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)

In the repair process after lung injury, the regeneration of alveolar epithelial cells plays an important role by covering the damaged alveolar wall and preventing the activated fibroblasts from invading the intra- alveolar spaces. Hepatocyte growth factor (HGF) is a potent mitogen for alveolar epithelial cells and has been reported to be capable of repressing the fibrosing process by connecting to the c-Met/HGF receptor on alveolar epithelial cells. However, it has been reported that the c-Met expression was downregulated in an acute phase of lung injury, which may limit the effect of HGF for therapeutic use. In the present study we observed that interferon (IFN)-gamma upregulates the c-Met messenger RNA (mRNA) and protein expression in A549 alveolar epithelial cells. We analyzed the mechanism of this upregulation and found that IFN-gamma enhances the transcription of the c-met proto-oncogene, and that it does not prolong the stability of the c-Met mRNA. HGF is known to act as a motogen as well as a mitogen for epithelial cells. We also found that the migratory activity of A549 cells induced by HGF is strongly enhanced by preincubation with IFN-gamma. Finally, we administered recombinant IFN-gamma to C57BL/6 mice and confirmed that this upregulation is also observed in vivo. These results suggest that the combination of HGF and IFN-gamma could be a new therapeutic approach for fibrosing pulmonary diseases.
Am J Respir Cell Mol Biol 1999 Oct
PMID:Interferon-gamma upregulates the c-Met/hepatocyte growth factor receptor expression in alveolar epithelial cells. 1050 59

Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering through the tyrosine kinase-type HGF/SF receptor c-Met. We have previously shown that Rho small G protein (Rho) is involved in the HGF/SF-induced scattering of Madin-Darby canine kidney (MDCK) cells by regulating at least the assembly and disassembly of stress fibers and focal adhesions, but it remains unknown how c-Met regulates Rho activity. We have found here a novel signaling pathway of c-Met consisting of SHP-2-Rho that regulates the assembly and disassembly of stress fibers and focal adhesions in MDCK cells. SHP-2 is a protein-tyrosine phosphatase that contains src homology-2 domains. Expression of a dominant negative mutant of SHP-2 (SHP-2-C/S) markedly increased the formation of stress fibers and focal adhesions in MDCK cells and inhibited their scattering. C3, a Clostridium botulinum ADP-ribosyltransferase, and Y-27632, a specific inhibitor for ROCK, reversed the stimulatory effect of SHP-2-C/S on stress fiber formation and the inhibitory effect on cell scattering. Vav2 is a GDP/GTP exchange protein for Rho. Expression of a dominant negative mutant of Vav2 blocked the stimulatory effect of SHP-2-C/S on stress fiber formation. Conversely, expression of mutants of Vav2 that increased stress fiber formation inhibited HGF/SF-induced cell scattering. These results indicate that SHP-2 physiologically modulates the activity of Rho to form stress fibers and focal adhesions and thereby regulates HGF/SF-induced cell scattering. In addition, Vav2 may be involved in the SHP-2-Rho pathway.
Mol Biol Cell 2000 Aug
PMID:Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering. 1093 Apr 54

Polycythemia vera (PV) is a rare, progressive myeloproliferative disorder thought to originate from the clonal expansion of a multipotent haemopoietic stem cell. This disease is characterised by hyperproliferation of the erythroid, myeloid and megakaryocyte lineages in the early phase, anaemia and fibrosis in the spent phase, and with a significant number of patients developing acute myeloid leukaemia (AML) in the final phase. Studies investigating the growth factor requirements of committed progenitors have shown hypersensitivity to a number of haemopoietic growth factors (HGF) in vitro and several HGF receptor and signalling molecule alterations have been reported. The findings to date, however, are unable to account for the transformation of a primitive stem cell and the many alterations to growth factor responses seen in PV progenitors. Identification of the primary lesion that leads to the pathogenesis of PV is of major importance given the profound effects on regulation of the haemopoietic stem cell compartment. In this article we focus on characteristics of the disease, research findings to date and possible mechanisms to explain altered growth factor responses, receptor alterations and signalling abnormalities in PV.
Int J Mol Med 2000 Sep
PMID:Molecular aspects of polycythemia vera (review). 1093 84

Retinoids participate in the onset of differentiation, apoptosis and the inhibition of growth in a wide variety of normal and cancerous cells. Several recent reports have shown that hepatocyte growth factor (HGF), and its receptor, c-Met, are expressed at abnormally high levels in various human malignant gliomas and exert a strong proliferative action in an autocrine fashion. These results, consequently, imply that HGF and its receptor may represent a major contributor to the progression of such malignancies. Since astrocytomas are the most frequently occurring glioma, we have shown here that U87 cells - a well-established, human astrocytoma cell line - express both HGF and c-Met, thereby providing a suitable astrocytic tumor model for studying the potential role of HGF, functioning in an autocrine mode, in astrocytic tumorigenesis. Furthermore, we demonstrated the expression of the retinoic acid receptor (RAR) isoforms, RARalpha, -beta and -gamma, as well as the retinoid x-receptor (RxR) isoforms, RxRalpha and -beta, by RT-PCR and western blot analysis in these cells. Since ligands of the RARs and RxRs are known to exert growth inhibitory effects on various tumor cells which include some astrocytomas, we speculated that such effect of retinoids might be mediated via inhibition of HGF secretion in human astrocytoma cells. Indeed, we have shown that the RAR agonists, all-trans retinoic acid (ATRA) and (E)-4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid (TTNPB), inhibited HGF secretion with half maximal inhibition occurring at 3.0 microM and 15 nM, respectively, as did the RxR agonists, 9-cis- and 13-cis retinoic acid (9cRA and 13cRA, respectively), which exerted half-maximal inhibitory effects at 40 and 25 nM, respectively. These actions of the RAR and RxR agonists appear to be exerted at the transcriptional level as assessed by Northern blot analysis. Taken together, our results show for the first time that retinoids, acting via the RAR and RxRs, significantly inhibit both the secretion and expression of HGF, thereby interrupting a potentially highly tumorigenic autocrine loop in astrocytoma cells.
Brain Res Mol Brain Res 2001 Feb 19
PMID:Agonists of the retinoic acid- and retinoid X-receptors inhibit hepatocyte growth factor secretion and expression in U87 human astrocytoma cells. 1122 64

The effect of HGF/SF on the association between the E-cadherin/catenin complex and the tyrosine kinase receptor c-Met, was examined in prostate cancer cells LNCap FGC. Stimulation by HGF/SF showed E-cadherin and beta-catenin to be co-precipitated and located at areas of cell-cell contact with the HGF/SF receptor c-Met, as detected by immunoprecipitation and immunofluorescence respectively. Furthermore, continued exposure to this motogen increased the level of co-precipitations between the E-cadherin/catenin complex with c-Met, and also increased tyrosine phosphorylation of c-Met. In contrast, continued stimulation by HGF/SF decreased the level of co-localised peripheral staining and increased the level of cytoplasmic staining. In conclusion, the association between the E-cadherin/catenin complex with the HGF/SF receptor c-Met, may influence or regulate intercellular adhesion in prostate cancer following stimulation by HGF/SF.
Int J Mol Med 2001 Apr
PMID:HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells. 1125 78

Induction of replication may potentiate in vivo gene therapy, as some viral vectors only transduce dividing cells. Hepatocyte growth factor (HGF) increases the percentage of replicating hepatocytes to 18-fold that in normal rats, and lipopolysaccharide (LPS) modestly potentiates this effect. In this study, the effect of iv HGF upon replication in other organs was determined. HGF at 10 mg/kg resulted in replication that was < or =3-fold that of normal rats in alveolar and proximal renal tubular cells. HGF alone had no effect upon replication of epithelial cells from the bronchi, thyroid, pancreas, or colon or upon cells from the muscle, pancreatic islets, spleen, blood vessels, or thymus. HGF and LPS at 5 mg/kg resulted in replication that was 9-fold that of normal rats in alveolar cells, 25-fold in bronchial epithelial cells, 4-fold in thyroid epithelial cells, 1.5-fold in the red pulp of the spleen, and 2-fold in colonic epithelial cells. The synergistic effect may be due to the fact that LPS upregulated the HGF receptor c-met in thyroid, spleen, and colon. We conclude that iv administration of HGF alone is relatively specific for inducing hepatocyte replication and would allow selective gene transfer into the liver.
Mol Ther 2001 Apr
PMID:Lipopolysaccharide potentiates the effect of hepatocyte growth factor upon replication in lung, thyroid, spleen, and colon in rats in vivo. 1131 6

Hepatocyte growth factor (scatter factor) (HGF/SF) is a pleiotrophic mediator of epithelial cell motility, morphogenesis, angiogenesis, and tumorigenesis. HGF/SF protects cells against DNA damage by a pathway from its receptor c-Met to phosphatidylinositol 3-kinase (PI3K) to c-Akt, resulting in enhanced DNA repair and decreased apoptosis. We now show that protection against the DNA-damaging agent adriamycin (ADR; topoisomerase IIalpha inhibitor) requires the Grb2-binding site of c-Met, and overexpression of the Grb2-associated binder Gab1 (a multisubstrate adapter required for epithelial morphogenesis) inhibits the ability of HGF/SF to protect MDCK epithelial cells against ADR. In contrast to Gab1 and its homolog Gab2, overexpression of c-Cb1, another multisubstrate adapter that associates with c-Met, did not affect protection. Gab1 blocked the ability of HGF/SF to cause the sustained activation of c-Akt and c-Akt signaling (FKHR phosphorylation). The Gab1 inhibition of sustained c-Akt activation and of cell protection did not require the Gab1 pleckstrin homology or SHP2 phosphatase-binding domain but did require the PI3K-binding domain. HGF/SF protection of parental MDCK cells was blocked by wortmannin, expression of PTEN, and dominant negative mutants of p85 (regulatory subunit of PI3K), Akt, and Pak1; the protection of cells overexpressing Gab1 was restored by wild-type or activated mutants of p85, Akt, and Pak1. These findings suggest that the adapter Gab1 may redirect c-Met signaling through PI3K away from a c-Akt/Pak1 cell survival pathway.
Mol Cell Biol 2001 Aug
PMID:The multisubstrate adapter Gab1 regulates hepatocyte growth factor (scatter factor)-c-Met signaling for cell survival and DNA repair. 1143 54

Hepatocyte growth factor (HGF) is a pleiotropic growth factor that acts on various epithelial cells. The objectives of this study were to determine whether HGF altered the proliferation and prostaglandin (PG) secretion of bovine endometrial stromal and epithelial cells in vitro. We also observed HGF and HGF receptor (c-met) mRNA expression in cultured bovine endometrial stromal and epithelial cells by RT-PCR. Stromal and epithelial cells obtained from cows in early stage of the estrous cycle (days 2-5) were cultured in DMEM/Ham's F-12 supplemented with 10% calf serum. The cells were exposed to HGF (0-10 ng/ml) for 2, 4, or 6 days. HGF significantly increased the total DNA in epithelial (P < 0.05), but not stromal cells. In another experiment, when the cells reached confluence, the culture medium was replaced with fresh medium with 0.1% BSA containing HGF 0-100 ng/ml and the cells were cultured for 24 hr. The HGF stimulated PGF2alpha secretion in epithelial, but not stromal cells. RT-PCR revealed that mRNA of HGF is expressed only in stromal cells, and that c-met mRNA is expressed in both stromal and epithelial cells. These results suggest that HGF plays roles in the proliferation and the regulation of secretory function of bovine endometrial epithelial cells in a paracrine fashion.
Mol Reprod Dev 2001 Dec
PMID:Expression and action of hepatocyte growth factor in bovine endometrial stromal and epithelial cells in vitro. 1174 58

Hepatocyte growth factor/scatter factor (HGF/SF) induces proliferation, motility and morphogenesis of cells that express the proto-oncogene for the tyrosine kinase receptor, c-Met. Because these cellular events occur in the endometrium during the menstrual cycle and in placenta during development, we have initiated studies of this growth factor in these tissues from macaques. Several HGF/SF alternatively spliced transcripts have been previously reported in other tissues. However, expression of HGF/SF isoforms in the endometrium has not been studied. Here we describe the relative transcript amounts of HGF/SF isoforms in the endometrium and placenta using RNase protection analyses. During these analyses, we discovered two unexpected protected bands that were found through sequence analyses to represent isoforms similar to the previously reported NK1 and NK2 except that they encode a five amino acid deletion in the first kringle domain. We designated these two isoforms as dNK1 and dNK2. Endometrium expressed all of the isoforms; however, dNK2 was consistently expressed at higher levels than NK2 transcripts. In contrast, placenta expressed NK2 and dNK2 mRNA at equal levels, and both NK1 and dNK1 were undetectable in placenta. HGF/SF function in endometrium and placenta may involve complex interactions between the isoforms of HGF/SF and those of c-Met.
Mol Hum Reprod 2002 Jan
PMID:Novel hepatocyte growth factor/scatter factor isoform transcripts in the macaque endometrium and placenta. 1175 73

Hepatocyte growth factor (HGF) affects tumor growth/invasion and tumor neovascularization. A proposed HGF antagonist, NK4 (an amino-terminal kringle-domain peptide of HGF), inhibits tumor growth/invasion through the competition of HGF binding to its receptor, c-Met, and acts as an angiogenesis inhibitor. To investigate the in vivo effect of NK4 gene transfer, we constructed an adenovirus vector expressing human NK4 (AdCMV.NK4). Human lung cancer cell lines (A549 and H358) infected in vitro with AdCMV.NK4 yielded NK4 protein without a change in the cell growth rate. In contrast, direct injection of AdCMV.NK4 (1 x 10(9) pfu, twice) into established subcutaneous tumors in BALB/c nu/nu mice resulted in suppression of the tumors by 64% for A549 or by 91% for H358 compared with controls (P<0.02 or P<0.01, respectively). Counting of the tumor vessels revealed suppressed vascularity by 57% in H358 tumors when using AdCMV.NK4 (P<0.0001). Furthermore, systemic NK4 delivery by intraperitoneal injection of AdCMV.NK4 effectively suppressed both angiogenesis in the Matrigel assay (86% reduction, P<0.032), subcutaneous tumor growth in vivo (by 65% for H358, P<0.001), and hematogenous lung metastases without obvious side effects. These results indicate that NK4 elicits tumor-growth suppression in vivo through its anti-angiogenic activity and anti-HGF activity and that NK4 gene transfer can be an effective tool in the treatment of cancer.
Mol Ther 2002 Feb
PMID:Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy. 1182 25


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