Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor

Miyazawa, Keiji; Tsubouchi, Hirohito; Naka, Daiji; Takahashi, Kazuhiro; Okigaki, Mitsuhiko; Arakaki, Naokatu; Nakayama, Hiroyuki; Hirono, Shuichi; Sakiyama, Osamu; Takahashi, Kozo; Gohda, Eiichi; Daikuhara, Yasushi; Kitamura, Naomi

doi:10.1016/0006-291x(89)92316-4

Cited by 658 publications

(385 citation statements)

References 8 publications

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“…In vivo, MET function is particularly important for the regeneration of the liver and the kidney in response to both acute and chronic insults. Production of HGF increases steeply following liver damage, and the ensuing activation of MET in hepatocytes provides strong mitogenic and antiapoptotic stimuli for organ repair 14,15,124 . Accordingly, conditional deletion of MET in the liver results in impaired organ reconstitution after toxic insult and hepatectomy 125,126 (Fig.…”

Section: Met Signalling In Development and Diseasementioning

confidence: 99%

MET signalling: principles and functions in development, organ regeneration and cancer

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,083

1,076

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The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.Throughout embryogenesis, cells bud off from developing tissues and move outwards to shape and pattern the complex architecture of prospective organs 1 . A similar process occurs in adult life during wound healing and tissue repair, when lingering cells migrate into injury sites to recreate the pre-existing structures 2 . The acquisition of cell motility is necessary, but not sufficient, for this event. Cells that detach from their neighbours must elude anoikis, a form of apoptotic cell death that occurs when cells lose adhesion with the extracellular matrix 3 . Moreover, migratory cells undergo extensive mitotic divisions to produce 'founder populations', which settle in newly forming organs during development or colonize worn tissues during repair 4,5 . The normal phases of embryogenesis and organ regeneration strongly resemble the pathological process of tumour invasiveness: similarly to cells at the wound edge, cells at the tumour's leading front disrupt intercellular contacts and infiltrate the adjacent surroundings, where they resist anoikis and grow before lodging in the blood vessels for systemic dissemination 6 . This resemblance is not simply a biological correlate, it has a common mechanistic basis: cancer cells resurrect the latent schemes of cellular reorganization, which are usually confined to embryonic development and damaged adult organs, and leverage them to become competent for metastasization 7 . The activities -motility, survival and proliferation -that occur in developing, injured and neoplastic tissues embody a biological programme that is defined as 'invasive growth' 8 . This is triggered by extracellular stimuli that regulate the activity of several transcription factors that, in turn, modulate the expression of a number of proteins, ranging from cytoskeletal and cell-cell junctional components to cell cycle regulators and anti-apoptotic effectors 9, 10 . One major environmental inducer of invasive growth is hepatocyte growth factor (HGF, also known as scatter factor), the ligand for the MET tyrosine kinase receptor (also known as the HGF receptor) 11,12,13,14,15,16,17,18,19,20 (Box 1). ...

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Section: Met Signalling In Development and Diseasementioning

confidence: 99%

MET signalling: principles and functions in development, organ regeneration and cancer

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,083

1,076

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“…[1][2][3][4][5] HGF/SF is produced by a variety of mesenchymal cells as a single chain pro-HGF/SF, which is enzymatically, cleaved into biologically active HGF/SF consisting of an ␣-and a ␤-chain. [6][7][8][9][10] The receptor for HGF/SF is encoded by the MET proto-oncogene, c-MET, which is a cell surface tyrosine kinase receptor also consisting of an extracellular ␣-and a transmembrane ␤-chain. 11 The ␤-chain contains the tyrosine kinase domain, as well as sites for tyrosine autophosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells

et al. 1998

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Hepatocyte growth factor (HGF), also known as scatter factor (SF), is produced by mesenchymal cells, including bone marrow (BM) stromal cells, and has mitogenic and motogenic effects on a variety of cell types. Recently, a role has been assigned to HGF/SF and its receptor, c-MET, in both normal and malignant hemopoiesis. We investigated the function of HGF/SF on hemopoietic mononuclear cells (MNC) from patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with circulating blasts. In contrast to results with normal MNC, HGF/SF alone stimulated the proliferation and colony formation of MNC from these patients. MNC from some (4/13) of the AML patients also produced HGF/SF (0.1-0.2 ng/ml/day), while we could not detect HGF/SF in cultures from normal MNC. Furthermore, it appeared that HGF/SF induced migration of leukemic cells in Boyden using KG1a cells as a model for leukemic blasts. The membranes dividing the two compartments of the Boyden chambers were coated with fibronectin. HGF/SF significantly promoted migration in 3/5 samples of MDS patients and in 5/7 samples of AML patients. Supernatant of human BM stromal cells, which is chemoattractive for normal human hemopoietic progenitor cells, also promoted migration of MNC from 4/5 MDS patients and 6/7 AML patients. Since HGF/SF is one of the growth factors produced by BM stromal cells, a neutralizing antibody directed against HGF/SF was added to the BM stroma supernatant, which reduced migration significantly in 2/3 MDS and in 3/6 AML responders to BM stroma supernatant. In conclusion, HGF/SF promotes proliferation and migration of hemopoietic cells from AML and MDS patients in vitro and may therefore contribute to the malignant potential of these cells.

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“…Hepatocyte growth factor (HGF), initially identified and cloned as a potent mitogen for hepatocytes (Nakamura et al, 1984(Nakamura et al, , 1989Miyazawa et al, 1989), is a stromal-derived multi-potent factor that exhibits mitogenic, motogenic, and morphogenic activities. Accumulating evidence has shown that HGF plays a distinct role in tumour-stromal interactions (Seslar et al, 1993;Rosen et al, 1994;Matsumoto et al, 1996;Inoue et al, 1997;Nakamura et al, 1997;Jiang et al, 1999).…”

mentioning

confidence: 99%

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

et al. 2001

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Summary Because of the highly aggressive behaviour, i.e. invasive, disseminative and metastatic properties, the outcome for patients with pancreatic cancer is morbid. A better understanding and interference with the malignant behaviour of pancreatic cancer may provide new directions for treatment. We report here the induction of highly motile and invasive properties in human pancreatic cancer cells by hepatocyte growth factor (HGF) and blockage of these properties by NK4, a newly identified antagonist for HGF. In all of eight human pancreatic cancer cell lines we used (AsPC-1, BxPC-3, H-48N, KP-1N, KP-2, KP-3, MIA PaCa-2 and SUIT-2 cells), the c-Met/HGF receptor was expressed at varying levels. Although weak mitogenic activity of HGF was seen only in SUIT-2 and KP-3 cells, HGF strongly stimulated migration and invasion of these pancreatic cancer cells, except for BxPC-3 and MIA PaCa-2 cells. In contrast, migration and invasion potently induced by HGF in KP-1N, KP-3 and SUIT-2 cells were inhibited by NK4. The invasion of SUIT-2 cells was also potently stimulated with the influence of cocultured pancreatic fibroblasts and by ascitic fluid obtained after pancreatic cancer resection, however, invasiveness of the cancer cells in such conditions was practically abolished by NK4. Consistently, the ascitic fluid in patients who had undergone pancreatic cancer surgery contained high levels of HGF. These findings mean that HGF is probably involved in invasion, dissemination, and metastasis of pancreatic cancer, particularly through tumour-stromal interaction and after resection of the pancreatic cancer. While competitive inhibitory effects of NK4 on HGF and cMet/receptor interaction have been demonstrated in some distinct types of human cancer cells (Date et al, 1998;Hiscox et al, 2000;Kuba et al, 2000;Parr et al, 2000), inhibitory and promising therapeutic effects of NK4 have to be evaluated in cases of highly aggressive pancreatic cancer. In the current study, cancer-stromal interaction through HGF and c-Met coupling and inhibitory effects of NK4 were investigated in human pancreatic cancer cells. The invasion of pancreatic cancer cells was potently stimulated by HGF, cocultivation with fibroblasts, and by ascitic fluid from patients who had undergone pancreatic cancer resection, but this invasion was almost completely inhibited by NK4. The potential inhibition of pancreatic cancer invasion and dissemination by NK4 was thus deemed worthy of investigation. MATERIALS AND METHODS MaterialsHuman recombinant HGF was purified from the conditioned medium of Chinese hamster ovary cells transfected with human HGF cDNA (Nakamura et al, 1989;Seki et al, 1990). Polyclonal antibody against human HGF was prepared from the serum of a rabbit immunized with human recombinant HGF and IgG was purified using protein A-Sepharose (Pharmacia Biotech, Uppsala). Anti-human HGF IgG (1 µg ml -1 ) completely neutralized the biological activities of 1 ng ml -1 human HGF. NK4 was prepared by proteolytic digestion with elastase, as described elsewher...

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Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor

Cited by 658 publications

References 8 publications

MET signalling: principles and functions in development, organ regeneration and cancer

MET signalling: principles and functions in development, organ regeneration and cancer

Hepatocyte growth factor/scatter factor (HGF/SF) affects proliferation and migration of myeloid leukemic cells

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

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