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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ubiquitously expressed SH2-containing tyrosine phosphatases interact physically with tyrosine kinase receptors or their substrates and relay positive mitogenic signals via the activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. Conversely, the structurally related phosphatase SHP-1 is predominantly expressed in hemopoietic cells and becomes tyrosine phosphorylated upon colony-stimulating factor 1 treatment of macrophages without associating with the colony-stimulating factor 1 receptor tyrosine kinase. Mice lacking functional SHP-1 (me/me and me(v)/me(v)) develop systemic autoimmune disease with accumulation of macrophages, suggesting that SHP-1 may be a negative regulator of hemopoietic cell growth. By using macrophages expressing dominant negative Ras and the me(v)/me(v) mouse mutant, we show that SHP-1 is activated in the course of mitogenic signal transduction in a Ras-dependent manner and that its activity is necessary for the Ras-dependent activation of the MAPK pathway but not of the Raf-1 kinase. Consistent with a role for SHP-1 as an intermediate between Ras and the MEK-MAPK pathway, Ras-independent activation of the latter kinases by bacterial lipopolysaccharide occurred normally in me(v)/me(v) cells. Our results sharply accentuate the diversity of signal transduction in mammalian cells, in which the same signaling intermediates can be rearranged to form different pathways.
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PMID:Involvement of the protein tyrosine phosphatase SHP-1 in Ras-mediated activation of the mitogen-activated protein kinase pathway. 888 25

Fas-mediated cell death was examined in MCF-10AT preneoplastic human breast epithelial cells. Treatment with anti-Fas for 48 h induced apoptosis with cells exhibiting typical apoptotic features including loss of cell contact, condensation of chromatin, and increased staining of the nuclear membrane. DNA fragmentation occurred in response to anti-Fas treatment. Anti-Fas treatment resulted in decreased p53 protein levels, while bcl-2 and bax protein levels remained unaffected. Cells treated with anti-Fas also exhibited increased tyrosine phosphorylation of the c-met growth factor receptor tyrosine kinase. Immunoprecipitation experiments demonstrated that Fas associated with c-erbB2 and c-met in untreated cells. Treatment with anti-Fas, however, significantly decreased Fas-c-erbB2 and Fas-c-met association. Anti-Fas treatment of these cells caused a significant decrease in p120-GAP levels, ERK-1 levels, and phosphorylation, as well as Grb2-Sosl and MEK-1-ERK-1 association. These results show that Fas-signaling exerted a suppressive effect on p53 levels and on downstream effectors of receptor tyrosine kinase signal transduction, thereby ensuring cell death.
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PMID:Fas-signaling and effects on receptor tyrosine kinase signal transduction in human breast epithelial cells. 902 68

Binding of estrogen to its receptor (ER) activates early genes that drive responsive cells through the proliferative phase. Earlier studies to evaluate the expression of protooncogenes, growth factors, growth factor receptor and steroid hormone receptor gene activities in the rat uterine system indicated complex pathways that involve significant 'crosstalk' between ER-systems and signal transduction pathways (Bhattacharyya et al., 1994). To analyze the interactions between these factors, we examined two well characterized estrogen dependent (MCF-7) and estrogen independent (MDA-MB-231) human breast cancer cell lines. Antibodies to estrogen receptor, epidermal growth factor receptor, c-Fos, c-Jun, and Ras proteins, protein kinases involved in receptor tyrosine kinase signal transduction pathway, MEK1 and phosphotyrosine were utilized in immunocytochemical localization experiments to evaluate temporal expression of these factors in response to estrogen treatment. ER, which was diminished in MCF-7 cells grown in estrogen-stripped medium, increased 9-fold in estrogen-reconstituted medium by 120 min. Fos and Jun appeared at nuclear and perinuclear cytoplasmic sites within 60 min after estrogen treatment in MCF-7 cells. Fos/Jun proteins were prominent in MDA-MB-231 cells, especially in association with actin filaments. Immunolabeling studies revealed no EGF-r in MCF-7 cells, while MDA-MB-231 cells contained intense EGF-r labeling in the plasma membrane. Ras protein was prominent in the cytoplasm and at the cell surface within 60 min after treatment of MCF-7 cells with estrogen. Ras was intense in MDA cells. Similarly, MCF-7 and MDA cells contained high concentrations of MEK1 and phosphotyrosine (pTyr) containing proteins in their cytoplasm and immunolabeling remained high as long as MCF-7 cells were grown in medium containing estrogen. It is speculated that MEK1 (cytoplasmic) functioning through Fos/Jun or Myc/Max (nuclear) may regulate the activity of AP-1 transcription factor. In all cases however, MEK1 and pTyr protein labeling was more intense in the highly metastatic and hormone independent MDA-MB-231 breast cancer cells. Results revealed signal transduction pathway proteins in ER+ estrogen dependent cells suggesting possible crosstalk between both receptor pathways during the proliferative phase of MCF-7 cells.
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PMID:Estrogen receptor, growth factor receptor and protooncogene protein activities and possible signal transduction crosstalk in estrogen dependent and independent breast cancer cell lines. 906 37

14-3-3 proteins have been shown to interact with Raf-1 and cause its activation when overexpressed. However, their precise role in Raf-1 activation is still enigmatic, as they are ubiquitously present in cells and found to associate with Raf-1 in vivo regardless of its activation state. We have analyzed the function of the Drosophila 14-3-3 gene leonardo (leo) in the Torso (Tor) receptor tyrosine kinase (RTK) pathway. In the syncytial blastoderm embryo, activation of Tor triggers the Ras/Raf/MEK pathway that controls the transcription of tailless (tll). We find that, in the absence of Tor, overexpression of leo is sufficient to activate tll expression. The effect of leo requires D-Raf and Ras1 activities but not KSR or DOS, two recently identified essential components of Drosophila RTK signaling pathways. Tor signaling is impaired in embryos derived from females lacking maternal expression of leo. We propose that binding to 14-3-3 by Raf is necessary but not sufficient for the activation of Raf and that overexpressed Drosophila 14-3-3 requires Ras1 to activate D-Raf.
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PMID:The Drosophila 14-3-3 protein Leonardo enhances Torso signaling through D-Raf in a Ras 1-dependent manner. 937 12

We have characterized some of the nerve growth factor (NGF) stimulated receptor tyrosine kinase (TrkA) signalling cascades in adult rat primary dorsal root ganglia (DRG) neuronal cultures and compared the pathways with those found in PC12 cells. TrkA receptors were phosphorylated on tyrosine residues in response to NGF in DRG neuronal cultures. We also saw phosphorylation of phospholipase Cgamma1 (PLCgamma1). We used recombinant glutathione-S-transferase (GST)-PLCgamma1 SH2 domain fusion proteins to study the site of interaction of TrkA receptors with PLCgamma1. TrkA receptors derived from DRG neuronal cultures bound preferentially to the amino terminal Src homology-2 (SH2) domain of PLCgamma1, but there was enhanced binding with tandemly expressed amino- and carboxy-terminal SH2 domains. The most significant difference in NGF signalling between PC12 cells and DRG was with the Shc family of adapter proteins. Both ShcA and ShcC were expressed in DRG neurons but only ShcA was detected in PC12 cells. Different isoforms of ShcA were phosphorylated in response to NGF in DRG and PC12 cells. NGF phosphorylated only one whereas epidermal growth factor phosphorylated both isoforms of ShcC in DRG cultures. Activation of the downstream mitogen-activated protein (MAP) kinase, p42Erk2 was significantly greater than p44Erk1 in DRG whereas both isoforms were activated in PC12 cells. Blocking the MAP kinase cascade using a MEK1/2 inhibitor, PD98059, abrogated NGF dependent capsaicin sensitivity, a nociceptive property specific to sensory neurons.
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PMID:Differential regulation of SHC proteins by nerve growth factor in sensory neurons and PC12 cells. 975 87

Activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway is required for ligand-dependent regulation of numerous cellular functions by receptor tyrosine kinases. We have shown previously that although many receptor tyrosine kinase ligands are mitogens for keratinocytes, cell migration and induction of the 92-kilodalton gelatinase/matrix metalloproteinase (MMP)-9 are selectively regulated by the epidermal growth factor and scatter factor/hepatocyte growth factor receptors. In this report we present evidence of an underlying mechanism to account for these observed differences in receptor tyrosine kinase-mediated response. Ligands that are mitogenic, but do not induce MMP-9 or colony dispersion, transiently activate the p42/p44 ERK/MAP kinases. In contrast, ligands that stimulate MMP-9 induction and colony dispersion induced sustained activation of these kinases. The functional significance of sustained MAPK activation was demonstrated by inhibition of the MAP kinase kinase MEK1. Disruption of the prolonged signal by addition of the MEK1 inhibitor PD 98059 up to 4 h after growth factor stimulation substantially impaired ligand-dependent colony dispersion and MMP-9 induction. These findings support the conclusion that duration of MAPK activation is an important determinant for certain growth factor-mediated functions in keratinocytes.
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PMID:Sustained activation of the mitogen-activated protein kinase pathway. A mechanism underlying receptor tyrosine kinase specificity for matrix metalloproteinase-9 induction and cell migration. 993 37

We have studied the osmotically induced gene expression (measured as chloramphenicol acetyl transferase (CAT) reporter gene expression) in rat smooth muscle cell primary cultures (rSMC), under the control of osmotic response elements (ORE). It was found that osmotically induced gene expression is sensitive to signal transduction inhibitors and activators. In particular, protein kinase C inhibition by calphostin C prevented gene expression by osmotic response. On the other hand, receptor tyrosine kinase inhibition has been shown to produce an enhancement of gene expression. This suggests that tyrosine kinase receptor activation exerts an inhibitory action on ORE induced gene expression. Gene expression was also induced by treating cells with PD098059, a specific inhibitor of mitogen-activated protein kinase kinase. Moreover, the same inhibitors and activators have been shown to affect the hyperosmosis induced expression of aldose reductase gene.
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PMID:Signal transduction in rat vascular smooth muscle cells: control of osmotically induced aldose reductase expression by cell kinases and phosphatases. 1008 47

In HL-60 human myeloblastic leukemia cells, retinoic acid is known to cause cFMS, RAF, MEK, and ERK2 dependent myeloid cell differentiation and G0 arrest associated with RB tumor suppressor protein hypophosphorylation, implicating receptor tyrosine kinase signal transduction in propelling these retinoic acid-induced cellular effects. Furthermore, ectopic expression of polyoma middle T antigen, which activates similar early signal transduction molecules as PDGF class receptors such as cFMS, accelerates these retinoic acid-induced effects. To determine if this depends on middle T's ability to activate PLCgamma, PI-3 kinase, and src-like kinases, stable transfectants of HL-60 cells expressing either the polyoma middle T dl23 mutant, which is defective for PLCgamma and PI-3 kinase activation, or the Delta205 mutant, which in addition has greatly attenuated src-like kinase activation ability, were created and compared to wild-type middle T-transfected HL-60. The transgenes were under control of the retinoic acid (or 1, 25-dihydroxy vitamin D3) inducible Moloney murine leukemia virus LTRs. Expression of the dl23 or Delta205 mutant accelerated retinoic acid-induced cell differentiation. The effects of the mutants were comparable to those of the wild-type middle T. Likewise, retinoic acid-induced G0 arrest of mutant transfected cells and wild-type middle T transfected cells was similar. The same was true for 1, 25-dihydroxy vitamin D3-induced monocytic differentiation as for retinoic acid-induced myeloid differentiation. The mutants did not cause the same slight shortening of the cell cycle as wild-type middle T. Both the mutants and the wild-type middle T caused a similar increase in the cellular basal level of activated ERK2 MAPK. Since retinoic acid increases ERK2 activation, which is necessary for differentiation, the data suggest that mutant and wild-type middle T enhanced the retinoic acid effects by increasing basal levels of ERK2 activation. Consistent with this, the polyoma-induced foreshortening of the time for differentiation coincided with the time for retinoic acid to significantly increase ERK2 activation. As in wild-type HL-60, retinoic acid induced the early down-regulation of RXRalpha in mutant transfectants similar to wild-type middle T transfectants, consistent with no loss or gain of relevant functions due to the mutations. In contrast, vitamin D3 did not down-regulate RXRalpha in HL-60 or transfectants. Polyoma middle T and these transformation-defective mutants thus enhanced ERK2 activation to have an early effect in promoting retinoic acid-induced differentiation without a strong dependence on activating PLCgamma, PI-3 kinase, or src-like kinase.
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PMID:Transformation-defective polyoma middle T antigen mutants defective in PLCgamma, PI-3, or src kinase activation enhance ERK2 activation and promote retinoic acid-induced, cell differentiation like wild-type middle T. 1022 45

There is at present, much optimism about the possibility of finding selective anticancer drugs that will eliminate the cytotoxic side effects associated with conventional cancer chemotherapy. This hope is based on uncovering many novel molecular targets that are 'cancer-specific', which will allow the targeting of cancer cells while normal cells are spared. Thus far, encouraging results have been obtained with several of these novel agents at the preclinical level, and clinical trials have begun. These targets are involved at one level or more in tumor biology, including tumor cell proliferation, angiogenesis and metastasis. Novel targets for which advances are being made include the following: growth factor receptor tyrosine kinases such as the epidermal growth factor receptor and HER-2/neu (proliferation); the vascular endothelial growth factor receptor and the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP-binding protein Ras (especially agents targeting Ras farnesylation, farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation and drug resistance); cyclin-dependent kinases (proliferation); and matrix metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored, but potentially useful targets include the receptor tyrosine kinase platelet-derived growth factor receptor, mitogen-activated protein kinase cascade oncogenes such as Raf-1 and mitogen-activated protein kinase kinase, cell adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2 and survivin, and the cell life-span target telomerase.
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PMID:Novel anticancer drug discovery. 1041 54

The proliferation and metabolism of H4IIE hepatoma cells is apparently mediated through the insulin receptor. These cells, however, also have high-affinity binding sites for insulin-like growth factor-I (IGF-I). Addition of insulin to H4IIE cells increased RNA synthesis, DNA synthesis and cell number. IGF-I, on the other hand, was ineffective at concentrations equivalent to the lowest effective insulin dose, although stimulation was observed with concentrations 100-fold higher. Similar results were obtained when glucose uptake was measured. Western blot analysis demonstrated that tyrosine phosphorylation patterns produced by insulin and IGF-I differed. In particular, phosphorylation of insulin receptor substrate-1 (IRS-1) was evident after treatment with insulin, but not after treatment with IGF-I. Correspondingly, insulin, but not IGF-I, stimulated receptor tyrosine kinase activity. In contrast with these results, both insulin and IGF-I induced mitogen-activated protein (MAP) kinase phosphorylation and activity at a concentration of 10 nM. The correlation between insulin-dependent and IGF-I-dependent MAP kinase activation was confirmed by Western blot analysis of phosphorylated MAP kinase kinase (MEK). These results suggest that phosphorylation of IRS-1 is essential for both cell proliferation and glucose metabolism, but is uncoupled from the MAP kinase cascade. Furthermore, stimulation of MEK and MAP kinase is independent of receptor tyrosine kinase activity.
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PMID:Insulin-like growth factor-I (IGF-I)-dependent activation of pp42/44 mitogen-activated protein kinase occurs independently of IGF-I receptor kinase activation and IRS-1 tyrosine phosphorylation. 1058 12


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