Function of hepatocyte growth factor and its receptor c-met in endothelial cells

Hepatocyte growth factor (HGF), also known as scatter factor (SF), exerts a spectrum of biological activities in epithelial and endothelial cells (ECs), including the stimulation of cell growth or motility, and the promotion of matrix invasion. This chapter introduces the molecular characteristics of HGF/SF and its receptor c-Met, with special emphasis given to the functional activities of this system in the endothelium. HISTORY HGF was originally identified in 1984, in the serum of partially hepatectomized rats as a mitogenic factor for cultured rat hepatocytes (1), and also has been isolated from rat platelets (2), human serum (3), and rat liver (4). This factor was independently discovered as an embryo fibroblast-derived molecule and termed “scatter factor” for its effects on epithelial cell dissociation and motility (5). HGF and SF were later determined to be identical molecules on the basis of functional, structural, genetic, and immunological characteristics (6–8). In the remainder of the chapter, we will refer to the protein as HGF. STRUCTURAL AND FUNCTIONAL CHARACTERISTICS OF HGF The HGF gene localizes as a single copy to chromosome 7q11.1–21 in humans, and consists of 18 exons and 17 introns spanning approximately 70 kb (9). HGF originates from a primary transcript of 6-kb as a biologically inactive single-chain precursor molecule of 728 amino acids (pro-HGF) (10–11). The mature form of HGF generated by proteolytic cleavage consists of a 69-kD α-subunit and a 34 kDa β-subunit (12). The α-chain contains an N-terminal hairpin loop and four kringle domains, which are 80-amino acid structures stabilized by intramolecular disulfide bridges that mediate protein-protein interactions (13).