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 c-MET proto-oncogene encodes the receptor for the Hepatocyte Growth Factor/Scatter Factor, which is known to mediate mitogenic, motogenic and invasive responses of several cell types. We have analysed by immunohistochemistry and biochemically the expression of c-MET in benign and malignant melanocytic lesions. The Met/HGF receptor which in the melanocytic lineage displays the structural features of the authentic receptor was undetectable in tissue melanocytes and in nevocytic nevi. Only four out of 23 primary melanomas scored positive. Expression was increased to a significant level in 17 out of the 44 metastatic lesions examined. The c-MET expression was homogeneous in multiple metastases from the same patients. Comparative analyses showed both lack of correlation with the expression of the tumour progression associated ICAM-1 adhesion molecule and, in 23% of cases, co-expression with the c-KIT encoded receptor. These findings show that the c-MET gene is expressed at late stages of melanoma progression and suggest that the presence of Met/HGF receptor may contribute to the acquisition of an invasive phenotype.
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PMID:Expression of the c-Met/HGF receptor in human melanocytic neoplasms: demonstration of the relationship to malignant melanoma tumour progression. 810 62

The Met proto-oncogene product is a tyrosine kinase receptor whose ligand is hepatocyte growth factor (HGF). The Met protein is first synthesized in the hepatocytes as a single chain precursor, or p170MET proreceptor, and is then processed to a mature heterodimer receptor consisting of an extracellular alpha subunit (p50 alpha MET) and a transmembrane beta subunit (p 145 beta MET). The beta subunit has a protein kinase domain which is activated through phosphorylation on tyrosine residue by the binding of HGF to the receptor. In order to elucidate the function of the Met gene product in hepatic disorders, we analyzed the expression and tyrosine phosphorylation of the Met protein on regeneration and carcinogenesis of the liver. For studies on carcinogenesis we used human hepatoma tissues, and for studies on regeneration we used rat hepatectomy. Two antibodies were used for western blotting; a mouse monoclonal anti-phosphotyrosine antibody, which recognizes phosphorylated tyrosine residue in proteins, and a polyclonal rabbit anti-Met antibody, which recognizes the C-terminus of both the Met beta chains and proreceptor. To compare the amount of protein in each experiment, the results of western blotting were evaluated using an image analyzing system. In experiments involving rats with partial hepatectomy, a decreased expression of the proreceptor with a decreased amount of tyrosine phosphorylation was observed within 12 hours of hepatectomy. However, there were no significant changes of the Met beta subunit during the experiment. These data suggest that the Met proreceptor is decreased in the early stages of liver regeneration. In experiments on human samples surgically removed from 18 patients with hepatocellular carcinoma, the met proteins, p 145 beta MET and p 160 MET proreceptor, were expressed both in cancer tissues (12/18, and 10/18, respectively) and in non-cancer tissues (8/18, and 15/18, respectively). From the comparative analyses of the intensity of the signals in cancerous region against those of non-cancerous region in the 18 individual cases, it was demonstrated that expression of p 160 MET proreceptor was increased in non-cancerous region more significantly than in cancerous region (p < 0.05). On the contrary, expression of p145 beta MET was increased in cancerous region more significantly than in non-cancerous region (p < 0.05), except for a few cases of poorly differentiated carcinomas in which p 145 beta MET signal was not detected. These findings suggested that a processing pathway from the proreceptor to the mature Met receptor is amplified in carcinogenesis of the liver.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Analysis of the hepatocyte growth factor receptor in regeneration and oncogenesis of hepatocytes]. 815 55

The c-MET proto-oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), also known as scatter factor, a potent mitogen and motogen for epithelial cells. The level of the HGF receptor expressed by epithelial cells varies in different growth conditions, being lower in growth arrested confluent monolayers and higher in growing sparse cells. The amount of HGF receptor mRNA increases from 3- to 5-fold after stimulation of confluent monolayers by serum and up to 10-fold after stimulation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (TPA). An increased level of the receptor mRNA was also observed after cell stimulation with nanomolar concentration of HGF itself. The effect was transient, dose, and time-dependent. Transcription of a reporter gene under control of the cloned 297 base pair c-MET promoter was also stimulated by serum, TPA, or HGF. The accumulation of specific mRNA is followed by appearance of the HGF receptor precursor protein, which is further processed to the receptor mature form. After HGF stimulation, HGF receptor expression follows c-FOS and c-JUN induction with a peak approximately 4 h. Pretreatment with the protein synthesis inhibitor puromycin strongly reduced the response to HGF, while cycloheximide alone increased the level of the receptor mRNA. These data show that c-MET behaves as a delayed early-response gene and suggest that the HGF response is autoamplified by inducing the specific receptor.
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PMID:Hepatocyte growth factor (HGF) receptor expression is inducible and is part of the delayed-early response to HGF. 817 99

The c-MET proto-oncogene product is a transmembrane tyrosine kinase receptor which was recently shown to transmit an array of important cellular responses induced by Hepatocyte Growth Factor (HGF). These biological effects include induction of mitogenesis, motogenesis, morphogenesis, metastogenesis and anti-tumor activity on a variety of epithelial cells. All of these processes are known to be associated with normal and abnormal tissue growth and development. The 190 kDa c-MET protein is encoded by a major transcript of 8 kilobases (kb), which is reported to be expressed predominantly in epithelial tissues. The expression pattern of c-MET mRNA and protein are drastically modified in many tumor tissues and cell lines. Currently, no information is available on the molecular mechanisms that regulate c-MET mRNA level. In the present communication, we report for the first time that the inflammatory cytokines such as IL-1 alpha, IL-6 and TNF-alpha, as well as TGF-beta 1, EGF, HGF and the steroidal hormones (estrogen, progesterone, tamoxifen and dexamethasone) markedly influence the steady-state levels of the 8 kb c-MET mRNA in human carcinoma cell lines derived from human tissues such as ovary, breast and endometrium. We demonstrate that c-MET receptor protein is present at high levels in primary tumors of human ovaries (clear cell carcinomas). We present evidence that the 8 kb c-MET mRNA undergoes rapid degradation with a half-life of less than 30 min and that this decay can be quickly inhibited by cycloheximide. Our results suggest that the expression of the c-met proto-oncogene resembles that of an immediate early response gene.
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PMID:Modulation of c-MET proto-oncogene (HGF receptor) mRNA abundance by cytokines and hormones: evidence for rapid decay of the 8 kb c-MET transcript. 820 49

A cDNA encoding mouse hepatocyte growth factor (HGF) has been cloned and completely sequenced by use of reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent cloning. Sequence analysis reveals that mouse HGF, similar to its human and rat counterparts, consists of 728 amino acids, and both the alpha- and beta-chains are encoded in a single open reading frame. Strong homology exists in the primary structure of HGF among the three species of mouse, rat and human (more than 90%), especially in Kringle 1 of the alpha chain which is assumed to be an essential domain for binding of HGF to its receptor, c-MET, a proto-oncogene product. Our results suggest the existence of evolutionary pressure to conserve the distinct structure, and presumably the biological functions, of HGF.
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PMID:Molecular cloning and characterization of cDNA encoding mouse hepatocyte growth factor. 824 Dec 72

The incidence of genetic abnormalities have been investigated in a variety of preleukaemic states RAS and FMS oncogene, p53 suppressor gene mutations and monoclonality in myelodysplastic syndromes (MDS), a paradigm for pre-leukemias have been observed. Other patients at risk of developing either secondary leukaemia or evolving into leukaemia have been similarly studied including haematologically normal patients in remission from lymphoma. Time from treatment to detection of genetic abnormalities is a significant factor in some of these patients which is consistent with the expansion of an abnormal clone. A case of non-dysplastic MDS has been identified with a 7q-karyotypic abnormality typical of therapy related MDS, abnormal progenitor growth and RAS mutations but with normal clinical features. Normal individuals have also been under investigation and found to have a low incidence of proto-oncogene mutations. A prospective study should enable us to determine if these parameters are indeed prognostic indicators.
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PMID:Genetic lesions in preleukemia. 824 36

The proto-oncogene c-met encodes a heterodimeric (alpha, beta) tyrosine kinase receptor which binds the hepatocyte growth factor (HGF). Recently, overexpression of the Met/HGF receptor gene has been detected in fresh samples of carcinomas and in epithelial tumor cell lines but not in cell lines derived from human leukemia and lymphoma. Our analysis of 50 primary samples of human leukemia and lymphoma and 23 hematopoietic cell lines revealed expression of mRNA and protein of the met/HGF receptor in 6 out of the 73 hematopoietic tumor samples analyzed. Four of the six samples positive for expression of the Met/HGF receptor gene were derived from patients with Hodgkin's disease. In addition, in one Burkitt's lymphoma cell line and in one acute myeloid leukemia (AML), expression of the Met/HGF receptor gene was detected. In normal unstimulated lymphocytes, granulocytes or monocytes we did not find expression of the Met/HGF receptor gene. Upon stimulation with the phorbol ester TPA we detected a weak expression of Met/HGF receptor specific transcripts of 9.0 kb in peripheral blood mononuclear cells of a healthy donor. Cytogenetic analyses of three of the four cell lines which express the Met/HGF receptor gene revealed structural or numerical abnormalities of the long arm of chromosome 7, where the Met/HGFR gene is located, in each of the three cell lines analyzed. In one of these cell lines (L540) the Met/HGFR gene is translocated to a marker chromosome. Southern blot and pulsed field gel electrophoresis experiments did not show any rearrangement in a region of 600 kb around the Met/HGF receptor gene excluding an activation of Met/HGFR by a TPR/Met oncogenic rearrangement as described for MNNG-HOS cells and for some gastric tumors. Our data indicate that the Met/HGFR gene is deregulated in a few cases of human leukemia, Burkitt's lymphoma and Hodgkin's disease possibly by chromosomal rearrangements resulting in an overexpression of the normal Met/HGF receptor mRNA and protein without formation of a hybrid gene.
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PMID:The Met/hepatocyte growth factor receptor (HGFR) gene is overexpressed in some cases of human leukemia and lymphoma. 828 71

The tyrosine kinase encoded by the MET proto-oncogene (p190MET) is the receptor for Hepatocyte Growth Factor/Scatter Factor (HGF/SF). Previous work has shown that autophosphorylation of p190MET enhances its enzymatic activity and that the major phosphorylation site is Tyr1235, located in the catalytic domain. This residue is part of a 'three tyrosine' motif, including Tyr1230, Tyr1234, and Tyr1235, conserved in several other receptor kinases. We studied the role of these tyrosines in the positive regulation of the p190MET kinase by site-directed mutagenesis. Substitution of either Tyr1235 or Tyr1234 with phenylalanine severely reduced the in vitro kinase activity toward exogenous substrates. Kinetic experiments showed that the residual activity of these mutants could still be enhanced by autophosphorylation. Phosphopeptide mapping indicated that, in the absence of Tyr1235, Tyr1234 is phosphorylated. Only the replacement of both Tyr1234 and Tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation. In stable transfectants expressing the HGF/SF receptor with single substitution of either Tyr1234 or Tyr1235 the response to HGF/SF was impaired. The ligand did not induce tyrosine phosphorylation of the receptor nor stimulated chemotaxis. These data show that Tyr1234 and Tyr1235 are critical for the activation of the HGF/SF receptor kinase both in vitro and in response to the ligand in intact cells.
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PMID:Tyrosines1234-1235 are critical for activation of the tyrosine kinase encoded by the MET proto-oncogene (HGF receptor). 830 3

Hepatocyte Growth Factor (HGF) and Scatter Factor (SF) are identical glycoproteins secreted by cells of mesodermal origin. The factor has several activities on epithelial cells, including mitogenesis, dissociation of epithelial sheets, stimulation of cell motility, and promotion of matrix invasion. HGF is the ligand for p190MET, the receptor tyrosine kinase encoded by the MET proto-oncogene. This was proved by HGF binding to immunopurified p190MET, chemical cross-linking of radiolabelled ligand, HGF-induced tyrosine phosphorylation of p190MET, and reconstitution of high-affinity binding sites for HGF into insect cells infected with a recombinant baculovirus carrying the human MET cDNA. p190MET is a 190 kDa heterodimer of two (alpha beta) disulfide-linked protein subunits. The alpha subunit is heavily glycosylated and extracellular. The beta subunit bears an extracellular portion involved in ligand binding, a membrane spanning segment and a cytoplasmic tyrosine kinase domain with phosphorylation sites regulating its activity. Both subunits originate from glycosylation and proteolytic cleavage of a common precursor of 170 kDa. Alternative post-transcriptional processing originates two truncated Met proteins, endowed with ligand binding activity, lacking the cytoplasmic kinase domain of the beta subunit. One form is soluble and released from the cells. HGF binding triggers tyrosine autophosphorylation of the receptor beta subunit in intact cells. Autophosphorylation upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. The major phosphorylation site has been mapped to Tyr1235. Negative regulation of the receptor kinase activity occurs through distinguishable pathways involving protein kinase C activation or increase in the intracellular Ca2+ concentration. Both lead to the serine phosphorylation of a unique phosphopeptide of the receptor and to a decrease in its kinase activity. Receptor autophosphorylation also triggers the signal transduction pathways inside the target cells. The phosphorylated receptor associates ras GAP, phospholipase C-gamma, and src-related tyrosine kinase in vitro; Phosphatidylinositol 3-kinase, in vitro and in vivo, indicating that the generation of the D-3 phosphorylated inositol lipids is involved in effecting the motility and/or the growth response to HGF. The p190MET HGF receptor is expressed in several epithelial tissues and it is often overexpressed in neoplastic cells. In some tumors of the gastrointestinal tract the Met tyrosine kinase is constitutively activated, either by overexpression of the amplified MET oncogene or by lack of cleavage of the receptor precursor, due to defective post-translational processing.
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PMID:Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells. 838 Jul 35

The c-MET proto-oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), also known as scatter factor, a powerful mitogen and motility factor for epithelial cells. We now show that the two previously described forms of the Met/HGF receptor, the intact p190MET and the truncated p140MET, are expressed in physiological conditions in the human central nervous system (CNS). The receptors were identified by Western blot analysis with monoclonal antibodies directed against different epitopes. By immunohistochemical staining the Met/HGF receptor was found to be expressed in a homogeneous cell population, equally distributed between the grey and the white matter, showing morphological features and immunochemical markers specific for the resident microglial cells. These data suggest a possible role for the c-MET proto-oncogene and HGF in microglial reactions to CNS injuries.
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PMID:Selective expression of the Met/HGF receptor in human central nervous system microglia. 838 Sep 19


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