Hepatocyte Growth Factor (HGF), also known as Scatter Factor and Hepatopoietin A, is a pleiotropic protein in the Plasminogen subfamily of S1 peptidases. It is a multidomain molecule that includes an N-terminal PAN/APPLE-like domain, four Kringle domains, and a serine proteinase-like domain that has no detectable protease activity [1-5]. Mouse HGF is secreted as an inactive 728 amino acid (aa) single chain propeptide. It is cleaved after the fourth Kringle domain by a serine protease to form bioactive disulfide-linked HGF with a 60 kDa alpha and 30 kDa beta chain. Alternate splicing generates an isoform that lacks the peptidase and the second, third, and fourth Kringle domains. Mouse HGF shares 91% - 95% aa sequence identity with bovine, canine, feline, human, and rat HGF. HGF binds heparan-sulfate proteoglycans and the widely expressed receptor tyrosine kinase, HGF R/c-MET [6, 7]. HGF-dependent c-MET activation is implicated in the development of many human cancers [8]. HGF regulates epithelial morphogenesis by inducing cell scattering and branching tubulogenesis [9, 10]. HGF induces the up-regulation of integrin alpha 2 beta 1 in epithelial cells by a selective increase in alpha 2 gene transcription [11]. This integrin serves as a collagen I receptor, and its blockade disrupts epithelial cell branching tubulogenesis [11, 12]. HGF can also alter epithelium morphology by the induction of nectin-1 alpha ectodomain shedding, an adhesion protein component of adherens junctions [13]. In the thyroid, HGF induces the proliferation, motility, and loss of differentiation markers of thyrocytes and inhibits TSH-stimulated iodine uptake [14].
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