Le facteur de croissance des hépatocytes HGF-SF et son récepteur c-Met : fonctions biologiques et activation oncogénique

Abstract

HGF-SF (hepatic growth factor-scatter factor) est un puissant mitogène pour les cellules hépatiques, mais aussi rénales ; en outre, il accroît la mobilité et la dispersion des cellules épithéliales et endothéliales. Nombreuses sont les cellules présentant à leur surface le récepteur c-Met, spécifique du HGF-SF. CMet possède un domaine cytoplasmique doué d’une activité tyrosine kinase ; ce récepteur s’autophosphoryle avant d’activer sa fonction enzymatique vis-à-vis de substrats exogènes, transmettant le signal aux protéines cibles par plusieurs voies dont celle de Ras. Les propriétés tyrosine kinase de c-Met peuvent être activées de façon constitutive à la suite d’un réarrangement chromosomique et la protéine de fusion codée par le gène hybride a un pouvoir transformant. Le gène c-MET est souvent surexprimé dans les tumeurs malignes, et joue peutêtre un rôle dans la dissémination métastatique. L’interruption de la transmission du signal passant par c-Met pourrait donc avoir un grand intérêt thérapeutique dans les cancers.

The c-MET proto-oncogene encodes the transmembrane tyrosine kinase receptor for the hepatocyte growth factor-scatter factor (HGF-SF). This gene is widely expressed in adult and embryonic tissues as well as in many primary cell cultures and continuous cell lines, mostly of epithelial origin. The HGF-SF, a growth factor of mesenchymatous origin, was first considered as a mitogen for hepatocytes and a scatter factor for epithelial cells in culture. Actually, through the c-Met receptor signal transduction pathway, the HGF-SF interacts with a variety of epithelial or endothelial cells promoting such pleitropic effects as: stimulation or inhibition of cell proliferation, chemotaxis, chemokinesis, invasiveness and capillary-like tubulogenesis in vitro, endothelial cell migration in vivo, developmental as well as tumoral angiogenesis. The c-Met/HGF-SF complex is also capable of mediating mesenchymal to epithelial cell transition. The stimulation of c-Met by HGF-SF activates several intracellular signalling cascades: a 'mitogenic' one including MAP2 kinase and one or two others with 'motogenic' effects comprising (PI)-3-kinase and still unknown SH factors (Shc). The oncogenic activation of c-MET can be achieved through different mechanisms. Indeed, this gene was originally identified as an oncogene (TPR-MET) in transfected NIH-3T3 cells. In this case the activation was the consequence of a chromosomal rearrangement which substituted for the extracellular and transmembrane domains of MET, the N-terminal region of an unrelated gene denominated TPR (for translocated promoter region). Only two examples of a MET proto-oncogene activated by rearrangement have been reported until now, in two different human cell lines transformed in vitro after treatment by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). In naturally occurring tumors and in vitro cultivated cancer cells, the c-MET proto-oncogene has been frequently found amplified and/or over expressed. Transfection of a foreign c-MET gene can also lead NIH-3T3 cells to transformation by creating an autocrine loop involving ectopic met expression and endogenous murine HGF-SF production. Finally, spontaneously transformed NIH-3T3 cells often exhibit an endogenous c-met amplification and overexpression. The pleiotropic activity of the c-Met/HGF-SF complex, may result in different preventive and therapeutic applications.