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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One major function of elevated Src kinase in epithelial cancer cells is to drive adhesion changes that are associated with the mesenchymal transition and metastasis. Here we review recent work that describes Src-induced shape changes, and the mechanisms involved, in cells derived from a model of colon cancer metastasis. Src activity in these cells is associated with formation and dynamic regulation of integrin adhesions and disorganization of E-cadherin-dependent cell-cell contacts. Furthermore, Src-induced deregulation of E-cadherin requires integrin signalling, demonstrating a complex interdependence between integrin- and cadherin-associated adhesion changes induced by Src. The integrin-induced signals that co-operate with Src to cause deregulation of cadherin-dependent cell-cell contacts include activation of the MEK/ERK and MLCK/myosin activities. Inhibition of this pathway suppresses integrin complexes formed on fibronectin, while promoting E-cadherin redistribution to sites of cell-cell contacts. Also, in embryonic fibroblasts that express N-cadherin (which is normally diffusely cytoplasmic as these cells maintain a fibroblastic morphology) suppressing integrin signalling and inhibiting the MEK/ERK/MLCK/myosin pathway relocalizes N-cadherin to cell-cell contacts. Our recent data therefore imply an important, and perhaps general, role for spatially controlled contractility in suppressing normal cadherin localization and inducing a mesenchymal-like phenotype.
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PMID:The SRC-induced mesenchymal state in late-stage colon cancer cells. 1594 95

Intratumoral levels of E1 (oestrone), E1S (oestrone sulphate) and E2 (oestradiol) are significantly reduced by treatment with the aromatase inhibitor anastrozole regardless of treatment response. The purpose of the present pilot study was to look for additional markers of biochemical response to aromatase inhibitors on mRNA expression level. Whole genome expression was studied using microarray analysis of breast cancer tissue from 12 patients with locally advanced tumors, both before and following 15 weeks of treatment with the aromatase inhibitor anastrozole (Arimidex). Intratumoral mRNA levels for a subset of genes coding for steroid metabolizing enzymes, hormone receptors and some growth mediators involved in cell cycle control were analysed by quantitative RT-PCR. There was a correlation between the two methods for some but not all genes. The mRNA expression levels of the different genes were correlated to each other and to the intratumoral levels of E1, E2 and E1S, before and after the treatment. Notably, a correlation of the E1/E2 metabolic ratio to the mRNA levels of CYP19A1 was observed before treatment (r=0.745, p<0.005). Whole genome expression analysis of these 12 breast cancer patients revealed similar tumor classification to previously published larger studies. Tumors with no or low expression of ESR1 (oestrogen receptor) clustered together and were characterized by a strong basal-like signature highly expressing keratins 5/17, cadherin 3, frizzled and apolipoprotein D, among others. The luminal epithelial tumor cluster, on the other hand, highly expressed ESR1, GATA binding protein 3 and N-acetyl transferase. An evident ERBB2 cluster was observed due to the marked over-expression of the ERBB2 gene and GRB7 and PPARBP in this patient material). Using significance analysis of microarrays (SAM), we identified 298 genes significantly differently expressed between the partial response and progressive disease groups.
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PMID:Effects of anastrozole on the intratumoral gene expression in locally advanced breast cancer. 1602 38

Ras proteins control the signalling pathways that are responsible for normal growth and malignant transformation. Raf protein kinases are direct Ras effector proteins that initiate the mitogen-activated protein kinase (MAPK) cascade, which mediates diverse biological functions such as cell growth, survival and differentiation. Here we show that prohibitin, a ubiquitously expressed and evolutionarily conserved protein is indispensable for the activation of the Raf-MEK-ERK pathway by Ras. The membrane targeting and activation of C-Raf by Ras needs prohibitin in vivo. In addition, direct interaction with prohibitin is required for C-Raf activation. C-Raf kinase fails to interact with the active Ras induced by epidermal growth factor in the absence of prohibitin. Moreover, in prohibitin-deficient cells the adhesion complex proteins cadherin and beta-catenin relocalize to the plasma membrane and thereby stabilize adherens junctions. Our data show an unexpected role of prohibitin in the activation of the Ras-Raf signalling pathway and in modulating epithelial cell adhesion and migration.
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PMID:Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration. 1604 67

There is increasing evidence that factors originally identified due to their neurotrophic activity also function within the immune system. This study focused on the related molecules glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) as well as their receptors. GDNF and NTN signaling is mediated by a two-component receptor: a signal-transducing component, RET, which is shared by both ligands, and a ligand-specific binding component, GFR alpha-1 (higher GDNF affinity) or GFR alpha-2 (higher NTN affinity). We report that human T cells, B cells, and monocytes produce NTN but not GDNF, as seen by RT-PCR and immunocytochemistry. RET was expressed by B cells, T cells, and monocytes. Exons 2-5 of RET encoding the cadherin-like domains 1-3 in the extracellular part and exons 16-19 encoding a section of the second tyrosine kinase domain were transcribed in CD4+ T cells, CD8+ T cells, B cells, and monocytes. Different splice variants encoding the C-terminal intracellular part (exons 19-21) of RET were detected. The ligand-binding receptors GFR alpha-1 and GFR alpha-2 were transcribed in all immune cell subsets. Quantitative PCR showed that GFR alpha-2 is by far the dominant ligand binding chain in T cells, B cells, and monocytes. Addition of GDNF or NTN to activated PBMCs reduced the amount of detectable TNF protein without altering its transcription. Together, this suggests that immune cells communicate with each other via NTN. Production of NTN by immune cells might also contribute to the neuroprotective immunity in the CNS observed in different model systems.
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PMID:Expression and function of glial cell line-derived neurotrophic factor family ligands and their receptors on human immune cells. 1608 99

Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-kappaB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.
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PMID:A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. 1616 60

Prohibitin has been connected to diverse cellular functions including cell cycle control, senescence, apoptosis and stabilization of mitochondrial proteins. By employing a loss of function approach using siRNAs we have demonstrated an unexpected role of PHB in the activation of Raf/MEK/ERK pathway by active Ras and in modulating epithelial cell adhesion and migration. PHB directly interacts with C-Raf and is required for the displacement of 14-3-3 from C-Raf by active Ras to facilitate plasma membrane localization and activation. Further, the adherent complex proteins cadherin and beta-catenin were localized to plasma membrane suggesting stabilized adherent junctions in PHB silenced cells. Our findings demonstrated a function of PHB in the control of a central signaling pathway involved in cell growth and malignant transformation.
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PMID:Ras-Raf signaling needs prohibitin. 1629 14

Familial medullary thyroid carcinoma (FMTC) is an autosomal dominant inherited disease, characterized by germ-line mutations in the RET proto-oncogene, mainly in exons 10 and 11, but also in exons 13, 14 and 15. Recently, mutations in exons 8 and 16 associated with FMTC were also described. In the herein presented study, single strand conformation polymorphism (SSCP) method for rapid screening of mutations in the RET proto-oncogene and fluorescent sequencing method were used. In one Czech family with FMTC, we have identified a novel missense point mutation of the RET proto-oncogene in exon 5, that results in substitution of arginine by glycine at codon 321 in the cadherin-like domain of ret protein. It seems that this mutation causes FMTC as no other mutation was found in the classical risk exons (10, 11, 13, 14, 15 and 16) of the RET proto-oncogene. The mutation cosegregates with medullary thyroid carcinoma (MTC) or C cell hyperplasia (CCH) in two patients; two other family members are mutation carriers without clinical signs of MTC so far. To improve the diagnosis of FMTC, analysis of exon 5 of the RET proto-oncogene should be considered in families with no identified classical RET mutations.
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PMID:Exon 5 of the RET proto-oncogene: a newly detected risk exon for familial medullary thyroid carcinoma, a novel germ-line mutation Gly321Arg. 1641 93

A fundamental requirement during organogenesis is to preserve tissue integrity to render a mature and functional structure. Many epithelial organs, such as the branched tubular structures, undergo a tremendous process of tissue remodelling to attain their final pattern. The cohesive properties of these tissues need to be finely regulated to promote adhesion yet allow flexibility during extensive tissue remodelling. Here, we report a new role for the Egfr pathway in maintaining epithelial integrity during tracheal development in Drosophila. We show that the integrity-promoting Egfr function is transduced by the ERK-type MAPK pathway, but does not require the downstream transcription factor Pointed. Compromising Egfr signalling, by downregulating different elements of the pathway or by overexpressing the Mkp3 negative regulator, leads to loss of tube integrity, whereas upregulation of the pathway results in increased tissue stiffness. We find that regulation of MAPK pathway activity by Breathless signalling does not impinge on tissue integrity. Egfr effects on tissue integrity correlate with differences in the accumulation of markers for cadherin-based cell-cell adhesion. Accordingly, downregulation of cadherin-based cell-cell adhesion gives rise to tracheal integrity defects. Our results suggest that the Egfr pathway regulates maintenance of tissue integrity, at least in part, through the modulation of cell adhesion. This finding establishes a link between a developmental pathway governing tracheal formation and cell adhesiveness.
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PMID:Egfr is essential for maintaining epithelial integrity during tracheal remodelling in Drosophila. 1683 30

In the Drosophila retina, photoreceptor differentiation is preceded by significant cell shape rearrangements within and immediately behind the morphogenetic furrow. Groups of cells become clustered into arcs and rosettes in the plane of the epithelium, from which the neurons subsequently emerge. These cell clusters also have differential adhesive properties: adherens junction components are upregulated relative to surrounding cells. Little is known about how these morphological changes are orchestrated and what their relevance is for subsequent neuronal differentiation. Here, we report that the transcription factor Atonal and the canonical EGF receptor signalling cascade are both required for this clustering and for the accompanying changes in cellular adhesion. In the absence of either component, no arcs are formed behind the furrow, and all cells show low Armadillo and DE-cadherin levels, although in the case of EGFR pathway mutants, single, presumptive R8 cells with high levels of adherens junction components can be seen. Atonal regulates DE-cadherin transcriptionally, whereas the EGFR pathway, acting through the transcription factor Pointed, exerts its effects on adherens junctions indirectly, at a post-transcriptional level. These observations define a new function for EGFR signalling in eye development and illustrate a mechanism for the control of epithelial morphology by developmental signals.
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PMID:Epithelial cell adhesion in the developing Drosophila retina is regulated by Atonal and the EGF receptor pathway. 1696 16

In the present work we used a murine mammary cancer model of two related adenocarcinomas with different lung metastasizing abilities, to compare their global gene expression profiles. Clontech Atlas mouse cDNA microarrays of primary cultured tumor cells were employed to identify genes that are modulated in the more metastatic variant MM3 relative to its parental tumor M3. A total of 88 from 1,176 genes were differentially expressed in MM3 primary cultures, most of them (n=86) were upregulated. Genes were grouped according to their functions as associated with signal transduction and transcription regulation (e.g. Stat1 and Zfp 92), with cell adhesion and motility (cadherin 1, fibronectin), with invasion and angiogenesis (uPA, 72 kDa MMP2), with the regulation of cell proliferation and cell death (cyclins G and A2, TNF), and also included growth factors and receptors, oncogenes and tumor suppressors genes (p107, TGFbeta2, TBR-I, PDGFR). Only 2 genes, TTF1 and fibronectin (FN), showed a significant downregulation. Notably FN expression, loss of which has been associated with a malignant phenotype, was reduced about 19-fold in the more metastatic MM3 cells. Previously known differences in expression patterns associated with the metastatic capacity of MM3 and M3 adenocarcinomas, including downregulation of FN or upregulated expression of TGFbeta and proteases, were confirmed by the array data. The fact that FN was one of the only two genes significantly down-regulated out of the 1,176 genes analyzed stresses the hypothesis that FN may behave as an important metastasis suppressor gene in mammary cancer.
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PMID:Fibronectin is distinctly downregulated in murine mammary adenocarcinoma cells with high metastatic potential. 1708 68


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