Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A benzodiazepine peptidomimetic, BZA-5B, inhibits farnesylation of H-Ras and normalizes the morphology of Rat-1 cells transformed with H-RasV12 at concentrations that do not affect the growth of untransformed Rat-1 cells. In the current experiments, we show that BZA-5B decreases the active forms of enzymes in the mitogen-activated protein (MAP) kinase signaling cascade, including Raf, MAP kinase kinase (MEK), and MAP kinase, in cells transformed with H-RasV12. BZA-5B had no effect on these enzymes in cells transformed with H-RasV12,L189, which is geranylgeranylated rather than farnesylated. In cells transformed with H-RasV12, BZA-5B reduced the activities of enzymes in the MAP kinase pathway at concentrations that only partially blocked farnesylation of H-RasV12, suggesting that nonfarnesylated H-RasV12 is a dominant inhibitor of the action of farnesylated H-RasV12 in the BZA-5B treated cells. In untransformed Rat-1 cells, BZA-5B did not inhibit MAP kinase activity nor did it prevent the acute activation triggered by epidermal growth factor, even though farnesylated endogenous H-Ras was no longer detectable. These data raise the possibility that untransformed cells contain a form of Ras (K-Ras or N-Ras) whose prenylation is not inhibited by BZA-5B, thus allowing them to resist the effects of BZA-5B.
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PMID:Benzodiazepine peptidomimetic BZA-5B interrupts the MAP kinase activation pathway in H-Ras-transformed Rat-1 cells, but not in untransformed cells. 796 91

Growth factors activate mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs) and Jun kinases (JNKs). Although the signaling cascade from growth factor receptors to ERKs is relatively well understood, the pathway leading to JNK activation is more obscure. Activation of JNK by epidermal growth factor (EGF) or nerve growth factor (NGF) was dependent on H-Ras activation, whereas JNK activation by tumor necrosis factor alpha (TNF-alpha) was Ras-independent. Ras activates two protein kinases, Raf-1 and MEK (MAPK, or ERK, kinase) kinase (MEKK). Raf-1 contributes directly to ERK activation but not to JNK activation, whereas MEKK participated in JNK activation but caused ERK activation only after overexpression. These results demonstrate the existence of two distinct Ras-dependent MAPK cascades--one initiated by Raf-1 leading to ERK activation, and the other initiated by MEKK leading to JNK activation.
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PMID:Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. 799 57

Hepatocyte growth factor (HGF)/scatter factor (SF) is a potent mitogenic factor or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the met protooncogene. In the present work, we demonstrate the powerful mitogenic activity of this growth factor on dog thyroid cells in primary culture. This effect, maximal at 50 ng/ml, was superior to those of other thyroid mitogenic agents, such as TSH, forskolin, and epidermal growth factor (EGF). HGF inhibited both TSH- and forskolin-stimulated iodide uptake (a thyroid-specific differentiation marker) in the same way as EGF. However, as with basic fibroblast growth factor, this dedifferentiating action appeared only during the growing phase concomitantly with the enhanced proliferation. HGF treatment also markedly decreased TSH receptor and thyroglobulin messenger RNA levels, two other markers of differentiated thyrocytes. Besides its proliferative and dedifferentiating effects, HGF enhanced the motility of the cultured thyroid cells. Concerning the mechanism of its action, we showed that HGF had no effect on basal cAMP levels, but like EGF and 12-O-tetradecanoyl-phorbol 13-acetate, it induced the rapid tyrosine phosphorylation of mitogen-activated protein kinases p42 and p44. These data establish HGF as the strongest mitogenic agent for dog thyroid cells and may explain the important role of met oncogene expression in human thyroid tumors.
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PMID:Mitogenic, dedifferentiating, and scattering effects of hepatocyte growth factor on dog thyroid cells. 801 45

Src homology/collagen (SHC) proteins are thought to participate in signaling through both receptor tyrosine kinases, such as the insulin receptor and the EGF (epidermal growth factor) receptor, and cytoplasmic tyrosine kinases, such as v-src and v-fps. Here we approached the insulin-induced and the insulin-like-growth-factor-I-induced (IGF-I-induced) phosphorylation of SHC proteins, and the possible role of these proteins in insulin and IGF-I signaling. First, we showed that SHC proteins are phosphorylated on tyrosine residues upon insulin and IGF-I treatment of fibroblasts transfected with a SHC cDNA construct. More important, ligand-activated insulin and IGF-I receptors phosphorylate SHC proteins in vitro, indicating that SHC proteins could be direct substrates for insulin and IGF-I receptors. Further, insulin or IGF-I treatment of SHC-transfected fibroblasts leads to immunoprecipitation of SHC proteins with insulin-receptor substrate 1 (IRS-1). We next looked at the possible effect of SHC proteins on biological responses in SHC-transfected fibroblasts. We found that the expression of exogenous SHC proteins results in an increased basal MEK (MAPK/ERK-activating kinase) activity. Further, neither the basal nor the insulin-induced or IGF-I-induced PtdIns-3-kinase activity were modified by expression of exogenous SHC proteins. These results illustrate that SHC proteins are implicated in the MAP (mitogen-activated protein)-kinase pathway, but not in that of PtdIns-3-kinase. Finally, we show that SHC-transfected cells, unlike control cells, are able to advance into the early phases of the cell cycle, and are more sensitive to the growth-promoting effect of insulin. In conclusion, SHC proteins are substrates for insulin and IGF-I receptors, and would appear to function as early post-receptor signaling components.
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PMID:Involvement of Src-homology/collagen (SHC) proteins in signaling through the insulin receptor and the insulin-like-growth-factor-I-receptor. 803 92

Rat adipocytes were incubated with insulin or epidermal growth factor (EGF) before the mitogen-activated protein (MAP) kinases, ERK-1 and ERK-2, and the ribosomal protein S6 kinases, Rsk-2 and p70S6K, were resolved by ion exchange chromatography and identified by immunoblotting. EGF was more effective than insulin in increasing the activity of two kinases that reacted with Rsk-2 antibody (2- and 2.5-fold with EGF versus 1.6- and 1.2-fold with insulin). EGF was also more effective than insulin in increasing the activity of ERK-1 (5-fold versus 2-fold) and ERK-2 (2.5-fold versus 1.5 fold). The activity of p70S6K was increased by approximately the same extent by EGF and insulin (1.7-fold versus 2-fold). Rapamycin blocked activation of p70S6K by insulin, but it did not attenuate the effect (2-fold) of insulin on increasing the glycogen synthase activity ratio (+/-glucose-6-P). Insulin increased glucose incorporation into glycogen and 2-deoxyglucose uptake by approximately 5-fold, whereas EGF and phorbol 12-myristate were without effect. Thus, activation of MAP kinases and ribosomal protein S6 kinases appears insufficient to activate glycogen synthase or glucose transport, the two key components in the stimulation of glycogen synthesis by insulin.
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PMID:Activation of ribosomal protein S6 kinases does not increase glycogen synthesis or glucose transport in rat adipocytes. 806 49

Tyrphostins are synthetic compounds which have been described as in vitro inhibitors of epidermal growth factor (EGF)-receptor tyrosine kinase activity. In NIH3T3 cells, stimulation of EGF-receptor tyrosine kinase leads to an increase of intracellular protein phosphorylations, among them the phosphorylation of mitogen-activated protein (MAP) kinase and the S6 kinases p90rsk and p70S6K. Phosphorylation of these proteins, either on tyrosine or serine/threonine residues or on both residues increases their protein kinase activity. Unexpectedly, treatment of NIH3T3 cells with both tyrphostin (RG 50864) and EGF results in an increase in the level of tyrosine phosphorylation of the MAP kinase. During this treatment, we also observed an increase in MAP kinase and S6 kinase p90rsk activities. Tyrphostin treatment diminishes the level of c-fos mRNA but has no effect on c-myc mRNA expression nor on S6 kinase p70S6K activity. Mitogenic signalling induced by EGF in NIH3T3 cells was blocked by tyrphostin, suggesting that the target(s) for this event may be elements downstream from the MAP kinase or independent of this signal transduction.
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PMID:Activation of the mitogen-activated protein kinase cascade by tyrphostin (RG 50864). 806 37

Son of sevenless-1 and -2 (Sos-1 and -2) are guanosine nucleotide exchange factors implicated in the activation of Ras by both the insulin and epidermal growth factor signal transduction pathways. Ras appears to function by initiating the activation of cellular protein kinases including mitogen-activated protein (MAP) kinases. Sos proteins contain numerous sequences in their carboxyl-terminal regions which correspond to consensus sites for MAP kinase phosphorylation. To examine whether these sites are substrates for MAP kinases, the cDNA encoding Drosophila Sos (dSos) was tagged with sequences encoding the major antigenic epitope of the influenza virus hemagglutinin (HA) to create a dSosHA fusion construct. dSosHA was transiently expressed in COS-1 cells and immunoprecipitated with anti-HA antibodies. When immune complexes were incubated with purified MAP kinase and [gamma-32P]ATP, a phosphorylated band of 180 kDa was observed when analyzed by SDS-polyacrylamide gel electrophoresis. This band was not present in immunoprecipitations from cells transfected with vector alone. No phosphorylation of the 180 kDa band was seen when immunoprecipitates were incubated with [gamma-32P]ATP in the absence of MAP kinase. Two dimensional analysis of tryptic peptides from dSosHA phosphorylated by MAP kinase in vitro revealed two major phosphorylated species that were also found in dSosHA isolated from COS-1 cells labeled with 32Pi. These results are consistent with the hypothesis that a feedback loop exists wherein growth factor-activated MAP kinases phosphorylate and regulate Sos proteins.
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PMID:Phosphorylation of the Ras nucleotide exchange factor son of sevenless by mitogen-activated protein kinase. 810 39

Intracellular signalling following mitogenic stimulation of quiescent cells involves the initiation of a phosphorylation cascade that leads to the rapid and reversible activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2. MAP kinase activation is mediated by dual phosphorylation within the motif Thr-Glu-Tyr by MAP kinase kinase (MEK). Following activation, the MAP kinases translocate into the nucleus where they phosphorylate several transduction targets, including transcription factors. We have previously identified PAC1 as an immediate-early mitogen-inducible tyrosine phosphatase in nuclei of T cells. Here we present several lines of evidence indicating that PAC1 is a physiologically relevant MAP kinase phosphatase. Recombinant PAC1 in vitro is a dual-specific Thr/Tyr phosphatase with stringent substrate specificity for MAP kinase. Constitutive expression of PAC1 in vivo leads to inhibition of MAP kinase activity normally stimulated by epidermal growth factor, phorbol myristyl acetate, or T-cell receptor crosslinking. The inactivation of MAP kinase by PAC1 results in inhibition of MAP kinase-regulated reporter gene expression.
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PMID:Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1. 810 50

Activation of the mitogen-activated protein kinases (MAPKs) is a common event of many signal transduction pathways. MAPKs are phosphorylated and activated by an immediate upstream activating kinase, MEK. The proto-oncogene c-raf, encoding a serine/threonine kinase, has been reported to be a direct activator of MEK. In this paper, it is shown that growth factors activate MEK by stimulating c-raf and a raf-independent MEK activator. Treatment of Swiss3T3 cells with epidermal growth factor (EGF) rapidly increased the activity of MEK activator. Maximal activation was detected by 2.5 min and declined to the prestimulated level within 10 min. This stimulation of the MEK activator was temporally followed by increased activities of MEK and MAPK. The activation of MEK was accompanied by phosphorylation of this protein. To determine the relationship of this MEK activator and the c-raf kinase, cell lysates were immunoprecipitated with anti-raf antibody and assayed for MEK activation. Only a fraction (< 20%) of the MEK activating activity was detected in anti-raf immunoprecipitates from EGF-stimulated Swiss3T3 cells. Similar experiments with nerve growth factor stimulated pheochromocytoma 12 (PC-12) cells revealed that the raf kinase contributed less than 5% of the total MEK activating activity while the overwhelming majority of MEK activating activity remained in the postimmunoprecipitation supernatant in which the raf protein had been quantitatively depleted. These data demonstrate that Swiss3T3 and PC-12 cells contain at least two different growth factor sensitive MEK activators, one residing in anti-raf immunoprecipitates and a second activity that is separate from raf.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth factor induced MEK activation is primarily mediated by an activator different from c-raf. 818 Jan 83

We previously reported that epidermal growth factor (EGF) induced the disruption of gap junctional communication (gjc) and serine phosphorylation of connexin43 (Cx43) in T51B rat liver epithelial cells. However, the cascade of events linking EGF receptor activation to these particular responses have not been fully characterized. Furthermore, the serine kinase(s) acting directly on Cx43 remain unidentified. In the current study, we demonstrate that downmodulation of 12-0-tetradecanoylphorbol 13-acetate (TPA)-sensitive protein kinase C (PKC) activity does not affect EGF's ability to reduce junctional permeability or phosphorylate Cx43 in T51B cells. EGF in the presence or absence of chronic TPA treatment stimulated marked increases in Cx43 phosphorylation on numerous sites as determined by two-dimensional tryptic phosphopeptide mapping. Computer-assisted sequence analysis of Cx43 identified several protein kinase phosphorylation consensus sites including two sites for mitogen-activated protein (MAP) kinase. EGF stimulated activation of MAP kinase in a time- and dose-dependent manner where the kinetics of kinase activity corroborated its possible involvement in mediating EGF's effects. Moreover, purified MAP kinase directly phosphorylated Cx43 on serine residues in vitro. Two-dimensional tryptic and chymotryptic phosphopeptide mapping demonstrated that the in vitro phosphopeptides represented a specific subset of the in vivo phosphopeptides produced in response to EGF after chronic TPA treatment. Therefore, EGF-induced disruption of gjc and phosphorylation of Cx43 may be mediated in part by MAP kinase in vivo.
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PMID:Epidermal growth factor stimulates the disruption of gap junctional communication and connexin43 phosphorylation independent of 12-0-tetradecanoylphorbol 13-acetate-sensitive protein kinase C: the possible involvement of mitogen-activated protein kinase. 824 69


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