Hepatocyte Growth Factor Isoforms in Tissue Repair, Cancer, and Fibrotic Remodeling

Abstract

Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a pleotropic factor required for normal organ development during embryogenesis. In the adult, basal expression of HGF maintains tissue homeostasis and is up-regulated in response to tissue injury. HGF expression is necessary for the proliferation, migration, and survival of epithelial and endothelial cells involved in tissue repair in a variety of organs, including heart, lung, kidney, liver, brain, and skin. The administration of full length HGF, either as a protein or using exogenous expression methodologies, increases tissue repair in animal models of tissue injury and increases angiogenesis. Full length HGF is comprised of an N-terminal hairpin turn, four kringle domains, and a serine protease-like domain. Several naturally occurring alternatively spliced isoforms of HGF were also identified. The NK1 variant contains the N-terminal hairpin and the first kringle domain, and the NK2 variant extends through the second kringle domain. These alternatively spliced forms of HGF activate the same receptor, MET, but they differ from the full length protein in their cellular activities and their biological functions. Here, we review the species-specific expression of the HGF isoforms, their regulation, the signal transduction pathways they activate, and their biological activities.

Keywords: MET receptor; NK1; NK2; hepatocyte growth factor; signal transduction; tissue repair; truncated isoforms.

Figure 1

Generation of the NK2 message. (A) A schematic comparison of hepatocyte growth factor (HGF) genes. Bars and numbers indicate exons. The alternative exon used for NK2 splicing is indicated by a triangle at the corresponding introns. The murine intron does not contain this alternative exon; (B) The exon (capital letters)–intron (small letters) boundary sequences for NK2 splicing. Predicted splice donor and acceptor sites are underlined. The murine sequence lacks characteristics commonly found in splice acceptor sites. The carboxy-terminal amino acids of NK2 and the stop codon (*) are shown below the coding sequence.

Figure 2

Multiple alignment of the human NK2 3'UTR with predicted 3'UTR sequences from species using the European Molecular Biology Laboratory—European Bioinformatics Institute Clustal Omega program [45]. Asterisks indicate nucleotides identical with the human sequence; non-identical nucleotides are shown as red letters. The first two nucleotides (AG, blue) are the predicted primate splice acceptor site.