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)

Hepatocyte growth factor (HGF), a heparin-binding polypeptide mitogen, stimulates DNA synthesis in adult rat and human hepatocytes and in several other cells of epithelial origin. Recently, it was determined that scatter factor (SF), a protein that has been shown to cause the dispersion and migration of epithelial cells in culture, is identical to HGF. Moreover, the receptor for HGF was identified as the product of the proto-oncogene, c-MET, a tyrosine kinase-containing transmembrane protein. c-MET expression has been reported in a variety of adult and embryonic mouse tissues. Similarly, we and others have demonstrated that HGF is expressed in various adult rat and human tissues. In the present study, the tissue distribution of HGF during rat development was determined by immunohistochemistry using an HGF-specific polyclonal antiserum. Between day 12 and day 19, immunoreactivity for HGF was present in various locations such as hematopoietic cells, somites, squamous epithelium of the esophagus and skin, periventricular germinal matrix of the brain, bronchial epithelium, renal collecting tubules and chondrocytes. After day 19, HGF immunoreactivity was also present in the pancreas, submaxillary glands and neural tissues. In addition to immunolocalizing HGF in tissue sections, bioreactive and immunoreactive HGF was extracted and purified from rat fetuses. Other studies demonstrated the presence of HGF and c-MET mRNA in total fetal rat, and in fetal and neonatal rat liver. Addition of purified HGF to fetal and neonatal rat liver cultures enriched for hepatocytes stimulated DNA synthesis up to six-fold over controls. These findings strongly suggest a pivotal role for this potent regulator of growth and development.
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PMID:The presence of hepatocyte growth factor in the developing rat. 128 14

Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a polypeptide which induces motility and/or mitogenesis in epithelial cells. The receptor for HGF/SF, p190MET, is a two-chain transmembrane tyrosine kinase encoded by the MET proto-oncogene. To identify the cytoplasmic effectors involved in signal transduction we have produced the human HGF/SF receptor in insect cells (Sf9) by means of a recombinant baculovirus. Two 170-kDa forms of the receptor were synthesized in Sf9 cells: the uncleaved single-chain precursor (which is by far the more abundant) and the proteolytically processed two-chain molecule. Both receptor species are phosphorylated on tyrosine in vivo and are active kinases in vitro. The recombinant receptor binds and phosphorylates in vitro four known cytoplasmic transducers containing src homology region 2 (SH2) domains: the 85-kDa subunit of phosphatidylinositol 3-kinase (Pl 3-kinase), rasGAP, phospholipase-C gamma (PLC-gamma), and p59Fyn, a tyrosine kinase of the src family. In all cases the association is strictly dependent on tyrosine phosphorylation of the receptor, indicating that it occurs via specific interaction with the SH2 domains. These results show that the HGF/SF receptor has the sequence requirements for binding a spectrum of cytoplasmic transducers whose different combinations in target cells may result in the observed pleiotropic biological response.
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PMID:Autophosphorylation promotes complex formation of recombinant hepatocyte growth factor receptor with cytoplasmic effectors containing SH2 domains. 132 86

The proto-oncogene c-MET encodes a transmembrane tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF stimulates the proliferation and motility of various cell types. Because HGF/SF is also a melanocyte mitogen, we investigated the biological role of HGF/SF, including c-Met expression, activation and signal transduction, in normal and malignant human melanocytes. We show that HGF/SF is mitogenic in the presence of synergistic factors, such as basic fibroblast growth factor (bFGF) and mast cell growth factor (MGF) and that, by itself, it stimulates the motility of normal human melanocytes. The ligand also maintained high levels of tyrosinase activity and melanin content in theses cells. Signal transduction by HGF/SF included phosphorylation of tyrosyl residues on c-Met, a cascade of tyrosine phosphorylations on several other proteins and activation of microtubule-associated protein kinase/extracellular signal-regulated kinase. Met expression and activity are normal in human melanomas, and constitutive activity of HGF/SF in retrovirally infected autonomously proliferative mouse melanocytes is insufficient to confer the malignant phenotype. Our findings suggest that activation of Met in response to HGF/SF may contribute to malignant progression synergistically with the aberrant expression of bFGF in malignant melanocytes and that, in addition, the peptide may promote dispersion of factor-dependent melanocytes from early stages of primary melanomas to ectopic sites.
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PMID:Met and hepatocyte growth factor/scatter factor signal transduction in normal melanocytes and melanoma cells. 133 34

The receptor for hepatocyte growth factor, also known as scatter factor (HGF/SF), has recently been identified as the 190-kDa heterodimeric tyrosine kinase encoded by the MET proto-oncogene (p190MET). The signaling pathway(s) triggered by HGF/SF are unknown. In A549 cells, a lung epithelial cell line, nanomolar concentrations of HGF/SF induced tyrosine phosphorylation of the p190MET receptor. The autophosphorylated receptor coprecipitated with phosphatidylinositol 3-kinase (PI 3-kinase) activity. In GTL16 cells, a cell line derived from a gastric carcinoma, the p190MET receptor, overexpressed and constitutively phosphorylated on tyrosine, coprecipitated with PI 3-kinase activity and with the 85-kDa PI 3-kinase subunit. In these cells activation of protein kinase C or the increase of intracellular [Ca2+] inhibits tyrosine phosphorylation of the p190MET receptor as well as the association with both PI 3-kinase activity and the 85-kDa subunit of the enzyme. In an in vitro assay, tyrosine phosphorylation of the immobilized p190MET receptor was required for binding of PI 3-kinase from cell lysates. These data strongly suggest that the signaling pathway activated by the HGF/SF receptor includes generation of D-3-phosphorylated inositol phospholipids.
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PMID:The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. 171 89

The MET proto-oncogene encodes a transmembrane tyrosine kinase of 190 kDa (p190MET), which has recently been identified as the receptor for hepatocyte growth factor/scatter factor. p190MET is a heterodimer composed of two disulfide-linked chains of 50 kDa (p50 alpha) and 145 kDa (p145 beta). We have produced four different monoclonal antibodies that are specific for the extracellular domain of the Met receptor. These antibodies immunoprecipitate with p190MET two additional Met proteins of 140 and 130 kDa. The first protein (p140MET) is membrane bound and is composed of an alpha chain (p50 alpha) and an 85-kDa C-terminal truncated beta chain (p85 beta). The second protein (p130MET) is released in the culture supernatant and consists of an alpha chain (p50 alpha) and a 75-kDa C-terminal truncated beta chain (p75 beta). Both truncated forms lack the tyrosine kinase domain. p140MET and p130MET are consistently detected in vivo, together with p190MET, in different cell lines or their culture supernatants. p140MET is preferentially localized at the cell surface, where it is present in roughly half the amount of p190MET. The two C-terminal truncated forms of the Met receptor are also found in stable transfectants expressing the full-length MET cDNA, thus showing that they originate from posttranslational proteolysis. This process is regulated by protein kinase C activation. Together, these data suggest that the production of the C-terminal truncated Met forms may have a physiological role in modulating the Met receptor function.
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PMID:C-terminal truncated forms of Met, the hepatocyte growth factor receptor. 194 72

Hepatocyte growth factor (scatter factor) and its receptor, the c-met proto-oncogene product (c-MET), have been implicated in embryogenesis, tissue reorganization, and tumor progression. Little is known, however, of the expression and functional significance of these molecules in prostatic cells and tissue. In this investigation, we assessed the expression of hepatocyte growth factor (HGF) and c-MET in prostatic tissues and cell lines and also determined the effect of purified recombinant HGF on cell proliferation and scattering of prostatic carcinoma cell lines. HGF was expressed by human prostatic stromal myofibroblasts in primary culture but not by three human prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3) as assessed by Northern blot analysis. HGF was also detected by reverse transcriptase-polymerase chain reaction in both benign and malignant tissues from radical prostatectomy specimens. c-MET transcripts were identified by Northern blot in two androgen-insensitive human prostatic carcinoma cell lines (DU 145 and PC-3) but not the androgen-sensitive LNCaP cell line. Additional evidence of linkage of androgen responsiveness and c-MET was provided by experiments in which androgen deprivation of normal rat prostates via castration produced a marked up-regulation of c-MET expression as determined by Northern blot and immunohistochemistry. c-MET protein was detected by immunohistochemical analysis in a substantial percentage (58 of 128 or 45%) of prostatic carcinomas and was found more often in metastatic growths of human prostatic carcinoma (15 of 20 patients) compared with primary tumors (43 of 108 patients; P < 0.005). Moreover, in Dunning R-3327 rat prostatic carcinoma cell lines, c-MET expression was highest in the androgen-insensitive subline with the highest metastatic capacity. Purified recombinant human HGF induced dose-dependent cellular proliferation and scattering in the DU 145 carcinoma cell line. These data indicate that HGF may function in the prostate gland as a paracrine growth factor, with synthesis by stromal cells and with biological target cells being the epithelial cells. Expression of the HGF receptor, c-MET, is up-regulated by androgen deprivation and c-MET appears to be preferentially expressed on androgen-insensitive, metastatic cells, suggesting a possible linkage of c-MET expression with prostatic carcinoma progression.
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PMID:Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. 763 32

The pleiotropic effects (mitogenesis, motogenesis, and morphogenesis) elicited by hepatocyte growth factor/scatter factor (HGF/SF) are mediated by the activation of the tyrosine kinase receptor encoded by the MET proto-oncogene. Following autophosphorylation, the receptor associates with the p85/110 phosphatidylinositol (PI) 3-kinase complex in vivo and in vitro. By a combination of two complementary approaches, competition with synthetic phosphopeptides and association with Tyr-Phe receptor mutants, we have identified Y-1349 and Y-1356 in the HGF/SF receptor as the binding sites for PI 3-kinase. Y-1349VHV and Y-1356VNV do not conform to the canonical consensus sequence YXXM for PI 3-kinase binding and thus define YVXV as a novel recognition motif. Y-1349 and Y-1356 are located within the C-terminal portion of the HGF/SF receptor and are phosphorylation sites. The affinity of the N- and C-terminal src homology region 2 (SH2) domains of p85 for the phosphopeptides including Y-1349 and Y-1356 is 2 orders of magnitude lower than that measured for Y-751 in the platelet-derived growth factor receptor binding site. However, the closely spaced duplication of the novel recognition motif in the native HGF/SF receptor may allow binding with both SH2 domains of p85, thus generating an efficient docking site for PI 3-kinase. In agreement with this model, we have observed that a phosphopeptide including both Y-1349 and Y-1356 activates PI 3-kinase in vitro.
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PMID:A novel recognition motif for phosphatidylinositol 3-kinase binding mediates its association with the hepatocyte growth factor/scatter factor receptor. 768 41

The receptor for the growth and motility factor, hepatocyte growth factor/scatter factor (HGF/SF), is a transmembrane tyrosine kinase encoded by the MET oncogene. Previous work has shown that receptor phosphorylation on tyrosine is critical for both kinase activation and association with intracellular signal transducers. In this paper, we report that a protein tyrosine phosphatase activity (PTP) coprecipitates with the HGF/SF receptor. The associated PTP activity correlates with the kinase activation of the receptor, increasing up to 5-fold over the basal level after HGF/SF stimulation. The increase is reversible and time- and dose-dependent. A comparable level of activity is associated with constitutively tyrosine-phosphorylated receptors immunoprecipitated from cells where the MET oncogene is amplified and overexpressed. In these cells, a parallel decrease in PTP activity is observed after inhibition of receptor tyrosine phosphorylation following protein kinase C activation. The associated PTP activity is effective in dephosphorylating the HGF/SF receptor. These data show that a protein tyrosine phosphatase is functionally coupled to the HGF/SF receptor.
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PMID:A protein tyrosine phosphatase activity associated with the hepatocyte growth factor/scatter factor receptor. 768 41

Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding polypeptide which shares structural domains with enzymes of the blood clotting cascade. HGF/SF is secreted by cells of mesodermal origin and has powerful mitogenic, motogenic and morphogenic activity on epithelial and endothelial cells. HGF/SF is produced as a biologically inactive single-chain precursor (pro-HGF/SF) most of which is sequestered on the cell surface or bound to the extracellular matrix. Maturation into the active alpha beta heterodimer results from proteolytic cleavage by a urokinase-type protease, which acts as a pro-HGF/SF convertase. The primary determinant for receptor binding appears to be located within the alpha-chain. The interaction of the alpha-chain with the receptor is sufficient for the activation of the signal cascade involved in the motility response. However, the complete HGF/SF protein seems to be required to elicit a mitogenic response. HGF/SF binds with high affinity to a transmembrane receptor, p190MET, encoded by the MET proto-oncogene. p190MET is the prototype of a distinct subfamily of heterodimeric tyrosine kinases, including the putative receptors Ron and Sea. The mature form of p190MET is a heterodimer of two disulfide-linked subunits (alpha and beta). The alpha-subunit is extracellular and heavily glycosylated. The beta-subunit consists of an extracellular portion involved in ligand binding, a membrane spanning segment, and a cytoplasmic tyrosine kinase domain. Both subunits derive from glycosylation and proteolytic cleavage of a common precursor of 170 kDa. In polarized epithelial cells the HGF/SF receptor is selectively exposed in the basolateral plasmalemma, where it is associated with detergent-insoluble components. Two Met isoforms, carrying an intact ligand binding domain but lacking the kinase domain due to truncation of the beta-subunit, arise from alternative post-transcriptional processing of the mature form. One truncated form is soluble and released from the cells. HGF/SF binding triggers tyrosine autophosphorylation of the receptor beta-subunit. Autophosphorylation on the major phosphorylation site Y1235 upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. Negative regulation of the kinase activity occurs through phosphorylation of a unique serine residue (S985) located in the juxtamembrane domain of the receptor. This phosphorylation is triggered by two distinct pathways involving either protein kinase C activation or increase in intracellular Ca2+ concentration. Upon ligand binding, the HGF/SF receptor recruits and activates several cytoplasmic effectors, including phosphatidylinositol 3-kinase (PI 3-K), phospholipase C-gamma (PLC-gamma), pp60c-Src, a tyrosine phosphatase, and a Ras-guanine nucleotide exchanger.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering. 776 52

The c-MET oncogene encodes the receptor for hepatocyte growth factor (HGF) scatter factor, a multifunctional cytokine able to mediate morphogenesis as well as invasive growth of epithelial cells. The c-MET-encoded receptor is detectable only at low levels in the normal human exocrine pancreas, but it is up-regulated in the majority of pancreatic ductal adenocarcinomas. The c-MET-encoded HGF receptor is also overexpressed in a proportion of the panel of 31 human pancreatic cancer cell lines examined, which have a range of different growth properties and degrees of differentiation. In most cases the HGF receptor found in the malignant cells has features of the normal receptor. When added to pancreatic cancer cell lines, HGF triggers receptor phosphorylation and stimulates cells to move and proliferate. In overexpressing cell lines, the Met/HGF receptor is phosphorylated in the absence of endogenously produced or exogenously added ligand. These data suggest that the Met/HGF receptor may be involved in the growth and behavior of pancreatic cancer and may contribute to the ductal phenotype of these tumors.
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PMID:Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. 786 99


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