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

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.

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The Role of Hepatocyte Growth Factor/Scatter Factor (Hgf/Sf) as a Mediator of Tumour Metastasis

Clinical Science ◽

10.1042/cs095014pc ◽

1998 ◽

Vol 95 (s39) ◽

pp. 14P-15P

Author(s):

S Hiscox ◽

WG Jiang

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Scatter Factor ◽

Tumour Metastasis ◽

Hepatocyte Growth

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

The Journal of Cell Biology ◽

10.1083/jcb.128.1.171 ◽

1995 ◽

Vol 128 (1) ◽

pp. 171-184 ◽

Cited By ~ 212

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.

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

Journal of Biological Chemistry ◽

10.1074/jbc.m112.409797 ◽

2012 ◽

Vol 287 (42) ◽

pp. 35382-35396 ◽

Cited By ~ 3

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.

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