Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A hallmark of metastasis is organ specificity; however, little is known about the underlying signaling pathways responsible for the colonization and growth of tumor cells in target organs. Since tyrosine kinase receptor activation is frequently associated with prostate cancer progression, we have investigated the role of a common signaling intermediary, activated Ras, in prostate cancer metastasis. Three effector pathways downstream of Ras, Raf/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase, and Ral guanine nucleotide exchange factors (RalGEFs), were assayed for their ability to promote the metastasis of a tumorigenic, nonmetastatic human prostate cancer cell line, DU145. Oncogenic Ras promoted the metastasis of DU145 to multiple organs, including bone and brain. Activation of the Raf/ERK pathway stimulated metastatic colonization of the brain, while activation of the RalGEF pathway led to bone metastases, the most common organ site for prostate cancer metastasis. In addition, loss of RalA in the metastatic PC3 cell line inhibited bone metastasis but did not affect subcutaneous tumor growth. Loss of Ral appeared to suppress expansive growth of prostate cancer cells in bone, whereas homing and initial colonization were less affected. These data extend our understanding of the functional roles of the Ral pathway and begin to identify signaling pathways relevant for organ-specific metastasis.
Mol Cell Biol 2007 Nov
PMID:Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. 1770 81

A limited number of whole-cell assays allow monitoring of receptor tyrosine kinase (RTK) activity in a signaling pathway-specific manner. We present the general use of the bioluminescence resonance energy transfer (BRET) technology to quantitatively study the pharmacology and signaling properties of the receptor tyrosine kinase (RTK) superfamily. RTK BRET-2 assays monitor, in living cells, the specific interaction between RTKs and their effector proteins, which control the activation of specific downstream signaling pathways. A total of 22 BRET assays have been established for nine RTKs derived from four subfamilies [erythroblastic leukemia viral (v-erb-b) oncogene homolog (ErbB), platelet-derived growth factor (PDGF), neurotrophic tyrosine kinase receptor (TRK), vascular endothelial growth factor (VEGF)] monitoring the interactions with five effectors (Grb2, p85, Stat5a, Shc46, PLCgamma1). These interactions are dependent on the RTK kinase activity and autophosphorylation of specific tyrosine residues in the carboxyl terminus. RTK BRET assays are highly sensitive for quantifying ligand-independent (constitutive), agonist-induced, or antagonist-inhibited RTK activity levels. We studied the signaling properties of the PDGF receptor, alpha polypeptide (PDGFRA) isoforms (V561D; D842V and delta842-845) carrying activating mutations identified in gastrointestinal stromal tumors (GIST). All three PDGFRA isoforms are fully constitutively activated, insensitive to the growth factor PDGF-BB, but show differential sensitivity of their constitutive activity to be inhibited by the inhibitor imatinib (Gleevec). Epidermal growth factor receptor (EGFR) BRET structure-function studies identify the tyrosine residues 1068, 1114, and 1148 as the main residues mediating the interaction of EGFR with the adapter protein Grb2. The BRET technology provides an assay platform to study signaling pathway-specific RTK structure-function and will facilitate drug discovery efforts for the identification of novel RTK modulators.
Mol Pharmacol 2007 Dec
PMID:Monitoring interactions between receptor tyrosine kinases and their downstream effector proteins in living cells using bioluminescence resonance energy transfer. 1771 95

The aim of the study was to determine whether or not the tyrosine kinase receptor ERBB2 is overexpressed in synovial sarcomas (SSs). We also focused on the cell cycle-related nuclear protein-Ki-67. Thirty-two samples were available for immunohistochemistry and only 1 case revealed a weak diffuse membrane ERBB-2 staining. The remaining cases showed either no staining (20 cases) or weak focal membrane staining (9 cases). In our 3 highly overexpressed ERBB2 mRNA samples, fluorescence in situ hybridization showed no amplification of the ERBB2 gene. ERBB2 mRNA expression was present in all samples of SSs at a comparable level to that in breast carcinoma control group, with a 2+ or 3+ immunopositivity. The high level of ERBB2 mRNA expression correlated with a high level of Ki-67 mRNA. The level of Ki-67 mRNA correlated with Ki-67 protein expression. The study shows that ERBB2 mRNA expression is very strong in SSs, but the membrane ERBB-2 protein expression is practically absent.
Diagn Mol Pathol 2007 Dec
PMID:Molecular and immunohistochemical analysis of ERBB2 expression in correlation with proliferation rate in synovial sarcoma. 1804 84

The tyrosine kinase receptor, c-Met, and its substrate, the hepatocyte growth factor (HGF), are implicated in the malignant progression of glioblastomas. In vivo detection of c-Met expression may be helpful in the diagnosis of malignant tumours. The C6 rat glioma model is a widely used intracranial brain tumour model used to study gliomas experimentally. We used a magnetic resonance imaging (MRI) molecular targeting agent to specifically tag the cell surface receptor, c-Met, with an anti-c-Met antibody (Ab) linked to biotinylated Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-albumin in rat gliomas to detect overexpression of this antigen in vivo. The anti-c-Met probe (anti-c-Met-Gd-DTPA-albumin) was administered intravenously, and as determined by an increase in MRI signal intensity and a corresponding decrease in regional T(1) relaxation values, this probe was found to detect increased expression of c-Met protein levels in C6 gliomas. In addition, specificity for the binding of the anti-c-Met contrast agent was determined by using fluorescence microscopic imaging of the biotinylated portion of the targeting agent within neoplastic and 'normal'brain tissues following in vivo administration of the anti-c-Met probe. Controls with no Ab or with a normal rat IgG attached to the contrast agent component indicated no non-specific binding to glioma tissue. This is the first successful visualization of in vivo overexpression of c-Met in gliomas.
J Cell Mol Med
PMID:In vivo detection of c-Met expression in a rat C6 glioma model. 1820 57

Angiopoietin-1 (Ang-1) is the primary agonist for Tie2 tyrosine kinase receptor (Tie2), and the effect of Ang-1-Tie2 signalling is context-dependent. Deficiency in either Ang-1 or Tie2 protein leads to severe microvascular defects and subsequent embryonic lethality in murine model. Tie2 receptors are expressed in several cell types, including endothelial cells, smooth muscle cells, fibroblasts, epithelial cells, monocytes, neutrophils, eosinophils and glial cells. Ang-1-Tie2 signalling induces a chemotactic effect in smooth muscle cells, neutrophils and eosinophils, and induces differentiation of mesenchymal cells to smooth muscle cells. Additionally, this signalling pathway induces the secretion of serotonin, matrix metalloproteinases (MMPs) and plasmin. Ang-1 inhibits the secretion of tissue inhibitor of matrix metalloproteinase (TIMPs). Aberrant expression and activity of Tie2 in vascular and non-vascular cells may result in the development of rheumatoid arthritis, cancer, hypertension and psoriasis. Ang-1 has an anti-inflammatory effect, when co-localized with vascular endothelial growth factor (VEGF) in the vasculature. Thus, Ang-1 could be potentially important in the therapy of various pathological conditions such as pulmonary hypertension, arteriosclerosis and diabetic retinopathy. In this article, we have summarized and critically reviewed the pathophysiological role of Ang-1-Tie2 signalling pathway.
J Cell Mol Med 2008 Jun
PMID:Intra and extravascular transmembrane signalling of angiopoietin-1-Tie2 receptor in health and disease. 1826 78

Fibroblast growth factor receptor 1 (FGFR1) is the only high-affinity FGFR in the vertebrate myocardium. FGFR1 is a tyrosine kinase receptor and has a non-redundant role in proliferation and differentiation of cardiomyocytes during embryogenesis. Results presented here demonstrate that FGFR1 gene expression declines as neonatal cardiomyocytes develop into adult cardiomyocytes. Furthermore, silencing FGFR1 gene expression reduced neonatal cardiomyocyte proliferation, indicating that FGFR1 gene expression is required for the optimal proliferative capacity of cardiomyocytes. To determine the mechanism that governs FGFR1 gene expression in cardiomyocytes, sequence analysis of the proximal mouse FGFR1 promoter identified a potential binding site for Sp transcription factors. Mutation of this site increased FGFR1 promoter activity compared to the wild-type promoter, indicating the presence of a negative transcriptional regulator of the FGFR1 promoter at this site in cardiomyocytes. Sp3 expression in neonatal cardiomyocytes and Drosophila SL2 cells reduced FGFR1 promoter activity in a dose-dependent manner. Western blots and immunocytochemistry indicated that Sp3 was present in the nuclear and cytoplasmic compartments of neonatal cardiomyocytes. Chromatin-immunoprecipitation studies verified that endogenous Sp3 in cardiomyocytes interacts with the FGFR1 promoter. Transient chromatin-immunoprecipitation studies using wild-type and mutated FGFR1 promoter constructs in SL2 cells identified the specific Sp3 binding site within the FGFR1 promoter. These studies implicate Sp3 as a negative transcriptional regulator of FGFR1 promoter activity in cardiomyocytes and as a suppressor of cardiomyocyte proliferation.
J Mol Cell Cardiol 2008 Mar
PMID:Fibroblast growth factor receptor 1 gene expression is required for cardiomyocyte proliferation and is repressed by Sp3. 1827 70

Mononuclear phagocytes play an important role in the removal of apoptotic cells by expressing cell surface receptors that recognize and remove apoptotic cells. Based on the knowledge that cigarette smoking is associated with increased lung cell turnover, we hypothesized that alveolar macrophages (AMs) of normal cigarette smokers may exhibit enhanced expression of apoptotic cell removal receptor genes. AMs obtained by bronchoalveolar lavage of normal nonsmokers (n = 11) and phenotypic normal smokers (n = 13; 36 +/- 6 pack-years) were screened for mRNA expression of all known apoptotic cell removal receptors using Affymetrix HG-U133 Plus 2.0 microarray chips with TaqMan RT-PCR confirmation. Of the 14 known apoptotic receptors expressed, only MER tyrosine kinase (MERTK), a transmembrane tyrosine kinase receptor, was significantly up-regulated in smokers. MERTK expression was then assessed in AMs of smokers versus nonsmokers by TaqMan RT-PCR, immunocytochemistry, Western analysis, and flow analysis. Smoker AMs had up-regulation of MERTK mRNA levels (smoker vs. nonsmoker: 3.6-fold by microarray, P < 0.003; 9.5-fold by TaqMan RT-PCR, P < 0.02). Immunocytochemistry demonstrated a qualitative increase in MERTK protein expression on AMs of smokers. Increased protein expression of MERTK on AMs of smokers was confirmed by Western and flow analyses (P < 0.007 and P < 0.0002, respectively). MERTK, a cell surface receptor that recognizes apoptotic cells, is expressed on human AMs, and its expression is up-regulated in AMs of cigarette smokers. This up-regulation of MERTK may reflect an increased demand for removal of apoptotic cells in smokers, an observation with implications for the development of chronic obstructive pulmonary disease, a disorder associated with dysregulated apoptosis of lung parenchymal cells.
Am J Respir Cell Mol Biol 2008 Dec
PMID:Overexpression of apoptotic cell removal receptor MERTK in alveolar macrophages of cigarette smokers. 1858 56

In the muscle-specific tyrosine kinase receptor gene MUSK, a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome (CMS). We generated one mouse line carrying the homozygous missense mutation V789M in musk (musk(V789M/V789M) mice) and a second hemizygous line, resembling the patient genotype, with the V789M mutation on one allele and an allele lacking the kinase domain (musk(V789M/-) mice). We report here that musk(V789M/V789M) mice present no obvious abnormal phenotype regarding weight, muscle function and viability. In contrast, adult musk(V789M/-) mice suffer from severe muscle weakness, exhibit shrinkage of pelvic and scapular regions and hunchback. Musk(V789M/-) diaphragm develops less force upon direct or nerve-induced stimulation. A profound tetanic fade is observed following nerve-evoked muscle contraction, and fatigue resistance is severely impaired upon a train of tetanic nerve stimulations. Electrophysiological measurements indicate that fatigable muscle weakness is due to impaired neurotransmission as observed in a patient suffering from a CMS. The diaphragm of adult musk(V789M/-) mice exhibits pronounced changes in endplate architecture, distribution and innervation pattern. Thus, the missense mutation V789M in MuSK acts as a hypomorphic mutation and leads to insufficiency in MuSK function in musk(V789M/-) mutants. These mutant mice represent valuable models for elucidating the roles of MuSK for synapse formation, maturation and maintenance as well as for studying the pathophysiology of a CMS due to MuSK mutations.
Hum Mol Genet 2008 Nov 15
PMID:A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions. 1871 36

Proteomics may help to elucidate differential signaling networks underlying the effects of compounds and to identify new therapeutic targets. Using a proteomic-multiplexed analysis of the phosphotyrosine signaling together with antibody-based validation techniques, we identified several candidate molecules for RET (rearranged during transfection) tyrosine kinase receptor carrying mutations responsible for the multiple endocrine neoplasia type 2A and 2B (MEN2A and MEN2B) syndromes in two human medullary thyroid carcinoma (MTC) cell lines, TT and MZ-CRC-1, which express the RET-MEN2A and RET-MEN2B oncoproteins, respectively. Signaling elements downstream of these oncoproteins were identified after treating cells with the indolinone tyrosine kinase inhibitor RPI-1 to knock down RET phosphorylation activity. We detected 23 and 18 affinity-purified phosphotyrosine proteins in untreated TT and MZ-CRC-1 cells, respectively, most of which were shared and sensitive to RPI-1 treatment. However, our data clearly point to specific signaling features of the RET-MEN2A and RET-MEN2B oncogenic pathways. Moreover, the detection of high-level expression of minimally phosphorylated epidermal growth factor receptor (EGFR) in both TT and MZ-CRC-1 cells, together with our data on the effects of EGF stimulation on the proteomic profiles and the response to Gefitinib treatment, suggest the relevance of EGFR signaling in these cell lines, especially since analysis of 14 archival MTC specimens revealed EGFR mRNA expression in all samples. Together, our data suggest that RET/EGFR multi-target inhibitors might be beneficial for therapy of MTC.
Mol Carcinog 2009 Mar
PMID:Proteomics study of medullary thyroid carcinomas expressing RET germ-line mutations: identification of new signaling elements. 1875 47

Inhibitors of fatty acid synthase (FASN), a key enzyme involved in the anabolic conversion of dietary carbohydrates to fat in mammals, are receiving increasingly more attention as they may provide therapeutic moieties for the treatment of human malignancies. Natural compounds, such as the green tea polyphenol epigallocatechin-3-gallate, have been shown to induce anti-cancer effects by suppressing FASN, which may account for the epidemiologically observed inverse correlation between green-tea drinking and cancer risk in Oriental populations. Since extra-virgin olive oil (EVOO)-derived phenolics have been suggested to possess biological activities that may explain the health-promoting effects of the 'Mediterranean diet', we evaluated their effects on the expression of FASN protein in human breast epithelial cell lines. First, we developed a reverse phase protein microspot array (RPPA) capable of rapidly assessing the relative amount of FASN protein in whole lysates from cultured human cells. Then we tested the effects of phenolic fractions from EVOO and its main constituents including single phenols (i.e. tyrosol, hydroxytyrosol, vanillin), phenolic acids (i.e. caffeic acid, p-coumaric acid, vanillic acid, ferulic acid, elenolic acid), lignans (i.e. 1-[+]-pinoresinol, 1-[+]-acetoxy-pinoresinol), flavonoids (i.e. apigenin, luteolin), or secoiridoids (i.e. deacetoxyoleuropein aglycone, ligstroside aglycone, oleuropein glycoside, oleuropein aglycone) on FASN protein expression. EVOO polyphenols lignans, flavonoids and secoiridoids were found to drastically suppress FASN protein expression in HER2 gene-amplified SKBR3 breast cancer cells. Equivalent results were observed in MCF-7 cells engineered to overexpress the HER2 tyrosine kinase receptor, a well-characterized up-regulator of FASN expression in aggressive sub-types of cancer cells. EVOO-derived lignans, flavonoids and secoiridoids were significantly more effective than the mono-HER2 inhibitor trastuzumab ( approximately 50% reduction) and as effective as the dual HER1/HER2 tyrosine kinase inhibitor lapatinib (> or =95% reduction) at suppressing high-levels of FASN protein in HER2-overexpressing SKBR3 and MCF-7/HER2 cells. EVOO single phenols and phenolic acids failed to modulate FASN expression in SKBR3 and MCF-7/HER2 cells. These findings reveal for the first time that phenolic fractions, directly extracted from EVOO, may induce anti-cancer effects by suppressing the expression of the lipogenic enzyme FASN in HER2-overexpressing breast carcinoma cells, thus offering a previously unrecognized mechanism for EVOO-related cancer preventive effects.
Int J Mol Med 2008 Oct
PMID:Analyzing effects of extra-virgin olive oil polyphenols on breast cancer-associated fatty acid synthase protein expression using reverse-phase protein microarrays. 1881 48


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