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.

scholarly journals c-Met and Its Ligand Hepatocyte Growth Factor/Scatter Factor Regulate Mature B Cell Survival in a Pathway Induced by CD74

2010 ◽  
Vol 185 (4) ◽  
pp. 2020-2031 ◽  
Author(s):  
Maya Gordin ◽  
Melania Tesio ◽  
Sivan Cohen ◽  
Yael Gore ◽  
Frida Lantner ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
B Cell ◽  
Cell Survival ◽  
Scatter Factor ◽  
B Cell Survival ◽  
Hepatocyte Growth

scholarly journals Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros.

1995 ◽  
Vol 128 (1) ◽  
pp. 171-184 ◽  
Author(s):  
A S Woolf ◽  
M Kolatsi-Joannou ◽  
P Hardman ◽  
E Andermarcher ◽  
C Moorby ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Early Development ◽  
Branching Morphogenesis ◽  
Mesenchymal Cells ◽  
T Antigen ◽  
Ureteric Bud ◽  
Scatter Factor ◽  
Hepatocyte Growth

Several lines of evidence suggest that hepatocyte growth factor/scatter factor (HGF/SF), a soluble protein secreted by embryo fibroblasts and several fibroblast lines, may elicit morphogenesis in adjacent epithelial cells. We investigated the role of HGF/SF and its membrane receptor, the product of the c-met protooncogene, in the early development of the metanephric kidney. At the inception of the mouse metanephros at embryonic day 11, HGF/SF was expressed in the mesenchyme, while met was expressed in both the ureteric bud and the mesenchyme, as assessed by reverse transcription PCR, in situ hybridization, and immunohistochemistry. To further investigate the expression of met in renal mesenchyme, we isolated 13 conditionally immortal clonal cell lines from transgenic mice expressing a temperature-sensitive mutant of the SV-40 large T antigen. Five had the HGF/SF+/met+ phenotype and eight had the HGF/SF-/met+ phenotype. None had the HGF/SF+/met- nor the HGF/SF-/met- phenotypes. Thus the renal mesenchyme contains cells that express HGF/SF and met or met alone. When metanephric rudiments were grown in serum-free organ culture, anti-HGF/SF antibodies (a) inhibited the differentiation of metanephric mesenchymal cells into the epithelial precursors of the nephron; (b) increased cell death within the renal mesenchyme; and (c) perturbed branching morphogenesis of the ureteric bud. These data provide the first demonstration for coexpression of the HGF/SF and met genes in mesenchymal cells during embryonic development and also imply an autocrine and/or paracrine role for HGF/SF and met in the survival of the renal mesenchyme and in the mesenchymal-epithelial transition that occurs during nephrogenesis. They also confirm the postulated paracrine role of HGF/SF in the branching of the ureteric bud.

The role of the HGF/Met axis in mesothelioma

2016 ◽  
Vol 44 (2) ◽  
pp. 363-370 ◽  
Author(s):  
Thivyan Thayaparan ◽  
James F. Spicer ◽  
John Maher
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Survival ◽  
Receptor Tyrosine Kinase ◽  
Branching Morphogenesis ◽  
Pleural Space ◽  
Regulated Expression ◽  
Promote Cell Survival ◽  
Hepatocyte Growth

Malignant mesothelioma is an asbestos-related cancer that occurs most commonly in the pleural space and is incurable. Increasing evidence suggests that aberrant receptor tyrosine kinase (RTK)-directed signalling plays a key role in the pathogenesis of this cancer. In the majority of mesotheliomas, up-regulated expression or signalling by Met, the receptor for hepatocyte growth factor (HGF) can be demonstrated. Following binding of ligand, Met relays signals that promote cell survival, proliferation, movement, invasiveness, branching morphogenesis and angiogenesis. Here we describe the HGF/Met axis and review the mechanisms that lead to the aberrant activation of this signalling system in mesothelioma. We also describe the cross-talk that occurs between HGF/Met and a number of other receptors, ligands and co-receptor systems. The prevalent occurrence of HGF/Met dysregulation in patients with mesothelioma sets the scene for the investigation of pharmaceutical inhibitors of this axis. In light of the inter-relationship between HGF/Met and other ligand receptor, combinatorial targeting strategies may provide opportunities for therapeutic advancement in this challenging tumour.

Possible role of hepatocyte growth factor/scatter factor and activin A produced by the target organ in liver metastasis

2000 ◽  
Vol 153 (1-2) ◽  
pp. 137-143 ◽  
Author(s):  
Sumiko Hyuga ◽  
Nana Kawasaki ◽  
Osamu Hashimoto ◽  
Masashi Hyuga ◽  
Miyako Ohta ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Metastasis ◽  
Hepatocyte Growth Factor ◽  
Activin A ◽  
Target Organ ◽  
Scatter Factor ◽  
Hepatocyte Growth

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.

Hepatocyte growth factor: Molecular biomarker and player in cardioprotection and cardiovascular regeneration

2012 ◽  
Vol 107 (04) ◽  
pp. 656-661 ◽  
Author(s):  
Rosalinda Madonna ◽  
Cihan Cevik ◽  
Maher Nasser ◽  
Raffaele De Caterina
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Types ◽  
Diagnostic Biomarker ◽  
Scatter Factor ◽  
Molecular Biomarker ◽  
Cardiovascular Regeneration ◽  
Hepatocyte Growth

SummaryThe liver possesses impressive regenerative capacities. Grafts of embryonic liver explants and liver explant-conditioned media have been shown to enhance the mitotic activity of hepatocytes. Hepatocyte growth factor (HGF), also named scatter factor (SF), has been identified as a primary candidate in promoting and regulating liver regeneration. Although initially thought to be a liver-specific mitogen, HGF was later reported to have mitogenic, motogenic, morphogenic, and anti-apoptotic activities in various cell types. By promoting angiogenesis and inhibiting apoptosis, endogenous HGF may play an important role in cardioprotection as well as in the regeneration of endothelial cells and cardiomyocytes after myocardial infarction. Since serum concentration of HGF increases in the early phase of myocardial infarction and in heart failure, HGF may also play a key role as a prognostic and diagnostic biomarker of cardiovascular disease. Here we discuss the role of HGF as a biomarker and mediator in cardioprotection and cardiovascular regeneration.

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.

scholarly journals Role of NF-κB signaling in hepatocyte growth factor/scatter factor-mediated cell protection

Oncogene ◽  
2005 ◽  
Vol 24 (10) ◽  
pp. 1749-1766 ◽  
Author(s):  
Saijun Fan ◽  
Min Gao ◽  
Qinghui Meng ◽  
John J Laterra ◽  
Marc H Symons ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Protection ◽  
Scatter Factor ◽  
Hepatocyte Growth
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