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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The scatter factor/hepatocyte growth factor regulates scattering and morphogenesis of epithelial cells through activation of the MET tyrosine kinase receptor. In particular, the noncatalytic C-terminal tail of MET contains two autophosphorylation tyrosine residues, which form a multisubstrate-binding site for several cytoplasmic effectors and are thought to be essential for signal transduction. We show here that a MET receptor mutated on the four C-terminal tyrosine residues, Y1311F, Y1347F, Y1354F, and Y1363F, can induce efficiently a transcriptional response and cell scattering, whereas it cannot induce cell morphogenesis. Although the mutated receptor had lost its ability to recruit and/or activate known signaling molecules, such as GRB2, SHC, GAB1, and PI3K, by using a sensitive association-kinase assay we found that the mutated receptor can still associate and phosphorylate a approximately 250-kDa protein. By further examining signal transduction mediated by the mutated MET receptor, we established that it can transmit efficient RAS signaling and that cell scattering by the mutated MET receptor could be inhibited by a pharmacological inhibitor of the MEK-ERK (MAP kinase kinase-extracellular signal-regulated kinase) pathway. We propose that signal transduction by autophosphorylation of the C-terminal tyrosine residues is not the sole mechanism by which the activated MET receptor can transmit RAS signaling and cell scattering.
Mol Biol Cell 1999 Mar
PMID:The multisubstrate docking site of the MET receptor is dispensable for MET-mediated RAS signaling and cell scattering. 1006 3

Transcription of the genes for sulfur assimilation and methionine biosynthesis in Saccharomyces cerevisiae is regulated by the size of the intracellular pool of an organic sulfur compound. The identity of this compound is not clear, but suggestions include S-adenosylmethionine (SAM) and cysteine. By studying the repression of selected sulfur assimilation (MET) genes, we found that the ability to form cysteine from homocysteine is crucial for methionine-mediated repression to take place. The transcription of MET14 and MET25 could not be repressed by methionine in strains in which either STR4 (which encodes cystathionine beta-synthase) or STR1 (cystathionine gamma-lyase) was disrupted, whereas the repression was independent of GSH1 (which encodes the enzyme responsible for the first step in glutathione biosynthesis from cysteine). In contrast, cysteine could repress the MET genes in all of these strains. Two genes that presumably encode cystathionine gamma-synthase and cystathionine beta-lyase were identified by genetic disruption (ORFs YJR130c and YGL184c), yielding yeast strains that cannot convert cysteine into homocysteine. Repression by cysteine was possible in either disruptant, suggesting a role in repression for cysteine alone. While some repression of MET genes could be accomplished by homocysteine in a strain that cannot form SAM from methionine, a low intracellular level of SAM seems to be necessary for full cysteine-mediated repression to take place.
Mol Gen Genet 2000 Apr
PMID:Cysteine is essential for transcriptional regulation of the sulfur assimilation genes in Saccharomyces cerevisiae. 1082 Nov 89

The Methoprene-tolerant (Met) gene product in Drosophila melanogaster facilitates the action of juvenile hormone (JH) and JH analog insecticides. Previous work resulted in the cloning and identification of the gene as a member of the bHLH-PAS family of transcriptional regulators. A Met(+) cDNA was expressed in Escherichia coli, and polyclonal antibody was prepared against the purified protein. A single band on a Western blot at the expected size of 79kD was detected in extracts from Met(+) larvae but not from Met(27) null mutant larvae, demonstrating the antibody specificity. Antibody detected MET in all stages of D. melanogaster development and showed tissue specificity of its expression. MET is present in all cells of early embryos but dissipates during gastrulation. In larvae it is present in larval fat body, certain imaginal cells, and immature salivary glands. In pupae it persists in fat body cells and imaginal cells, including abdominal histoblast cells. In adult females MET is present in ovarian follicle cells and spermathecae; in adult males it is present in male accessory gland and ejaculatory duct cells. In all of these tissues MET is found exclusively in the nucleus. Some of these tissues are known JH target tissues but others are not, suggesting either the presence of novel JH target tissues or another function for MET.
Insect Biochem Mol Biol
PMID:Intracellular localization and tissue specificity of the Methoprene-tolerant (Met) gene product in Drosophila melanogaster. 1087 28

We previously reported that MET-88, 3-(2,2,2-trimethylhydrazinium) propionate, improved left ventricular diastolic dysfunction induced by congestive heart failure (CHF) in rats. The present study was designed to investigate the mechanism by which MET-88 improved the cardiac relaxation impaired in CHF rats. The left coronary artery of the animals was ligated, and the rats were then orally administered vehicle (control), MET-88 at 50 or 100 mg/kg or captopril at 20 mg/kg for 20 days. Myocytes were isolated from the non-infarcted region in the left ventricle, and cell shortening and [Ca2+]i transients were measured with a video-edge detector and by fluorescence analysis, respectively. In CHF control rats, the diastolic phase of cell shortening was prolonged compared with that of the sham-operated (sham) rats. This prolongation was prevented by treatment with MET-88 at 100 mg/kg or captopril at 20 mg/kg. CHF control rats also showed an increase in the decay time of [Ca2+]i transients compared with sham rats. MET-88 at 100 mg/kg and captopril at 20 mg/kg attenuated the increase in decay time of [Ca2+]i transients. Ca2+ uptake activity of the sarcoplasmic reticulum (SR) isolated from the non-infarcted region in the left ventricle was measured, and Lineweaver-Burk plot analysis of the activity was performed. CHF control rats revealed a decrease in the Vmax for SR Ca2+ uptake activity without alteration in Kd. MET-88 at 100 mg/kg significantly prevented the decrease in Vmax, but had no effect on Kd. Also, treatment with MET-88 at 100 mg/kg improved myocardial high-energy phosphate levels impaired in CHF rats. These results suggest that one of the mechanisms by which MET-88 improved cardiac relaxation in CHF rats is based on the amelioration of [Ca2+]i transients through increase of SR Ca2+ uptake activity.
Mol Cell Biochem 2000 Jun
PMID:MET-88, a gamma-butyrobetaine hydroxylase inhibitor, improves cardiac SR Ca2+ uptake activity in rats with congestive heart failure following myocardial infarction. 1094 99

Putative RNA helicases are involved in most aspects of gene expression. All previously characterized members of the DEAH-box family of putative RNA helicases are involved in pre-mRNA splicing. Here we report the analysis of two novel DEAH-box RNA helicases, Dhr1p and Dhr2p, that were found to be predominantly nucleolar. Both genes are essential for viability, and MET-regulated alleles were therefore created. Depletion of Dhr1p or Dhr2p had no detectable effect on pre-mRNA splicing in vivo or in vitro. Both Dhr1p and Dhr2p were, however, required for 18S rRNA synthesis. Depletion of Dhr2p inhibited pre-rRNA cleavage at sites A(0), A(1), and A(2), while Dhr1p depletion inhibited cleavage at sites A(1) and A(2). No coprecipitation of snoRNAs was detected with ProtA-Dhr2p, but Dhr1p-ProtA was stably associated with the U3 snoRNA. Depletion of Dhr1p inhibited processing steps that require base pairing of U3 to the 5' end of the 18S rRNA. We speculate that Dhr1p is targeted to the preribosomal particles by the U3-18S rRNA interaction and is required for the structural reorganization of the rRNA during formation of the central pseudoknot.
Mol Cell Biol 2000 Oct
PMID:Dhr1p, a putative DEAH-box RNA helicase, is associated with the box C+D snoRNP U3. 1098 41

beta-Catenin is an oncogenic protein involved in regulation of cell-cell adhesion and gene expression. Accumulation of cellular beta-catenin occurs in many types of human cancers. Four mechanisms are known to cause increases in beta-catenin: mutations of beta-catenin, adenomatous polyposis coli, or axin genes and activation of Wnt signaling. We report a new cause of beta-catenin accumulation involving oncogenic mutants of RON and MET receptor tyrosine kinases (RTKs). Cells transfected with oncogenic RON or MET were characterized by beta-catenin tyrosine phosphorylation and accumulation; constitutive activation of a Tcf transcriptional factor; and increased levels of beta-catenin/Tcf target oncogene proteins c-myc and cyclin D1. Interference with the beta-catenin pathway reduced the transforming potential of mutated RON and MET. Activation of beta-catenin by oncogenic RON and MET constitutes a new pathway, which might lead to cell transformation by these and other mutant growth factor RTKs.
Mol Cell Biol 2001 Sep
PMID:Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta-catenin pathway. 1148 25

Hybridization with cDNA arrays was used to obtain expression profiles of 214 protein-tyrosine kinase, protein-tyrosine phosphatase, dual-specific phosphatase, and other genes for kidney carcinomas (KC) and normal kidney tissues of 34 patients and for seven carcinoma cell lines. Computer analysis revealed three clusters of genes coexpressed in KC. A proliferating-cell gene cluster included MET, VIM, MYC, TOP2A, PCNA, etc. A neoangiogenesis and blood-cell gene cluster included LCK, HCK, FGR, MMP9, CSFR1, VEGF, FLT1, and KDR. A cluster corresponding to normal, differentiated kidney cells included ERBB2 (HER2) for receptor protein-tyrosine kinase, several phosphatase genes (PTPRE, PTPRB, DUSP9), and EGF. The results suggested that MET, DUSP9, PCNA, TOP2A, and VIM may serve as diagnostic and prognostic markers in KC. Tubulin and topoisomerase II were assumed to be promising targets for cell proliferation inhibitors in KC.
Mol Biol (Mosk)
PMID:[Molecular portrait of human kidney carcinomas: the gene expression profiling of protein-tyrosine kinases and tyrosine phosphatases which controlled regulatory signals in the cells]. 1206 34

In previous research, we discovered that turkey deferent duct epithelial cells express a serine protease. Our experimental objective was to identify the gene that encodes this protein. A lambda phage cDNA library from duct cell mRNA was constructed. The library was screened using monoclonal antibodies previously produced against the turkey deferent-duct serine protease. Phage containing the protease cDNA was excised and re-circularized into plasmids. E. coli were transformed with plasmids containing protease cDNA, which was then isolated for sequencing. NCBI BLAST searches within the GenBank database returned 63.5 and 61.7% identity with murine and human hepatocyte growth-factor activator (HGFA) precursor, respectively. The turkey protease cDNA was then cloned into the pQE-32 expression vector and transformed into M15 cells for HIS-tagged expression of the recombinant protein, which was then purified using nickel-chelated Sepharose spin columns. Afterwards, Western blot analysis of the purified recombinant turkey protein revealed recognition by a monoclonal antibody specific to the proteolytic subunit of the turkey deferent duct protease. Therefore, these findings indicate that the recombinant HGFA precursor isolated from the deferent duct is the turkey seminal plasma protease that is secreted from the deferent duct. HGFA, a member of the Kringle-serine proteinase superfamily, can initiate diverse mitogenic, morphogenic and motogenic effects through its substrate hepatocyte growth factor. Although the presence of hepatocyte growth factor and its c-MET receptor have been reported in male mammalian reproductive tracts, our novel findings on the secretion of HGFA precursor from turkeys may help to elucidate the regulation of activated hepatocyte growth factor.
Comp Biochem Physiol B Biochem Mol Biol 2002 Aug
PMID:Expression of a hepatocyte growth-factor activator protein in turkey (Meleagris gallopavo) deferent duct epithelial cells. 1212 63

The ubiquitin system has been recently implicated in various aspects of transcriptional regulation, including proteasome-dependent degradation of transcriptional activators. In yeast, the activator Met4 is inhibited by the SCF(Met30) ubiquitin ligase, which recognizes and oligo-ubiquitylates Met4. Here, we demonstrate that in minimal media, Met4 is ubiquitylated and rapidly degraded in response to methionine excess, whereas in rich media, Met4 is oligo-ubiquitylated but remains stable. In the latter growth condition, oligo-ubiquitylated Met4 is not recruited to MET gene promoters, but is recruited to the SAM genes, which are required for production of S-adenosylmethionine, an unstable metabolite that is not present in rich medium. Thus, ubiquitylation not only regulates Met4 by distinct degradation-dependent and -independent mechanisms, but also controls differential recruitment of a single transcription factor to distinct promoters, thereby diversifying transcriptional activator specificity.
Mol Cell 2002 Jul
PMID:Dual regulation of the met4 transcription factor by ubiquitin-dependent degradation and inhibition of promoter recruitment. 1215 Sep 8

Molecular genetic analysis of familial and non-familial cases of conventional renal cell carcinoma (RCC) revealed a critical role(s) for multiple genes on human chromosome 3. For some of these genes, e.g. VHL, such a role has been firmly established, whereas for others, definite confirmation is still pending. Additionally, a novel role for constitutional chromosome 3 translocations as risk factors for conventional RCC development is rapidly emerging. Also, several candidate loci have been mapped to other chromosomes in both familial and non-familial RCCs of distinct histologic subtypes. The MET gene on chromosome 7, for example, was found to be involved in both forms of papillary RCC. A PRCC-TFE3 fusion gene is typically encountered in t(X;1)-positive non-familial papillary RCCs and results in abrogation of the cell cycle mitotic spindle checkpoint in a dominant-negative fashion, thus leading to RCC. Together, these data turn human RCC into a model system in which different aspects of both familial and non-familial syndromes may act as novel paradigms for cancer development.
Hum Mol Genet 2002 Oct 01
PMID:Understanding familial and non-familial renal cell cancer. 1235 85


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