Identification of the Hepatocyte Growth Factor Receptor As the c-
            <i>met</i>
            Proto-Oncogene Product

Bottaro, Donald P.; Rubin, Jeffrey S.; Faletto, D; Chan, Andrew M.; Kmiecik, Thomas E.; Woude, George F. Vande; Aaronson, S A

doi:10.1126/science.1846706

Cited by 2,135 publications

(1,265 citation statements)

References 24 publications

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“…Earlier studies have ®rmly established a role for both receptor (Baserga, 1994;Bottaro et al, 1991;D'Ambrosio et al, 1995;Khazaie et al, 1993) and non-receptor family tyrosine kinases (Egan et al, 1987a,b;Greenberg et al, 1989) in the transformation of normal cells. In particular, the product of the human src proto-oncogene, c-Src, has been implicated in the progression of colon cancer (Garcia et al, 1991;Cartwright et al, 1989Cartwright et al, , 1990Talamonti et al, 1991;Termuhlen et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential

et al. 1997

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Recent data suggest that signal transduction may have a critical role in the development and regulation of the metastatic phenotype. Here, we investigated the role of c-Src activation in the process of human colon cancer metastasis to the liver. Our data, derived from two di erent sets of human colon cancer cell line metastatic variants, suggest that not only do highly-metastatic cells display constitutively elevated c-Src protein kinase activity when compared to poorly metastatic cells, but also that receptor tyrosine kinases participate in the ligand-activation of c-Src above basal levels. Speci®cally, the epidermal growth factor receptor (EGFR), p185HER2/Neu and the hepatocyte growth factor receptor (c-Met) appear to be linked to the process because they preferentially activate c-Src in highlymetastatic cells. EGFR was found to associate with c-Src in colon cancer cells and speci®c inhibitors of the EGFR resulted in a reduction of c-Src activity to basal levels. In addition, c-Src transfectants displayed partially-activated EGFRs, suggesting a feedback role for c-Src in the regulation of the EGFR. p185HER2/Neu was also identi®ed in immunocomplexes of c-Src following ligand activation of the EGFR, but only in highly-metastatic cells. Collectively, these observations suggest a paradigm whereby c-Src interacts with multiple cell-surface growth factors in a catalytic fashion for the development of tumor cells with metastatic potential.

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Section: Introductionmentioning

confidence: 99%

Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential

et al. 1997

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“…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). MET function is required for various morphogenetic events in both embryonic and adult life 21,22 and it drives the malignant progression of several different types of tumours 23 .…”

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confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,060

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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“…6,8 Isolation and culture of human peritoneal mesothelial cells Peritoneal mesothelial cells were obtained from resected tissue specimens of the greater omentum from patients who had undergone a laparotomy for an early gastric cancer. Informed consent was obtained from the surgical patients before surgery.…”

Section: Methodsmentioning

confidence: 99%

“…[5][6][7] Many types of malignant cells, mainly adenocarcinomas, are responsive to HGF, which stimulates cell proliferation, invasion and metastasis through an association with its receptor c-met product (HGFR). [8][9][10] We previously reported that HGF induced invasion of human gallbladder cancer cells into collagen gel and matrigelt, and such induction was neutralized by an antibody against HGF. Interestingly, HGF is produced by such nonepithelial stromal cells as fibroblasts 11,12 or endothelial cells, 13 and this production was also stimulated by some cancer-producing cytokines of IL-1, PDGF or bFGF.…”

mentioning

confidence: 99%

Gallbladder cancer treatment using adenovirus expressing the HGF/NK4 gene in a peritoneal implantation model

Tanaka

Sasaki

et al. 2004

Cancer Gene Ther

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Gallbladder cancer cells are stimulated by hepatocyte growth factor (HGF) in vitro and in vivo. We constructed an adenovirus vector, AdCMV.NK4, carrying the HGF antagonist HGF/NK4 (NK4) and evaluated whether or not this vector can suppress the peritoneal implantation of gallbladder cancer in a novel peritoneal injury mouse model. A human gallbladder cancer cell line (GBd1) and human peritoneal mesothelial cells infected with the adenovirus vector produced a substantial level of NK4 protein. An invasion of GB-d1 cells was determined by a coculture with AdCMV.NK4-infected human mesothelial cells in vitro. Both the invasion and migration of GB-d1 cells were dramatically inhibited by this vector in a multiplicity of infection (MOI)-dependent manner. GB-d1 cells were intraperitoneally injected into the nude mice with peritoneal injury, followed by either AdCMV.NK4 or a control vector (AdCMV.LacZ). The incidence and the size of the metastatic tumor drastically decreased by AdCMV.NK4 (MOI 100: n ¼ 4, Po.0001). Real-time PCR analysis revealed a transient elevation of mouse HGF mRNA expression at the peritoneal injury sites. AdCMV.NK4 has been suggested to induce the inhibition of the implantation and growth of gallbladder cancer cells in vivo through its anti-HGF activity, and the use of NK4 gene transfer could be an effective modality for preventing peritoneal metastasis of gallbladder cancer.

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Identification of the Hepatocyte Growth Factor Receptor As the c- met Proto-Oncogene Product

Cited by 2,135 publications

References 24 publications

Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential

Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential

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

Gallbladder cancer treatment using adenovirus expressing the HGF/NK4 gene in a peritoneal implantation model

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