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.

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.

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 Hepatocyte Growth Factor in Synaptic Plasticity and Alzheimer's Disease

2010 ◽  
Vol 10 ◽  
pp. 457-461 ◽  
Author(s):  
Shiv K. Sharma
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Receptor Tyrosine Kinase ◽  
Hippocampal Neurons ◽  
Different Types ◽  
Hepatocyte Growth

The hepatocyte growth factor (HGF) was initially identified as a protein that promoted growth of hepatocytes. It regulates proliferation and survival of different types of cells. HGF signaling, which is initiated by its binding to a receptor tyrosine kinase, plays critical roles during development. HGF and its receptor are also present in brain cells. This review describes the role of HGF in hippocampal neurons, synaptic plasticity, and the memory impairment condition, Alzheimer's disease.

Role of Bcl-xL in hepatocyte growth factor-elicited epithelial protection in idiopathic pulmonary fibrosis

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
S Skwarna ◽  
I Henneke ◽  
W Seeger ◽  
T Geiser ◽  
A Günther ◽  
...  
Keyword(s):  
Growth Factor ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Hepatocyte Growth Factor ◽  
Hepatocyte Growth

Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes

Diabetes ◽  
1997 ◽  
Vol 46 (1) ◽  
pp. 138-142 ◽  
Author(s):  
R. Morishita ◽  
S. Nakamura ◽  
Y. Nakamura ◽  
M. Aoki ◽  
A. Moriguchi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Potential Role ◽  
Specific Growth ◽  
Endothelial Damage ◽  
Specific Growth Factor ◽  
Hepatocyte Growth

Hepatocyte Growth Factor Promotes Cell Survival by Phosphorylation of BAD in Gastric Cancer Cells

2008 ◽  
Vol 17 (1) ◽  
pp. 23-32 ◽  
Author(s):  
Kyung Hee Lee ◽  
Eun Young Choi ◽  
Min Kyoung Kim ◽  
Myung Soo Hyun ◽  
Jong Ryul Eun ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Survival ◽  
Cancer Cells ◽  
Gastric Cancer Cells ◽  
Hepatocyte Growth
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