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 RON receptor-type tyrosine kinase, a member of the hepatocyte growth factor receptor family, is a receptor for macrophage-stimulating protein (MSP). Recently, we observed that MSP induces morphological changes in interleukin (IL)-3-dependent Ba/F3 cells ectopically expressing RON. We show here that stimulation of those cells with either MSP or IL-3 increases tyrosine phosphorylation of proteins of 130, 110, 90, 62, and 58 kDa and induces similar morphological changes, accompanied by unique nuclear shape and redistribution of F-actin. A tyrosine kinase inhibitor, genistein, blocked both the increase in tyrosine phosphorylation and morphological changes. Upon stimulation with either MSP or IL-3, prominent tyrosine-phosphorylated pp90 was similarly co-immunoprecipitated with the common beta chain of IL-3 receptor (betac). Unlike IL-3, stimulation with MSP increased tyrosine phosphorylation of betac without activation of JAK2, resulting in morphological changes with modest cell growth. Confocal immunofluorescence analyses showed colocalization of RON, betac, and tyrosine-phosphorylated proteins. In vitro kinase assays revealed that autophosphorylated RON phosphorylated betac. These results suggest that the signaling pathway for morphological changes through betac and its associated protein pp90 is distinct from the pathway for cell growth in the IL-3 signal transduction system.
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PMID:Induction of cell shape changes through activation of the interleukin-3 common beta chain receptor by the RON receptor-type tyrosine kinase. 1033 78

Tank truck drivers' exposure to gasoline vapors was studied by collecting breathing zone samples during loading and unloading of gasoline. The field studies were conducted at three dispatches and at seven service stations in Finland. The gasolines included in the study (95, 98, 99 research octane number, RON) were of reformulated or oxygenated grade containing about 2% (w/w) oxygen and 0.5-1.5% (v/v) benzene. The sampling times ranged from 16 to 57 min (mean 35 min), and time-weighted average concentrations for a 30-min period were calculated. Using the time-adjusted values, geometric mean concentrations (GM) were calculated for three periods of dispatch measurements (n = 15,20,7) and a period of unloading measurements at service stations (n = 7). The GM for methyl tert-butyl ether ranged from 0.95 to 7.3 mg/m3 and that for tert-amyl methyl ether from 0.30 to 1.1 mg/m3. The GM concentrations of hexane, benzene, and toluene were in the range of 0.25-2.3 mg/m3, 0.15-0.28 mg/m3, and 0.73-1.7 mg/m3, respectively. Multiple regression analysis yielded an r2 value of 0.98 for the daily mean concentration of toluene and correspondingly 0.94 for benzene when daily wind speed (0.1-3.7 m/sec) and daily air temperature (-7.4(-)+17.2 degrees C) were used as independent variables. The average number of gasoline loads per tank truck was 2.5, corresponding to 23,000 L of gasoline.
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PMID:Tank truck driver exposure to vapors from oxygenated or reformulated gasolines during loading and unloading. 1046 86

The presence of RON and its variant isoform in malignant and non-malignant human colonic tissues was examined by immunohistochemistry using paraffin-embedded sections and RT-PCR analysis followed by direct sequencing of PCR product using RNAs isolated from frozen tissues. In normal colonic mucosa, RON was uniformly expressed in crypt cells, especially in the bottom of crypta. On the other hand, the expression was distributed heterogeneously in adenomas and in colon cancer. The expression of RON was significantly related to the degree of differentiation of colon cancer and the deletion of the expression was observed in colon cancer specimens with high incidence. The RT-PCR analysis of RNA isolated from non-malignant and malignant colonic tissue revealed the presence of two RON mRNA isoforms with 432-bp and 286-bp. Direct sequencing of major product of 432-bp was revealed to be identical to that of human wild-type RON. On the other hand, major product of 286-bp was revealed to be almost identical to that of a splicing variant of RON transcript which has been found in human gastric cancer cell line, KATO-III. The results obtained in this study may indicate that both wild-type RON and its variant isoform play an important role in regulating the normal function of colonic mucosa such as differentiation and motile activity and the expression of both wild-type RON and its variant isoform could be considered to be reduced during malignancy of human colonic mucosa.
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PMID:Presence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa. 1049 52

Ron and Met are structurally related receptor tyrosine kinases that elicit a complex biological response leading to invasive growth. Naturally occurring point mutations activate the Met kinase in papillary renal carcinomas (MET(PRC) mutations). By site-directed mutagenesis, we generated homologous amino acid substitutions in the Ron kinase domain and analyzed the biochemical and biological properties of the mutant receptors. Among the mutations studied, D(1232)H and M(1254)T displayed transforming activity in NIH3T3 cells, inducing focus formation and anchorage-independent growth. The D(1232)H and M(1254)T substitutions resulted in increased Ron autophosphorylation both in vivo and in vitro and constitutive binding to intracellular signal transducers. Both mutations yielded a dramatic increase in catalytic efficiency, indicating a direct correlation between kinase activity and oncogenic potential. Molecular modeling of the Ron D(1232)H mutation suggests that this single amino acid substitution favors the transition of the kinase from the inactive to the active state. These data demonstrate that point mutations can confer transforming activity to the Ron receptor and show that RON is a potential oncogene.
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PMID:MET(PRC) mutations in the Ron receptor result in upregulation of tyrosine kinase activity and acquisition of oncogenic potential. 1052 37

Plasminogen-related growth factors (PRGFs), also known as "scatter factors," trigger a unique biological program leading to "invasive growth." This is a result of the integration of apparently independent biological responses including cell proliferation, cell survival, cell motility, invasion of extracellular matrices, and induction of cell polarity. Under physiological conditions, the coordinated execution of the underlying genetic programs leads to the formation of tubular structures by epithelial organs (the so-called branching morphogenesis). PRGF receptors are tyrosine kinases, encoded by a family of oncogenes: MET and RON. They feature unique signal transduction properties as their cytoplasmic tails contain a two-tyrosine multifunctional docking site that binds multiple SH2-containing intracellular signal transducers. Invasive growth results from the concomitant activation of Ras (growth), phosphatidylinositol 3-kinase ("scattering"), and signal transducer and activator of transcription (cell polarity and morphogenesis). We recently identified a new human gene family, encoding large transmembrane proteins, sex/plexins, sharing homologies with Met. These molecules are receptors for semaphorins, involved in axon guidance and cell-cell repulsion, a process reminiscent of scattering and invasive growth. Deregulated activation of PRGF or semaphorin ligands or receptors, by mutation or overexpression, confers to cancer cells invasive and metastatic properties.
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PMID:Plasminogen-related growth factor and semaphorin receptors: a gene superfamily controlling invasive growth. 1057 14

IFN-gamma primes macrophages for antimicrobial activity, increased killing of intracellular pathogens, and Ag processing and presentation to lymphocytes by cooperating with a second signal (provided by LPS or endogenous TNF-alpha) to promote increased proinflammatory cytokine production, NO production, and MHC class II expression. Macrophage-stimulating protein (MSP) suppresses NO production by activated peritoneal macrophages in vitro. Furthermore, targeted deletion of the receptor for MSP, stem cell-derived tyrosine kinase receptor (STK/RON), resulted in increased production of NO by activated macrophages both in vitro and in vivo. Here we demonstrate that expression of STK in RAW264.7 cells resulted in suppression of NO production following IFN-gamma+/- LPS stimulation in the presence of MSP, reflecting a decrease in the levels of inducible NO synthase (iNOS) mRNA and protein, which was confirmed by decreased trans-activation of an iNOS reporter. The iNOS expression is regulated by the coordinate activity of the inducible transcription factors STAT-1, IFN response factor-1, and NF-kappaB. The presence of the STK receptor did not significantly alter the expression of the IFN-gamma receptor, STAT1 phosphorylation, or the up-regulation of IFN response factor-1 expression following IFN-gamma stimulation. However, nuclear translocation of NF-kappaB following stimulation of RAW cells with IFN-gamma and LPS was reduced in the presence of the MSP/STK signaling pathway. These results suggest that the negative regulation of macrophage responses by MSP/STK occurs at least in part via inhibition of costimulatory signals, resulting in NF-kappaB activation, that cooperate with IFN-gamma to promote activation.
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PMID:Negative regulation of macrophage activation in response to IFN-gamma and lipopolysaccharide by the STK/RON receptor tyrosine kinase. 1058 55

RON is a receptor tyrosine kinase that mediates cell scattering, migration, and tubular formation. This study focused on the function of two tyrosines, Y1330 and Y1337, in the C-terminus of RON in regulating epithelial cell scattering and migration. Substitution of both tyrosine residues with phenylalanine causes complete loss of cell scattering and migration in kidney 293 cells. In contrast, single mutation of either tyrosine residue has no effect. We found that mutation at Y1330 or Y1337 alone does not significantly affect the association of RON with PI-3 kinase, whereas a double mutation abolishes the recruitment of substrates. RON-mediated cell migration was inhibited by PI-3 kinase inhibitor wortmannin. This effect was also achieved by a dominant inhibitory p85 of PI-3 kinase. We conclude that Y1330 and Y1337 are required for RON-mediated cell motility. By associating with PI-3 kinase, the Y1330-Y1337 docking site plays a critical role in transducing motile signals of RON.
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PMID:Requirement of both tyrosine residues 1330 and 1337 in the C-terminal tail of the RON receptor tyrosine kinase for epithelial cell scattering and migration. 1063 Nov 20

Previous studies have shown that activation of the RON receptor tyrosine kinase inhibits inducible NO production in murine peritoneal macrophages. The purpose of this study is to determine whether inflammatory mediators such as LPS, IFN-gamma, and TNF-alpha regulate RON expression. Western blot analysis showed that RON expression is reduced in peritoneal macrophages collected from mice injected with a low dose of LPS. The inhibition was seen as early as 8 h after LPS challenge. Experiments in vitro also demonstrated that the levels of the RON mRNA and protein are diminished in cultured peritoneal macrophages following LPS stimulation. TNF-alpha plus IFN-gamma abrogated macrophage RON expression, although individual cytokines had no significant effect. Because LPS and TNF-alpha plus IFN-gamma induce NO production, we reasoned that NO might be involved in the RON inhibition. Two NO donors, S-nitroglutathione (GSNO) and (+/-)-S-nitroso-N-acetylpenicillamine (SNAP), directly inhibited macrophage RON expression when added to the cell cultures. Blocking NO production by NO inhibitors like TGF-beta prevented the LPS-mediated inhibitory effect. In Raw264.7 cells transiently transfected with a report vector, GSNO or SNAP inhibited the luciferase activities driven by the RON gene promoter. Moreover, GSNO or SNAP inhibited the macrophage-stimulating protein-induced RON phosphorylation and macrophage migration. We concluded from these data that RON expression in macrophages is regulated during inflammation. LPS and TNF-alpha plus IFN-gamma are capable of down-regulating RON expression through induction of NO production. The inhibitory effect of NO is mediated by suppression of the RON gene promoter activities.
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PMID:Regulation of the RON receptor tyrosine kinase expression in macrophages: blocking the RON gene transcription by endotoxin-induced nitric oxide. 1072 42

Cooperation between integrins and growth factor receptors plays an important role in the regulation of cell growth, differentiation, and survival. The function of growth factor receptor tyrosine kinases (RTKs) can be regulated by cell adhesion to extracellular matrix (ECM) even in the absence of ligand. We investigated the pathway involved in integrin-mediated RTK activation, using RON, the receptor for macrophage-stimulating protein. Adhesion of RON-expressing epithelial cells to ECM caused phosphorylation of RON, which depended on the kinase activity of both RON itself and c-Src. This conclusion is based on these observations: 1) ECM-induced RON phosphorylation was inhibited in cells expressing kinase-inactive c-Src; 2) active c-Src could phosphorylate immunoprecipitated RON from ECM-stimulated cells but not from unstimulated cells; and 3) ECM did not cause RON phosphorylation in cells expressing kinase-dead RON, nor could active c-Src phosphorylate RON immunoprecipitated from these cells. The data fit a pathway in which ECM-induced integrin aggregation causes both c-Src activation and RON oligomerization followed by RON kinase-dependent autophosphorylation; this results in RON becoming a target for activated c-Src, which phosphorylates additional tyrosines on RON. Integrin-induced epidermal growth factor receptor (EGFR) phosphorylation also depended on both EGFR and c-Src kinase activities. This sequence appears to be a general pathway for integrin-dependent growth factor RTK activation.
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PMID:Integrin-mediated RON growth factor receptor phosphorylation requires tyrosine kinase activity of both the receptor and c-Src. 1074 44

Scatter Factors control a complex genetic program known as 'invasive growth'. HGF (Scatter factor 1) and MSP (Scatter Factor 2) bind to tyrosine kinase receptors encoded by the proto-oncogenes MET and RON. Using the appropriate 'kinase inactive' mutant receptors, we show that ligand-induced activation of Met results in transphosphorylation of Ron, and vice versa. Transphosphorylation is direct, as it occurs in Met or Ron receptors lacking the docking sites for signal transducers. Phosphate groups are transferred to the tyrosine phosphorylation sites responsible both for kinase up-regulation (Met: Y1234/Y1235 and Ron: Y1238/Y1239) and for generation of signal transducer docking sites (Met: Y1349/Y1356 and Ron Y1353/Y1360). The transphosphorylation specifically takes place for the receptor subfamily, as it is not observed between Met or Ron and ErbB1, ErbB2 or TrkA. Cross-linking experiments show that non-covalent Met-Ron complexes are present on the cell surface, before ligand-induced dimerization. Co-expression of a kinase inactive Ron receptor with naturally-occurring oncogenic Met mutants suppresses the transforming phenotype, suggesting a dominant negative role for the inefficient kinase partner. These data show that, while specific for their ligands, scatter factor receptors cross-talk and cooperate in intracellular signaling.
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PMID:Cross-talk between the proto-oncogenes Met and Ron. 1087 56


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