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.
Highlights
Hepatocyte growth factor (HGF), or scatter factor (SF), was first identified as a factor from the plasma from humans and rabbits, and rat platelets, that could induce the proliferation of hepatocytes in culture [1,2,3]
HGF is expressed in most tissues, and both mRNA and protein have been detected in the liver, lung, kidney, skin, and brain
It was demonstrated that NK1 and NK2 bound to MET and induced its phosphorylation in a competitive manner with full length HGF [34,36,38,85]
Summary
Hepatocyte growth factor (HGF), or scatter factor (SF), was first identified as a factor from the plasma from humans and rabbits, and rat platelets, that could induce the proliferation of hepatocytes in culture [1,2,3]. An alternatively processed mRNA for human HGF was identified by Northern blot, with an estimated size of 1.5 kb, with a predicted translation product of ~33 kDa protein containing the N-terminal hairpin loop and the first two kringle domains of HGF (named NK2) [34,35]. A second splice variant of human HGF was later identified by Northern blotting, a ~1.2 kb transcript, encoding a protein of ~20 kDa protein containing the HGF N-terminal hairpin loop and the first kringle domain (named NK1) [36]. This later truncated isoform was identified in murine mRNA [37].
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