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)

The role of beta-catenin in breast cancer and its prognostic value is controversial. The prognostic value had been assessed previously in a series of nonquantitative immunohistochemical studies with conflicting results. In efforts to clarify the relationship between beta-catenin protein expression and breast cancer prognosis, we have assessed a retrospective 600 case cohort of breast cancer tumors from the Yale Pathology archives on tissue microarrays. They were assessed using automated quantitative analysis (AQUA) with a series of array-embedded cell lines for which the beta-catenin concentration was standardized by an ELISA assay. The expression levels of the standard clinical markers HER2, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 were also assessed on the same cohort. X-tile software was used to select optimal protein concentration cutpoints and to evaluate the outcome using a training set and a validation set. We found that low-level expression of membranous beta-catenin is associated with significantly worse outcome (38% versus 76%, 10-year survival, validation set log-rank P = 0.0016). Multivariate analysis of this marker, assessed in a proportional hazards model with tumor size, age, node status, nuclear grade, ER, PR, HER2, and Ki-67, is still highly significant with a hazard ratio of 6.8 (P < 0.0001, 95% confidence interval, 3.1-15.1). These results suggest that loss of beta-catenin expression at the membrane, as assessed by objective quantitative analysis methods, may be useful as a prognostic marker or may be part of a useful algorithm for prognosis in breast cancer.
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PMID:Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. 1670 78

The Src homology 2 phosphotyrosyl phosphatase (SHP2) is a nonreceptor-type phosphatase that acts as a positive transducer of receptor Tyr kinase (RTK) signaling, particularly the Ras-REK and PI3K-Akt pathways. Recently, we have demonstrated that SHP2 is required for cell transformation induced by the constitutively active fibroblast growth factor receptor 3 (K/E-FR3) (Oncogene, 22, 6909-6918). In that study, we had detected a phosphotyrosyl protein of approximately 100 KDa (p100) in cells expressing dominant-negative SHP2 (R/E-SHP2), but its identity and relevance in SHP2-meditaed transformation was not known. Here, we report the identification of p100 as alpha-catenin, a vinculin-related protein involved in adherens junction-mediated intercellular adhesion. We show that alpha-catenin becomes Tyr phosphorylated in intercellular adhesion-dependent manner and this event is counteracted by SHP2. Substrate trapping in intact cells and immunocomplex phosphatse assays confirmed that alpha-catenin is in deed an SHP2 substrate. Tyr phosphorylation of alpha-catenin enhances its translocation to the plasma membrane and its interaction with beta-catenin, leading to enhanced actin polymerization and stabilization of adherens junction-mediated intercellular adhesion, a phenomenon commensurate with loss of the transformation phenotype. Site-directed mutagenesis studies also suggested that Tyr phosphorylation of alpha-catenin enhances its inhibitory role on cell transformation. Based on our previous work and the current report, we demonstrate that mediation of cell transformation by SHP2 is a complex process that involves modulation of the Ras-ERK and PI3K-Akt signaling pathways, intercellular adhesion, focal adhesion and actin cytoskeletal reorganization. To our knowledge, this is the first report showing regulation of alpha-catenin function by Tyr phosphorylation and its inhibitory effect on cell transformation.
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PMID:Modulation of alpha-catenin Tyr phosphorylation by SHP2 positively effects cell transformation induced by the constitutively active FGFR3. 1676 62

Dysregulation of pleiotropic growth factors, receptors and their downstream signaling pathway components represent a central protumorigenic principle in human hepatocarcinogenesis. Especially the Insulin-like Growth Factor/IGF-1 receptor (IGF/IGF-1R), Hepatocyte Growth Factor (HGF/MET), Wingless (Wnt/beta-catenin/FZD), Transforming Growth Factor alpha/Epidermal Growth Factor receptor (TGFalpha/EGFR) and Transforming Growth Factor beta (TGFbeta/TbetaR) pathways contribute to proliferation, antiapoptosis and invasive behavior of tumor cells. This review focuses on the relevant alterations in these pathways identified in human human hepatocellular carcinomas (HCCs). Resultant functional effects are modulated by multiple cross-talks between the different signaling pathways and additional tumor-relevant factors, such as cyclooxygenase-2 and p53. Several specific strategies are currently under development such as receptor kinase inhibitors, neutralizing antibodies and antagonistic proteins, which may improve the systemic treatment of human HCCs.
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PMID:Dysregulation of growth factor signaling in human hepatocellular carcinoma. 1679 20

Overexpressed or activated hepatocyte growth factor receptor, encoded by the MET proto-oncogene, was found in the majority of colorectal carcinomas (CRCs), whose stepwise progression to malignancy requires transcriptional activation of beta-catenin. We here demonstrate that a functional crosstalk between Met and beta-catenin signaling sustains and increases CRC cell invasive properties. Hepatocyte growth factor (HGF) stimulation prompts beta-catenin tyrosine phosphorylation and dissociation from Met, and upregulates beta-catenin expression via the phosphatidylinositol 3-kinase pathway in conditions that mimic those found by the invading and metastasizing cells. Additionally, a transcriptionally active form of beta-catenin, known to be oncogenic, enhances Met expression. Furthermore, HGF treatment increases the activity of the beta-catenin-regulated T-cell factor transcription factor in cells expressing the wild-type or the oncogenic beta-catenin. In the mirror experiments, either Met or beta-catenin knocking down also reduces their protein level. In biological assays, beta-catenin knocking down abrogates the HGF-induced motile phenotype, whereas active beta-catenin fosters ligand-independent cell scattering. Met and beta-catenin also cooperate in promoting entry into the cell cycle and in protecting cells from apoptosis. In conclusion, Met and beta-catenin pathways are mutually activated in CRC cells. This might generate a self-amplifying positive feedback loop resulting in the upregulation of the invasive growth properties of CRC cells.
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PMID:A positive feedback loop between hepatocyte growth factor receptor and beta-catenin sustains colorectal cancer cell invasive growth. 1695 30

4-Hydroxy-2-nonenal (4-HNE), one of the major biologically active aldehydes formed during inflammation and oxidative stress, has been implicated in a number of cardiovascular and pulmonary disorders. 4-HNE has been shown to increase vascular endothelial permeability; however, the underlying mechanisms are unclear. Hence, in the current study, we tested our hypothesis that 4-HNE-induced changes in cellular thiol redox status may contribute to modulation of cell signaling pathways that lead to endothelial barrier dysfunction. Exposure of bovine lung microvascular endothelial cells (BLMVECs) to 4-HNE induced reactive oxygen species generation, depleted intracellular glutathione, and altered cell-cell adhesion as measured by transendothelial electrical resistance. Pretreatment of BLM-VECs with thiol protectants, N-acetylcysteine and mercaptopropionyl glycine, attenuated 4-HNE-induced decrease in transendothelial electrical resistance, reactive oxygen species generation, Michael protein adduct formation, protein tyrosine phosphorylation, activation of ERK, JNK, and p38 MAPK, and actin cytoskeletal rearrangement. Treatment of BLMVECs with 4-HNE resulted in the redistribution of FAK, paxillin, VE-cadherin, beta-catenin, and ZO-1, and intercellular gap formation. Western blot analyses confirmed the formation of 4-HNE-derived Michael adducts with the focal adhesion and adherens junction proteins. Also, 4-HNE decreased tyrosine phosphorylation of FAK without affecting total cellular FAK contents, suggesting the modification of integrins, which are natural FAK receptors. 4-HNE caused a decrease in the surface integrin in a time-dependent manner without altering total alpha5 and beta3 integrins. These results, for the first time, revealed that 4-HNE in redox-dependent fashion affected endothelial cell permeability by modulating cell-cell adhesion through focal adhesion, adherens, and tight junction proteins as well as integrin signal transduction that may lead dramatic alteration in endothelial cell barrier dysfunction during heart infarction, brain stroke, and lung diseases.
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PMID:Redox regulation of 4-hydroxy-2-nonenal-mediated endothelial barrier dysfunction by focal adhesion, adherens, and tight junction proteins. 1698 27

Studies in Caenorhabditis elegans and vertebrates have established that the MAP kinase-related protein NLK counteracts Wnt signalling by downregulating the transcription factor TCF. Here, we present evidence that during early development of the sea urchin embryo, NLK is expressed in the mesodermal precursors in response to Notch signalling and directs their fate by downregulating TCF. The expression pattern of nlk is strikingly similar to that of Delta and the two genes regulate the expression of each other. nlk overexpression, like ectopic activation of Notch signalling, provoked massive formation of mesoderm and associated epithelial mesenchymal transition. NLK function was found to be redundant with that of the MAP kinase ERK during mesoderm formation and to require the activity of the activating kinase TAK1. In addition, the sea urchin NLK, like its vertebrate counterpart, antagonizes the activity of the transcription factor TCF. Finally, activating the expression of a TCF-VP16 construct at blastula stages strongly inhibits endoderm and mesoderm formation, indicating that while TCF activity is required early for launching the endomesoderm gene regulatory network, it has to be downregulated at blastula stage in the mesodermal lineage. Taken together, our results indicate that the evolutionarily conserved TAK/NLK regulatory pathway has been recruited downstream of the Notch/Delta pathway in the sea urchin to switch off TCF-beta-catenin signalling in the mesodermal territory, allowing precursors of this germ layer to segregate from the endomesoderm.
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PMID:Nemo-like kinase (NLK) acts downstream of Notch/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo. 1703 19

Bone and cartilage and their disorders are addressed under the following headings: functions of bone; normal and abnormal bone remodeling; osteopetrosis and osteoporosis; epithelial-mesenchymal interaction, condensation and differentiation; osteoblasts, markers of bone formation, osteoclasts, components of bone, and pathology of bone; chondroblasts, markers of cartilage formation, secondary cartilage, components of cartilage, and pathology of cartilage; intramembranous and endochondral bone formation; RUNX genes and cleidocranial dysplasia (CCD); osterix; histone deacetylase 4 and Runx2; Ligand to receptor activator of NFkappaB (RANKL), RANK, osteoprotegerin, and osteoimmunology; WNT signaling, LRP5 mutations, and beta-catenin; the role of leptin in bone remodeling; collagens, collagenopathies, and osteogenesis imperfecta; FGFs/FGFRs, FGFR3 skeletal dysplasias, craniosynostosis, and other disorders; short limb chondrodysplasias; molecular control of the growth plate in endochondral bone formation and genetic disorders of IHH and PTHR1; ANKH, craniometaphyseal dysplasia, and chondrocalcinosis; transforming growth factor beta, Camurati-Engelmann disease (CED), and Marfan syndrome, types I and II; an ACVR1 mutation and fibrodysplasia ossificans progressiva; MSX1 and MSX2: biology, mutations, and associated disorders; G protein, activation of adenylyl cyclase, GNAS1 mutations, McCune-Albright syndrome, fibrous dysplasia, and Albright hereditary osteodystrophy; FLNA and associated disorders; and morphological development of teeth and their genetic mutations.
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PMID:The new bone biology: pathologic, molecular, and clinical correlates. 1710 47

Activation of the fibroblast growth factor (FGF) receptor 3 (FGFR3) has been linked to the development of human cancers by mechanisms that are not well understood. The MUC1 oncoprotein is aberrantly overexpressed by certain hematologic malignancies and most human carcinomas. The present studies show that MUC1 associates with FGFR3. Stimulation of cells with FGF1 increased the interaction between MUC1 and FGFR3. FGF1 stimulation also induced c-Src-dependent tyrosine phosphorylation of the MUC1 cytoplasmic domain on a YEKV motif. FGF1-induced tyrosine phosphorylation of MUC1 was associated with increased binding of MUC1 to beta-catenin and targeting of MUC1 and beta-catenin to the nucleus. FGF1 also induced binding of MUC1 to the heat shock protein 90 (HSP90) chaperone by a mechanism dependent on phosphorylation of the YEKV motif. Notably, beta-catenin and HSP90 compete for binding to the MUC1 cytoplasmic domain, indicating that MUC1 forms mutually exclusive complexes with these proteins. The results also show that inhibition of HSP90 with geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin attenuates FGF1-induced binding of MUC1 to HSP90 and targeting of MUC1 to the mitochondrial outer membrane. These findings indicate that FGF1 induces phosphorylation of MUC1 on YEKV and thereby activates two distinct pathways: (a) nuclear localization of MUC1 and beta-catenin and (b) delivery of MUC1 to mitochondria by HSP90.
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PMID:MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling. 1711 45

How cellular behaviors such as cell-to-cell communication, epithelial organization and cell shape reorganization are coordinated during development is poorly understood. The developing Drosophila eye offers an ideal model system to study these processes. Localized actin polymerization is required to constrict the apical surface of epithelial cells of the eye imaginal disc to maintain the refined arrangement of the developing ommatidia. The identity of each photoreceptor cell within the epithelium is determined by cell-to-cell contacts involving signal transduction events. The R7 photoreceptor cell requires the activity of the Sevenless RTK to adopt a proper cell fate. We performed an EP screen for negative regulators of this inductive process, and we identified the serine/threonine kinase Center divider (cdi) as a suppressor of the phenotype caused by an activated Sevenless receptor. Cdi is homologous to the human testis-specific kinase 1 (TESK1), a member of the LIM kinases involved in cytoskeleton control through ADF/cofilin phosphorylation. We have analyzed the effects of gain- and loss-of-function of cdi and found alterations in actin organization and in the adherens junctions proteins DE-cadherin and beta-catenin, as well as in Sevenless apical localization. Interference with the function of the ADF/cofilin phosphatase Slingshot (ssh), which antagonizes Cdi, also results in a suppression of signaling triggered by the Sevenless RTK. Our results reveal a critical interplay between the localization of molecules involved in epithelial organization and signal transduction.
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PMID:The Cdi/TESK1 kinase is required for Sevenless signaling and epithelial organization in the Drosophila eye. 1711 62

HER2 (also known as ErbB2) is a transmembrane tyrosine kinase whose surface overexpression is linked to tumorigenesis and poor prognosis in breast cancer patients. beta-catenin is a substrate of this kinase, and HER2-dependent phosphorylation of tyrosine 654 leads to dissociation of the E-cadherin-beta-catenin membrane complex and increased Wnt signaling. beta-catenin-mediated Wnt signaling promotes proliferation and invasion of breast cancer cells. In this study, we show that HER2 binds to beta-catenin and that geldanamycin (GA), a drug that destabilizes HER2 protein, causes rapid depletion of HER2, thereby disrupting its association with beta-catenin in SKBr3 human breast cancer cells. Interestingly, GA did not affect the stability of beta-catenin protein, but altered its subcellular localization, driving it out of the nucleus and increasing its association with E-cadherin. Importantly, the change in subcellular localization of beta-catenin was also associated with a significant decrease in proliferation and motility of GA-treated breast cancer cells. Moreover, GA treatment led to reduced expression of the Wnt signaling target and cell cycle-promoting gene cyclin D1, providing a potential mechanism for the reduced proliferation. In conclusion, GA treatment suppressed tumorigenicity in the human breast cancer cell line SKBr3, at least in part through destabilization of the HER2 oncoprotein and repression of the Wnt/beta-catenin signaling pathway. These findings provide evidence for the clinical importance of GA in treatment of HER2 overexpressing breast cancers.
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PMID:Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/beta-catenin signaling in HER2 overexpressing human breast cancer cells. 1714 83


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