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

---

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

Evidence suggests that myelin alterations could predispose to schizophrenia. Reduced expression of several myelin genes has been observed in schizophrenia patients. Recently, we identified the discoidin domain receptor 1 (DDR1; located at human chromosome 6p21.3) as a myelin gene in the mouse model and in a human oligodendroglial cell line. In the present study we screened for single nucleotide polymorphisms (SNPs) in the DNA from 100 schizophrenia patients. We identified a novel mutation within exon 10 that produces the amino-acid substitution N502S in the a-d isoforms, and M475V in the e isoform. However the frequency of the mutation (2%) was similar in schizophrenia patients and in control subjects. In a case-control assessment with 389 schizophrenic patients and 615 controls, we identified one SNP (SNP9, rs1049623) associated with schizophrenia (odds ratio=1.44, 95% confidence interval: 1.15-1.79, adjusted P=0.0016). This association was confirmed in haplotype analysis; the SNPs 9-10-11 (rs1049623, rs2267641 and rs2239518) haplotype remaining significant even after adjustment for multiple testing (adjusted P=0.0136). Of note was a strong gender dependence in the association, that is, statistical significance restricted to men (adjusted P-value=0.0002). Regression analysis of DDR1 mRNA expression in peripheral blood lymphocytes from schizophrenia patients showed that the presence of the G allele significantly decreased the relative number of mRNA copies in a dose-dependent manner (P=0.003). These data suggest that the risk haplotype tags a cis-acting variant involved in the transcription regulation system of the gene. In conclusion, we propose the DDR1 as a new susceptibility gene for schizophrenia.
...
PMID:The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia. 1744 Apr 35

Rapid progress in exploring the human and mouse genome has resulted in the generation of a multitude of mouse models to study gene functions in their biological context. However, effective screening methods that allow rapid noninvasive phenotyping of transgenic and knockout mice are still lacking. To identify murine models with bone alterations in vivo, we used flat-panel volume computed tomography (fpVCT) for high-resolution 3-D imaging and developed an algorithm with a computational intelligence system. First, we tested the accuracy and reliability of this approach by imaging discoidin domain receptor 2- (DDR2-) deficient mice, which display distinct skull abnormalities as shown by comparative landmark-based analysis. High-contrast fpVCT data of the skull with 200 microm isotropic resolution and 8-s scan time allowed segmentation and computation of significant shape features as well as visualization of morphological differences. The application of a trained artificial neuronal network to these datasets permitted a semi-automatic and highly accurate phenotype classification of DDR2-deficient compared to C57BL/6 wild-type mice. Even heterozygous DDR2 mice with only subtle phenotypic alterations were correctly determined by fpVCT imaging and identified as a new class. In addition, we successfully applied the algorithm to classify knockout mice lacking the DDR1 gene with no apparent skull deformities. Thus, this new method seems to be a potential tool to identify novel mouse phenotypes with skull changes from transgenic and knockout mice on the basis of random mutagenesis as well as from genetic models. However for this purpose, new neuronal networks have to be created and trained. In summary, the combination of fpVCT images with artificial neuronal networks provides a reliable, novel method for rapid, cost-effective, and noninvasive primary screening tool to detect skeletal phenotypes in mice.
...
PMID:Semi-automatic classification of skeletal morphology in genetically altered mice using flat-panel volume computed tomography. 1765 52

The BCR-ABL tyrosine kinase inhibitor imatinib represents the current frontline therapy in chronic myeloid leukemia. Because many patients develop imatinib resistance, 2 second-generation drugs, nilotinib and dasatinib, displaying increased potency against BCR-ABL were developed. To predict potential side effects and novel medical uses, we generated comprehensive drug-protein interaction profiles by chemical proteomics for all 3 drugs. Our studies yielded 4 major findings: (1) The interaction profiles of the 3 drugs displayed strong differences and only a small overlap covering the ABL kinases. (2) Dasatinib bound in excess of 30 Tyr and Ser/Thr kinases, including major regulators of the immune system, suggesting that dasatinib might have a particular impact on immune function. (3) Despite the high specificity of nilotinib, the receptor tyrosine kinase DDR1 was identified and validated as an additional major target. (4) The oxidoreductase NQO2 was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations, representing the first nonkinase target of these drugs.
...
PMID:Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. 1772 Aug 81

We describe a chemical proteomics approach to profile the interaction of small molecules with hundreds of endogenously expressed protein kinases and purine-binding proteins. This subproteome is captured by immobilized nonselective kinase inhibitors (kinobeads), and the bound proteins are quantified in parallel by mass spectrometry using isobaric tags for relative and absolute quantification (iTRAQ). By measuring the competition with the affinity matrix, we assess the binding of drugs to their targets in cell lysates and in cells. By mapping drug-induced changes in the phosphorylation state of the captured proteome, we also analyze signaling pathways downstream of target kinases. Quantitative profiling of the drugs imatinib (Gleevec), dasatinib (Sprycel) and bosutinib in K562 cells confirms known targets including ABL and SRC family kinases and identifies the receptor tyrosine kinase DDR1 and the oxidoreductase NQO2 as novel targets of imatinib. The data suggest that our approach is a valuable tool for drug discovery.
...
PMID:Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. 1784 28

A novel gene, prostate cancer antigen (PCA)-1, was recently reported to be expressed in the prostate; however, its biological roles remain unclear. Knockdown of the PCA-1 gene by small interfering RNA transfection induced apoptosis through reducing the expression of the anti-apoptotic molecule Bcl-xl and cytoplasmic release of cytochrome c in the androgen-independent prostate cancer cell line PC3. Moreover, in vitro matrigel and in vivo chorioallantoic membrane assays showed that silencing of PCA-1 significantly downregulated discoidin receptor (DDR)-1 expression, resulting in suppression of cancer-cell invasion. Transfection with PCA-1 increased the levels of both Bcl-xl and DDR1, which made the cells more invasive through the upregulation of matrix metalloproteinase 9 in DU145. Interestingly, long-term culture using androgen-free medium increased the level of PCA-1 and the related expression of Bcl-xl and DDR-1 in the androgen-sensitive cancer cell line LNCaP, suggesting that PCA-1 signaling is associated with androgen independence. Immunohistochemical analysis in a series of 169 prostate carcinomas showed that PCA-1 and DDR1 were strongly expressed in prostate cancer cells, including preneoplastic lesions, but there was little or no expression in normal epithelium. Moreover, the expression of PCA-1 and DDR-1 was associated with a hormone-independent state of prostate cancer. Taken together, we propose that PCA-1-DDR-1 signaling is a new important axis involved in malignant potential prostate cancer associated with hormone-refractory status.
...
PMID:Prostate cancer antigen-1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer. 1797 Jul 83

The discoidin domain receptor (DDR) is a class of receptor tyrosine kinases that binds to several collagens. DDR1 is widely expressed in fast-growing invasive tumors of the breast, ovary, esophagus, brain and lung. However, there is little information on the expression of DDR1 in hepatocellular carcinoma (HCC) or its function in migration and invasion. Western blot analysis was performed to determine if four HCC cell lines (HLE, Huh-7, HepG2 and SH-J1) express DDR1. The HLE and Huh-7 cell lines were transfected with two isoforms of DDR1, DDR1a and DDR1b. Immunoprecipitation for DDR1 was then performed. Migration and invasion assays were carried out and the number of migrating cells was counted in 6 randomly selected fields per well under an optical microscope. Zymography was used to determine the level of the matrix metalloproteinase (MMP)-2 and -9 expression. DDR1 was expressed in all four cell lines. In the migration assay, the number of migrating cells was significantly higher in the DDR1a- or DDR1b-overexpressing HLE and Huh-7 cells, particularly after collagen type I stimulation (P<0.001). Collagen type I stimulation activated DDR1. In the invasion assay, there was a significantly higher number of invading cells in the DDR1a- or DDR1b-overexpressing HLE cells and DDR1a-overexpressing Huh-7 cells than in the control (P<0.01). The DDR1a- and DDR1b-overexpressing HLE cells showed a remarkable increase in the MMP-9 and -2 expression, particularly the active MMP-2. The DDR1a- and DDR1b-overexpressing Huh-7 cells showed a slight increase in the MMP-9 and -2 expression. The increased invasiveness of the HCC may be associated with the overexpression of either DDR1a or DDR1b mediated by MMP-2 and -9. Although this study provided one possible mechanism for the invasion of HCC cells, more studies are needed to understand the signal through which DDR1a and DDR1b act in invasion.
...
PMID:Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase. 1798 27

Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.
...
PMID:Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. 1808 7

Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a "CNS signature." Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true "CNS signature" because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.
...
PMID:Pathway analysis of primary central nervous system lymphoma. 1912 20

Mammary gland development is coupled to reproductive events by hormonal cues of ovarian and pituitary origin, which activate a genomic regulatory network. Identification of the components and regulatory links that comprise this network will provide the basis for defining the network's dynamic response during normal development and its perturbation during breast carcinogenesis. In this study KIBRA was identified as a transcript showing decreased expression associated with failed mammary gland development in Prlr knockout mammary epithelium. It is strongly up-regulated during pregnancy, falls during lactation and is again up-regulated during involution of the gland at weaning. A bioinformatic approach was undertaken to identify potential binding partners which interact with the WW domains of KIBRA. We show that KIBRA binds to a WW domain binding motif, PPxY, in the tyrosine kinase receptor DDR1, and dissociates upon treatment with the DDR1 ligands collagen type I or IV. In addition we show that KIBRA and DDR1 also interact with PKCz to form a trimeric complex. Finally, overexpression and knockdown studies demonstrate that KIBRA promotes the collagen-stimulated activation of the MAPK cascade. Thus KIBRA may play a role in how the reproductive state influences the mammary epithelial cell to respond to changing cell-context information, such as experienced during the tissue remodeling events of mammary gland development.
...
PMID:KIBRA interacts with discoidin domain receptor 1 to modulate collagen-induced signalling. 1819 Jul 96

The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that are activated by native triple-helical collagen. Here we have located three specific DDR2 binding sites by screening the entire triple-helical domain of collagen II, using the Collagen II Toolkit, a set of overlapping triple-helical peptides. The peptide sequence that bound DDR2 with highest affinity interestingly contained the sequence for the high affinity binding site for von Willebrand factor in collagen III. Focusing on this sequence, we used a set of truncated and alanine-substituted peptides to characterize the sequence GVMGFO (O is hydroxyproline) as the minimal collagen sequence required for DDR2 binding. Based on a recent NMR analysis of the DDR2 collagen binding domain, we generated a model of the DDR2-collagen interaction that explains why a triple-helical conformation is required for binding. Triple-helical peptides comprising the DDR2 binding motif not only inhibited DDR2 binding to collagen II but also activated DDR2 transmembrane signaling. Thus, DDR2 activation may be effected by single triple-helices rather than fibrillar collagen.
...
PMID:Characterization of high affinity binding motifs for the discoidin domain receptor DDR2 in collagen. 1820 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---