with the GTP-bound form of Ras through its effector loop. The C-terminal region (amino acids 602-768) of RGL is responsible for binding to Ras. In this paper we characterized a Ras-interacting domain of RGL using deletion mutants of RGL(602-768). RGL(602-768), RGL(632-768), and RGL (602-734) bound to the GTP-bound form of Ras and inhibited the GAP activity of NF-1. RGL(646-768) showed a low binding activity to Ras and inhibited GAP activity of NF-1 weakly. None of RGL(659-768), RGL(685-768), RGL(602-709), and RGL(602-686) bound to Ras or inhibited GAP activity of NF-1. These results indicate that amino acids 632-734 of RGL constitute a nearly minimal domain that contains the binding element for Ras. RGL(632-734) inhibited v-Ras- but not progesterone-induced Xenopus oocyte maturation. Furthermore, RGL(632-734) inhibited v-Ras- but not v-Raf- dependent extracellular signal-regulated kinase activation in Xenopus oocytes. These results clearly demonstrate that the Ras-interacting domain of RGL is important for Ras-dependent signal transduction in vivo.
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PMID:Ras-interacting domain of RGL blocks Ras-dependent signal transduction in Xenopus oocytes. 860 17

Heregulins (HRGs) induce tyrosine phosphorylation of several members of the erb-B family of receptors. Although originally isolated as the ligands for p185c-erb-2, recent evidence suggests that other receptors of the erbB family, including p180erbB-3 and p180erbB-4, are their true cognate receptors. Stimulation of MDA MB-453 cells with HRG beta 2 resulted in the tyrosine phosphorylation of p185c-erbB-2 and p180erbB-4 in a time- and dose-dependent fashion. This event was accompanied by the formation of multimeric complexes between the activated receptors and SH2-containing proteins. Ligand caused p120-rasGTPase activating protein (GAP), SHC and the p85 subunit of phosphatidylinositol-3'-kinase (PI3K) to be associated with both p185c-erbB-2 and p180erbB-4. In addition, tyrosine phosphorylation of p85-PI3K and SHC, but not of GAP or of its associated p62 and p190 proteins, was also detected. HRG also induced the association of GRB2 with tyrosine phosphorylated p185c-erbB-2, p180erbB-4 and SHC. Activation of mitogen-activated protein kinase (MAPK) ( > 30-fold over untreated controls) was observed upon receptor(s) activation, as it was the induction of the immediate early gene c-fos ( > 200-fold). These observations suggest that p21ras activation plays a role in the HRG pathway. Furthermore, comparative analysis of the binding of p85-PI3K to 185c-erbB-2 and p180erbB-4, revealed a preferential association with activated p180erbB-4. These findings might suggest a model of HRG action in which the relative expression of the various erb-B family members and the partitioning of signal transduction molecules between each type of receptor might determine the nature of the signal elicited by the ligand and the biological response attained.
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PMID:Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells. 862 88

Insulin-induced differentiation of 3T3 L1 cells can be mimicked by expression of transfected ras oncogenes but is completely blocked by expression of dominant negative Ras mutants, demonstrating that Ras proteins mediate insulin signaling in these mammalian cells. In contrast, transfection of tyrosine kinase oncogenes including trk and src dose not result in adipocytic differentiation. Transfected raf-1 oncogenes induce partial adipocytic differentiation, while dominant negative raf mutants block partially the insulin-induced differentiation process. Exposure of 3T3 L1 cells to insulin results in formation of the active Ras-GTP complex without GAP tyrosine phosphorylation. Insulin treatment of untransfected 3T3 L1 cells also induced quick activation of cytosolic 42 kDa mitogen-activated protein kinase (MAPK) and a 90 kDa S6 kinase (RSK). The activation of these cytosolic serine-threonine kinases was also mimicked by Ras expression (in the absence of insulin) in the same cells transfected with inducible ras oncogenes. Furthermore, insulin-induced activation of MAPK and RSK could be blocked by expression of a transfected, inducible dominant negative Ras mutant (N17). These results indicate that Ras proteins are obligatory intermediates in the activation of cytosolic ERKs by insulin. Insulin treatment of 3T3 L1 cells or expression of transfected ras oncogenes resulted also in hyperphosphorylation of cellular Raf-1. Insulin-induced Raf hyperphosphorylation was inhibited by expression of an inducible, dominant negative Ras mutant (N17). Interestingly, however, expression of transfected raf oncogenes did not induce MAPK or RSK activation, and the insulin-induced activation of these kinases was not blocked by expression of transfected dominant negative raf mutants. These results suggest a functional dissociation between Raf-1 and MAPK/RSK activation in insulin/Ras signaling pathways leading to 3T3 L1 differentiation and are consistent with Raf-1 kinase acting in a parallel pathway to the MAPK/RSK pathway after Ras activation in these cells.
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PMID:The insulin/Ras pathway of adipocytic differentiation of 3T3 L1 cells: dissociation between Raf-1 kinase and the MAPK/RSK cascade. 868 Apr 77


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