Comparison of biological and immunochemical properties indicates that scatter factor and hepatocyte growth factor are indistinguishable

Scatter factor, a stimulant of epithelial cell motility, and Hepatocyte Growth Factor (HGF) were compared by cross-biological studies using naturally occurring and recombinant proteins in four bioassays. Both scatter factor and HGF produced similar effects in cell motility and DNA synthesis assays. Antibodies to scatter factor or HGF neutralized the biological activities of each cytokine, and in immunoblotting reacted with species of the same Mr. These results, together with the available sequence data, suggest that scatter factor and HGF are the same protein.

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The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells.

The Journal of Cell Biology ◽

10.1083/jcb.121.1.145 ◽

1993 ◽

Vol 121 (1) ◽

pp. 145-154 ◽

Cited By ~ 265

Author(s):

K M Weidner ◽

M Sachs ◽

W Birchmeier

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Hepatocyte Growth Factor ◽

Tyrosine Kinase ◽

Cell Motility ◽

Receptor Tyrosine Kinase ◽

Met Receptor ◽

Scatter Factor ◽

Met Receptor Tyrosine Kinase ◽

Hepatocyte Growth

Depending on the target cells and culture conditions, scatter factor/hepatocyte growth factor (SF/HGF) mediates several distinct activities, i.e., cell motility, proliferation, invasiveness, tubular morphogenesis, angiogenesis, or cytotoxicity. A small isoform of SF/HGF encoded by a natural splice variant, which consists of the NH2-terminal hairpin structure and the first two kringle domains but not the protease homology region, induces cell motility but not mitogenesis. Two types of SF/HGF receptors have recently been discovered in epithelial cells, the high affinity c-Met receptor tyrosine kinase, and low affinity/high capacity binding sites, which are probably located on heparan sulfate proteoglycans. In the present study, we have addressed the question whether the various biological activities of SF/HGF are transduced into cells by a single type of receptor. We have here examined MDCK epithelial cells transfected with a hybrid cDNA encoding the ligand binding domain of the nerve growth factor (NGF) receptor and the membrane-spanning and tyrosine kinase domains of the Met receptor. We demonstrate that all biological effects of SF/HGF upon epithelial cells such as the induction of cell motility, proliferation, invasiveness, and tubular morphogenesis can now be triggered by the addition of NGF. Thus, it is likely that all known biological signals of SF/HGF are transduced through the receptor tyrosine kinase encoded by the c-Met protooncogene.

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Hepatocyte Growth Factor (HGF)/NK1 Is a Naturally Occurring HGF/Scatter Factor Variant with Partial Agonist/Antagonist Activity

Journal of Biological Chemistry ◽

10.1074/jbc.271.22.13110 ◽

1996 ◽

Vol 271 (22) ◽

pp. 13110-13115 ◽

Cited By ~ 91

Author(s):

Vittoria Cioce ◽

Karl G. Csaky ◽

Andrew M.-L. Chan ◽

Donald P. Bottaro ◽

William G. Taylor ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Partial Agonist ◽

Antagonist Activity ◽

Scatter Factor ◽

Naturally Occurring ◽

Hepatocyte Growth

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Rho regulates the hepatocyte growth factor/scatter factor-stimulated cell motility of human oral squamous cell carcinoma cells

Oncology Reports ◽

10.3892/or.10.5.1351 ◽

2003 ◽

Author(s):

Hiroyuki Kitajo ◽

Toshiyuki Shibata ◽

Hiroki Nagayasu ◽

Takashi Kawano ◽

Jun-Ichi Hamada ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Growth Factor ◽

Oral Squamous Cell Carcinoma ◽

Hepatocyte Growth Factor ◽

Cell Motility ◽

Cell Carcinoma ◽

Squamous Cell ◽

Carcinoma Cells ◽

Scatter Factor ◽

Hepatocyte Growth

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NK1, a Natural Splice Variant of Hepatocyte Growth Factor/Scatter Factor, Is a Partial Agonist In Vivo

Molecular and Cellular Biology ◽

10.1128/mcb.18.3.1275 ◽

1998 ◽

Vol 18 (3) ◽

pp. 1275-1283 ◽

Cited By ~ 40

Author(s):

John L. Jakubczak ◽

William J. Larochelle ◽

Glenn Merlino

Keyword(s):

Growth Factor ◽

Transgenic Mice ◽

Hepatocyte Growth Factor ◽

Splice Variant ◽

Partial Agonist ◽

Biological Activities ◽

Tyrosine Kinase Receptor ◽

Scatter Factor ◽

Hepatocyte Growth

ABSTRACT Hepatocyte growth factor/scatter factor (HGF/SF) is a potent mitogen, motogen, and morphogen for epithelial cells expressing its tyrosine kinase receptor, the c-met proto-oncogene product, and is required for normal development in the mouse. Inappropriate stimulation of Met signal transduction induces aberrant morphogenesis and oncogenesis in mice and has been implicated in human cancer. NK1 is a naturally occurring HGF/SF splice variant composed of only the amino terminus and first kringle domain. While the biological activities of NK1 have been controversial, in vitro data suggest that it may have therapeutic value as an HGF/SF antagonist. Here, we directly test this hypothesis in vivo by expressing mouse NK1 in transgenic mice and comparing the consequent effects with those observed for mice carrying an HGF/SF transgene. Despite robust expression, NK1 did not behave as an HGF/SF antagonist in vivo. Instead, NK1-transgenic mice displayed most of the phenotypic characteristics associated with HGF/SF-transgenic mice, including enlarged livers, ectopic skeletal-muscle formation, progressive renal disease, aberrant pigment cell localization, precocious mammary lobuloalveolar development, and the appearance of mammary, hepatocellular, and melanocytic tumors. And like HGF/SF-transgenic livers, NK1 livers had higher levels of tyrosine-phosphorylated complexes associated with Met, suggesting that the mechanistic basis for the effects of NK1 overexpression in vivo was autocrine activation of Met. We conclude that NK1 acts in vivo as a partial agonist. As such, the efficacy of NK1 as a therapeutic HGF/SF antagonist must be seriously questioned.

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Expression of a human hepatocyte growth factor/scatter factor cDNA in MDCK epithelial cells influences cell morphology, motility, and anchorage-independent growth

The Journal of Cell Biology ◽

10.1083/jcb.117.4.889 ◽

1992 ◽

Vol 117 (4) ◽

pp. 889-894 ◽

Cited By ~ 30

Author(s):

Y Uehara ◽

N Kitamura

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Hepatocyte Growth Factor ◽

Cell Motility ◽

Mdck Cells ◽

Soft Agar ◽

Scatter Factor ◽

Anchorage Independent Growth ◽

Surface Receptors ◽

Hepatocyte Growth

The addition of exogenous hepatocyte growth factor (HGF)/scatter factor (SF) to MDCK epithelial cells results in fibroblastic morphology and cell motility. We generated HGF/SF producing MDCK cells by transfection with an expression plasmid containing human HGF/SF cDNA. Production of HGF/SF by these cells induced a change from an epithelial to a fibroblastic morphology and increased cell motility. In addition, the HGF/SF producing cells acquired efficient anchorage-independent growth in soft agar but did not form tumors in nude mice. The morphological change and the stimulation of the anchorage-independent growth were prevented by anti-HGF/SF antibody, suggesting that the factor is secreted and then exerts its effects through cell surface receptors.

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Characterization of the Scatter Factor/Hepatocyte Growth Factor Gene Promoter

Journal of Biological Chemistry ◽

10.1074/jbc.270.2.830 ◽

1995 ◽

Vol 270 (2) ◽

pp. 830-836 ◽

Cited By ~ 24

Author(s):

Antje Plaschke-Schlütter ◽

Jürgen Behrens ◽

Ermanno Gherardi ◽

Walter Birchmeier

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Gene Promoter ◽

Scatter Factor ◽

Factor Gene ◽

Growth Factor Gene ◽

Hepatocyte Growth

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Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway

Journal of Experimental Medicine ◽

10.1084/jem.185.12.2121 ◽

1997 ◽

Vol 185 (12) ◽

pp. 2121-2131 ◽

Cited By ~ 84

Author(s):

Robbert van der Voort ◽

Taher E.I. Taher ◽

Robert M.J. Keehnen ◽

Lia Smit ◽

Martijn Groenink ◽

...

Keyword(s):

Cell Adhesion ◽

T Cell ◽

B Cells ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Tyrosine Kinase ◽

B Cell ◽

Germinal Center ◽

Scatter Factor ◽

Hepatocyte Growth

T cell–dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met–encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38+CD77+ tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.

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