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

1998 ◽  
Vol 18 (3) ◽  
pp. 1275-1283 ◽  
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.

scholarly journals Disassociation of Met-Mediated Biological Responses In Vivo: the Natural Hepatocyte Growth Factor/Scatter Factor Splice Variant NK2 Antagonizes Growth but Facilitates Metastasis

2000 ◽  
Vol 20 (6) ◽  
pp. 2055-2065 ◽  
Author(s):  
Toshiyuki Otsuka ◽  
John Jakubczak ◽  
Wilfred Vieira ◽  
Donald P. Bottaro ◽  
Diane Breckenridge ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Hepatocyte Growth Factor ◽  
Melanoma Cells ◽  
Scatter Factor ◽  
Full Spectrum ◽  
Critical Determinant ◽  
Hepatocyte Growth

ABSTRACT Hepatocyte growth factor/scatter factor (HGF/SF) stimulates numerous cellular activities capable of contributing to the metastatic phenotype, including growth, motility, invasiveness, and morphogenetic transformation. When inappropriately expressed in vivo, an HGF/SF transgene induces numerous hyperplastic and neoplastic lesions. NK1 and NK2 are natural splice variants of HGF/SF; all interact with a common receptor, Met. Although both agonistic and antagonistic properties have been ascribed to each isoform in vitro, NK1 retains the full spectrum of HGF/SF-like activities when expressed as a transgene in vivo. Here we report that transgenic mice broadly expressing NK2 exhibit none of the phenotypes characteristic of HGF/SF or NK1 transgenic mice. Instead, when coexpressed in NK2-HGF/SF bitransgenic mice, NK2 antagonizes the pathological consequences of HGF/SF and discourages the subcutaneous growth of transplanted Met-containing melanoma cells. Remarkably, the metastatic efficiency of these same melanoma cells is dramatically enhanced in NK2 transgenic host mice relative to wild-type recipients, rivaling levels achieved in HGF/SF and NK1 transgenic hosts. Considered in conjunction with reports that in vitro NK2 induces scatter, but not other activities, these data strongly suggest that cellular motility is a critical determinant of metastasis. Moreover, our results demonstrate how alternatively structured ligands can be exploited in vivo to functionally dissociate Met-mediated activities and their downstream pathways.

scholarly journals Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-met signalling in human cells concomitant with induction of the urokinase proteolysis network.

1996 ◽  
Vol 16 (3) ◽  
pp. 1115-1125 ◽  
Author(s):  
M Jeffers ◽  
S Rong ◽  
G F Vande Woude
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Present Report ◽  
Metastatic Potential ◽  
Tyrosine Kinase Receptor ◽  
Scatter Factor ◽  
Protein Levels ◽  
Hepatocyte Growth

Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector of cells expressing the Met tyrosine kinase receptor. Although HGF/SF is synthesized by mesenchymal cells and acts predominantly on epithelial cells, we have recently demonstrated that human sarcoma cell lines often inappropriately express high levels of Met and respond mitogenically to HGF/SF. In the present report we show that HGF/SF-Met signalling in the human leiomyosarcoma cell line SK-LMS-1 enhances its in vivo tumorigenicity, an effect for which the mitogenicity of this signalling pathway is likely to play a role. In addition, we found that HGF/SF-Met signalling dramatically induces the in vitro invasiveness and in vivo metastatic potential of these cells. We have studied the molecular basis by which HGFSF-Met signalling mediates the invasive phenotype. A strong correlation has previously been demonstrated between the activation of the urokinase plasminogen activator (uPA) proteolysis network and the acquisition of the invasive-metastatic phenotype, and we show here that HGF/SF-Met signalling significantly increases the protein levels of both uPA and its cellular receptor in SK-LMS-1 cells. This results in elevated levels of cell-associated uPA and enhanced plasmin-generating ability by these cells. These studies couple HGF/SF-Met signalling to the activation of proteases that mediate dissolution of the extracellular matrix-basement membrane, and important property for cellular invasion-metastasis.

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

1991 ◽  
Vol 100 (1) ◽  
pp. 173-177 ◽  
Author(s):  
R.A. Furlong ◽  
T. Takehara ◽  
W.G. Taylor ◽  
T. Nakamura ◽  
J.S. Rubin
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Motility ◽  
Recombinant Proteins ◽  
Sequence Data ◽  
Biological Activities ◽  
Scatter Factor ◽  
Naturally Occurring ◽  
Biological Studies ◽  
Hepatocyte Growth

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.

Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo

FEBS Letters ◽  
2001 ◽  
Vol 509 (1) ◽  
pp. 95-100 ◽  
Author(s):  
Mitsuo Toyoda ◽  
Hisashi Takayama ◽  
Norio Horiguchi ◽  
Toshiyuki Otsuka ◽  
Toshio Fukusato ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Granulation Tissue ◽  
Tissue Formation ◽  
Scatter Factor ◽  
Granulation Tissue Formation ◽  
Hepatocyte Growth

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

1996 ◽  
Vol 271 (22) ◽  
pp. 13110-13115 ◽  
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

scholarly journals Anti-apoptotic Role of Caspase-cleaved GAB1 Adaptor Protein in Hepatocyte Growth Factor/Scatter Factor-MET Receptor Protein Signaling

2012 ◽  
Vol 287 (42) ◽  
pp. 35382-35396 ◽  
Author(s):  
Arnaud Le Goff ◽  
Zongling Ji ◽  
Bérénice Leclercq ◽  
Roland P. Bourette ◽  
Alexandra Mougel ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Survival ◽  
Adaptor Protein ◽  
Receptor Protein ◽  
Tyrosine Kinase Receptor ◽  
Protein Signaling ◽  
Scatter Factor ◽  
Hepatocyte Growth

The GRB2-associated binder 1 (GAB1) docking/scaffold protein is a key mediator of the MET-tyrosine kinase receptor activated by hepatocyte growth factor/scatter factor (HGF/SF). Activated MET promotes recruitment and tyrosine phosphorylation of GAB1, which in turn recruits multiple proteins and mediates MET signaling leading to cell survival, motility, and morphogenesis. We previously reported that, without its ligand, MET is a functional caspase target during apoptosis, allowing the generation of a p40-MET fragment that amplifies apoptosis. In this study we established that GAB1 is also a functional caspase target by evidencing a caspase-cleaved p35-GAB1 fragment that contains the MET binding domain. GAB1 is cleaved by caspases before MET, and the resulting p35-GAB1 fragment is phosphorylated by MET upon HGF/SF binding and can interact with a subset of GAB1 partners, PI3K, and GRB2 but not with SHP2. This p35-GAB1 fragment favors cell survival by maintaining HGF/SF-induced MET activation of AKT and by hindering p40-MET pro-apoptotic function. These data demonstrate an anti-apoptotic role of caspase-cleaved GAB1 in HGF/SF-MET signaling.

A novel recognition motif for phosphatidylinositol 3-kinase binding mediates its association with the hepatocyte growth factor/scatter factor receptor

1993 ◽  
Vol 13 (8) ◽  
pp. 4600-4608 ◽  
Author(s):  
C Ponzetto ◽  
A Bardelli ◽  
F Maina ◽  
P Longati ◽  
G Panayotou ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Consensus Sequence ◽  
Tyrosine Kinase Receptor ◽  
Scatter Factor ◽  
Receptor Binding Site ◽  
Sh2 Domains ◽  
Recognition Motif ◽  
Hepatocyte Growth

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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