Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

PHAS-I or the eIF4E-binding protein 1 regulates the cap-binding activity of eIF4E by sequestering eIF4E. Binding of elF4E to PHAS-I is regulated by phosphorylation of PHAS-I. PC12 cells were used to study the signal transduction pathway leading to phosphorylation of PHAS-I. Both EGF and NGF induced phosphorylation of PHAS-I. Wortmannin, a PI-3 kinase inhibitor, staurosporine, a PKC inhibitor, and rapamycin, a FRAP inhibitor all blocked the phosphorylation of PHAS-I. Of the three inhibitors, only wortmannin was able to inhibit MAPK phosphorylation. This excludes a role for MAPK in NGF- and EGF-induced PHAS-I phosphorylation in PC12 cells. Apparently, PHAS-I was phosphorylated in a PI-3 kinase-, PKC-, and FRAP-dependent manner after EGF or NGF stimulation. Only PI-3 kinase and FRAP are involved in the regulation of the basal level of PHAS-I phosphorylation.
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PMID:Phosphorylation of the eIF4E-binding protein PHAS-I after exposure of PC12 cells to EGF and NGF. 891 81

Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.
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PMID:Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. 897 28

The activation of glycolytic flux is a biochemical characteristic of growing cells. Several reports have demonstrated the role of fructose 2,6-bisphosphate in this process. In this paper we show that the levels of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (6PF2K/Fru-2,6-P2ase) mRNA are modulated in response to serum and growth factors and this effect is due to regulation of its transcription rate. The modulation of the expression of this enzyme by growth factors differs according their mitogenic effect; both lysophosphatidic acid and epidermal growth factor, when added alone, increased the mRNA levels, but endothelin had no effect. Furthermore, cAMP, which acts as an antimitogenic signal in Rat-1 fibroblasts, produced a decrease in 6PF2K/Fru-2, 6-P2ase mRNA and inhibited the effects of lysophosphatidic acid and epidermal growth factor on 6PF2K/Fru-2,6-P2ase expression. PD 098059, a specific inhibitor of the activation of the mitogen-activated protein kinase, was able to prevent the effect of EGF on 6PF2K/Fru-2, 6-P2ase gene expression. These results imply that activation of mitogen-activated protein kinase is required for the stimulation of the transcription of 6PF2K/Fru-2,6-P2ase by EGF.
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PMID:Effect of growth factors on the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in Rat-1 fibroblasts. 900 27

Functional interactions between protein kinase A (PKA) and epidermal growth factor receptor (EGF-R) signalling pathways have been suggested. Unlike the type II isoform of PKA (PKAII), the type I (PKAI) and/or its regulatory subunit RIalpha are generally overexpressed in cancer cells and are induced following transforming growth factor alpha (TGF alpha)/EGF-R-dependent transformation. Downregulation of RIalpha/PKAI inhibits TGF alpha expression and EGF-R-dependent signalling. We have previously shown that addition of EGF to quiescent human normal epithelial MCF-10A cells determines PKAI expression and cell membrane translocation before cells enter S phase, while PKAI inhibition prevents S phase entry. Constitutive overexpression of PKAI confers the ability to grow in serum free medium, bypassing EGF requirement. Here we demonstrate a direct interaction of PKAI, but not of PKAII, with the activated EGF-R, that occurs within 5 min following EGF treatment of MCF-10A cells. Moreover, induction of mitogen-activated protein kinase (MAPK) activity following EGF-R activation is mimicked by PKAI overexpression and inhibited by downregulators of PKAI. Finally, the PKAI-EGF-R association occurs through the binding of RIalpha to the SH3 domain(s) of Grb2 adaptor protein, thus allowing the recruitment of the PKAI holoenzyme to the activated EGF-R. This is the first demonstration of a direct interaction of PKAI with the activated EGF-R macromolecular signalling complex.
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PMID:The RIalpha subunit of protein kinase A (PKA) binds to Grb2 and allows PKA interaction with the activated EGF-receptor. 905 Sep 91

Tyrphostins are synthetic compounds that have been described as in vitro inhibitors of epidermal growth factor receptor (EGF-R) tyrosine kinase activity. The inhibitory effect of tyrphostins in intact cells has been shown only after prolonged treatment. However, these compounds appear to be readily incorporated, which suggests that tyrphostin acts indirectly on EGF-R. We studied the effects of a tyrphostin derivative, RG 50864, without preincubation in intact epithelial cells. We selected two human cell lines differing in degree of expression of the p185erbB2 protein, which is closely related to EGF-R. We showed that tyrphostin (RG 50864) had no effect on EGF-dependent EGF-R tyrosine phosphorylation in the parental cell line. On the contrary, it prolonged the EGF-dependent EGF-R and p185erbB2(V-E) tyrosine phosphorylation in p185erbB2(V-E)-expressing cells. Because tyrphostin has been shown to be an inhibitor of p185erbB2 and EGF-R in vitro, this finding indicates that the tyrphostin effect on p185erbB2(V-E) and EGF-R was the result of an indirect mechanism in transfected cells. Tyrphostin treatment alone led to the activation of mitogen-activated protein (MAP) kinase kinase or MAP kinase or extracellular signal-regulated kinase kinase (MEK), suggesting that one of the tyrphostin targets was upstream of MEK1. MAP kinase, however, was not activated after tyrphostin treatment. This finding indicates that tyrphostin had another target in intact cells because MEK1 activation by tyrphostin alone did not correlate with MAP kinase activation. In the two cell lines, tyrphostin modified the time course of EGF-dependent MEK and MAP kinase activation. We conclude that whereas tyrphostins were designed to inhibit EGF-R tyrosine kinase activity, under our conditions EGF-R is not a physiological target for tyrphostin, nor is one of its related protein tyrosine kinases, p185erbB2(V-E). On the contrary, our results show that tyrphostin targets are multiple, leading to complex effects on receptor signaling in these epithelial cells.
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PMID:Epidermal growth factor receptor signaling cascade as target for tyrphostin (RG 50864) in epithelial cells. Paradoxical effects on mitogen-activated protein kinase kinase and mitogen-activated protein kinase activities. 906 32

Recently, it has been shown that the activation of the Drosophila EGF receptor (DER) by its natural ligand Spitz is inhibited by Argos [Schweitzer, R., et al. (1995) Nature 376, 699-702]. Argos and Spitz both have an EGF-like domain which in the case of Argos differs from that of Spitz and other EGF receptor agonists in that it has an extended B-loop of 20 amino acids instead of 10 amino acids which in addition contains an unusual cluster of charged residues. To investigate whether B-loop sequences are an important determinant for receptor activation and play a causal role in the antagonistic activity of Argos, three human (h)EGF mutants were constructed in which amino acids derived from the Argos B-loop were introduced. In one mutant (E3A4E/B10), replacement of four amino acids in the B-loop of hEGF (123, E24, D27, and K28) by the corresponding Argos residues neither altered the binding affinity of the growth factor for the hEGF receptor nor did it change its ability to induce a mitogenic response. Insertion of 2 additional Argos residues (E3A4E/B12) or extension of the B-loop by 10 amino acids (E3A4E/B20) resulted, however, in a significant loss of binding affinity. In spite of this, both E3A4E/B12 and E3A4E/B20 appeared to be strong agonists for the hEGF receptor with similar dose-response curves for mitogenic activity and MAPK activation as wild-type hEGF. These data show that several nonconservative substitutions in the hEGF B-loop are tolerated without affecting receptor binding or activation. Furthermore, they show that receptor binding and receptor signaling efficiency can be uncoupled which is a prerequisite for the development of receptor antagonists.
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PMID:Insertion of Argos sequences into the B-loop of epidermal growth factor results in a low-affinity ligand with strong agonistic activity. 920 Jun 90

Heparin and heparan are potent inhibitors of vascular smooth muscle cell (VSMC) proliferation. To investigate the mechanisms by which heparin suppresses growth factor stimulated mitogenesis, the present experiments investigated the effects of heparin on platelet-derived growth factor (PDGF) stimulated signal transduction pathways. Heparin treatment substantially inhibited PDGF-BB stimulated rat VSMC growth. Western analysis showed a 30 min PDGF-BB treatment of VSMC induced the tyrosine phosphorylation of multiple protein bands; cotreatment with heparin inhibited mitogen-activated protein (MAP) kinase tyrosine phosphorylation but had little effect on PDGF receptor tyrosine phosphorylation. In-gel kinase assays demonstrated that heparin inhibited PDGF-BB stimulated MAP kinase activity at late (25 min) but not early (10 min) time points. These data indicate that heparin does not inhibit the initial signalling events after PDGF-BB binding but instead acts through an alternate mechanism to inhibit MAP kinase. To investigate if heparin directly stimulates tyrosine phosphatase-mediated suppression of MAP kinase, we treated VSMC with orthovanadate, a tyrosine phosphatase inhibitor. Heparin inhibited MAP kinase tyrosine phosphorylation after orthovanadate treatment, indicating that heparin does not suppress MAP kinase by enlistment of a tyrosine phosphatase. Experiments were performed to investigate signalling pathways upstream of MAP kinase. To determine if protein kinase C (PKC) mediates PDGF-BB, serum, and EGF stimulation of MAP kinase, we treated VSMC overnight with phorbol ester (PMA) to downregulate PKC. Abolition of conventional and novel PKC activity significantly suppressed both serum and PDGF-BB induced MAP kinase activation, indicating protein kinase C is an important mediator for these mitogens. In contrast, downregulation of these PKC isoforms had little effect on EGF stimulation of MAP kinase. As heparin inhibits PDGF and serum but not EGF stimulation of MAP kinase, there data precisely correlate heparin inhibition of MAP kinase with activation through PKC-dependent pathways. Immunoprecipitation analysis found that heparin inhibited serum, PMA, and PDGF but not EGF induced raf-1 phosphorylation. These studies demonstrate that heparin did not block PDGF-BB receptor activation, which initiates the mitogenic signalling cascade. Heparin did inhibit specific postreceptor second messenger signals, such as the late phase activation of MAP kinase, which may be mediated by suppression of PKC-dependent pathways.
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PMID:Mechanisms of inhibition by heparin of PDGF stimulated MAP kinase activation in vascular smooth muscle cells. 920 27

The type-III deletion variant of the epidermal growth factor receptor (EGFRvIII) is frequently found in glioblastomas and other malignant human tumours. Although EGFRvIII confers ligand-independent oncogenic transformation of cell lines, the mechanism by which it promotes aberrant cellular proliferation is unknown. Using cell lines expressing comparable numbers of either wild-type receptor (EGFRwt) or EGFRvIII, we compared several parameters of receptor activation: dimerization, tyrosine phosphorylation and activation of intracellular signalling proteins. Like activated EGFRwt, EGFRvIII was phosphorylated and bound constitutively to the Shc adapter protein. Indeed, EGFRvIII-associated Shc had a higher phosphotyrosine content than Shc associated with stimulated EGFRwt. EGFRwt dimerized in response to either EGF or transforming growth factor alpha. Higher cross-linker concentrations and incubation at higher temperatures (37 degrees C) allowed detection of EGFRwt dimers even in the absence of exogenous ligand. In contrast, EGFRvIII failed to dimerize under any conditions studied. Moreover, neither mitogen-activated protein kinase nor phospholipase Cgamma were phosphorylated in EGFRvIII-expressing cells. We conclude that the deletion of 267 amino acids from the 621-amino-acid N-terminal domain of EGFR does not result simply in a constitutively activated receptor, but alters the spectrum of signalling cascades utilized. Furthermore the ligand-independent transforming activity of EGFRvIII is independent of receptor dimerization.
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PMID:Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). 921 Apr 10

Cyclooxygenase-2 (Cox-2), the inducible form of cyclooxygenase, is up-regulated in tumors and transformed cells. Because this enzyme catalyzes the formation of prostaglandins from arachidonic acid, chemopreventive strategies that suppress its expression could be useful for preventing cancer. We investigated whether retinoids suppressed basal expression of Cox-2 or EGF-mediated induction of Cox-2 in human oral squamous carcinoma cells. Treatment with retinoids [all-trans-retinoic acid (all-trans-RA), 9-cis-RA, 13-cis-RA, and retinyl acetate] suppressed both basal levels of Cox-2 and EGF-mediated induction of Cox-2 protein and synthesis of prostaglandin E2. Retinoids also suppressed the induction of Cox-2 mRNA by EGF. Transient transfection experiments showed that EGF caused about a 100% increase in Cox-2 promoter activity, an effect that was suppressed by retinoids. Levels of epidermal growth factor receptor were unaffected by retinoids. Epidermal growth factor caused a nearly 10-fold increase in mitogen-activated protein kinase activity; this effect was not blocked by retinoids.
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PMID:Retinoids suppress epidermal growth factor-induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells. 923 Jan 97

We demonstrate herein the ability of transforming growth factor-beta-2 (TGFbeta2) to potently activate extracellular signal-regulated kinase 2 (ERK2) in the highly TGFbeta-sensitive breast cancer cell (BCC) line Hs578T. The ERK2 isoform was activated by 3-fold within 5 min of TGFbeta2 addition to Hs578T cells. However, TGFbeta2 only slightly activated ERK2 (1.5-fold) in the partially TGFbeta-responsive BCC line MDA-MB-23 1. The magnitude of the difference in activation of ERK2 by TGFbeta2 in the two cell lines paralleled the difference in the IC50 values for TGFbeta inhibition of DNA synthesis; the IC50 value in the MDA-MB-231 cells was 32-fold greater than that in the Hs578T cells. Further, our data demonstrate that TGFbeta2 activated the stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) type of mitogen-activated protein kinases (MAPKs); maximal induction levels were 2.5-fold above basal values and were attained at 30 min after TGFbeta2 treatment. Transient co-transfection of a luciferase reporter construct (3TP-Lux) containing three AP-1 sites and the plasminogen activator inhibitor-1 (PAI-1) promoter, in conjunction with a construct that directs expression of a dominant-negative mutant ERK2 (TAYF) protein, did not block the ability of TGFbeta to induce AP-1 or PAI-1 activity. In contrast, TAYF ERK2 was able to block EGF and insulin-induced 3TP-Lux-reporter activity. These results indicate that in these BCCs, the activation of ERK2 by TGFbeta is more tightly linked to the ability of TGFbeta to inhibit DNA synthesis than to the ability to stimulate promoter regions important for TGFbeta production and control of the extracellular matrix. In addition, this is the first demonstration that TGFbeta can activate the SAPK/JNK type of MAPK in TGFbeta-sensitive human BCCs.
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PMID:TGFbeta regulation of mitogen-activated protein kinases in human breast cancer cells. 923 30


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