Biological roles of hepatocyte growth factor-Met signaling from genetically modified animals

Abstract

Hepatocyte growth factor (HGF) is produced by stromal and mesenchymal cells, and it stimulates epithelial cell proliferation, motility, morphogenesis and angiogenesis in various organs via tyrosine phosphorylation of its cognate receptor, Met. The HGF-Met signaling pathway contributes in a paracrine manner to the development of epithelial organs, exerts regenerative effects on the epithelium, and promotes the regression of fibrosis in numerous organs. Additionally, the HGF-Met signaling pathway is correlated with the biology of cancer types, neurons and immunity. In vivo analyses using genetic modification have markedly increased the profound understanding of the HGF-Met system in basic biology and its clinical applications. HGF and Met knockout (KO) mice are embryonically lethal. Therefore, amino acids in multifunctional docking sites of Met have been exchanged with specific binding motifs for downstream adaptor molecules in order to investigate the signaling potential of the HGF-Met signaling pathway. Conditional Met KO mice were generated using Cre-loxP methodology and characterization of these mice indicated that the HGF-Met signaling pathway is essential in regeneration, protection, and homeostasis in various tissue types and cells. Furthermore, the results of studies using HGF-overexpressing mice have indicated the therapeutic potential of HGF for various types of disease and injury. In the present review, the phenotypes of Met gene-modified mice are summarized.

Keywords: c-Met; conditional knockout; development; hepatocyte growth factor; regeneration; transgenic mice.

Figure 1.

Structure of (A) HGF and (B) Met. (C) Downstream signaling pathway of HGF-Met signal. HGF, hepatocyte growth factor; R, arginine; V, valine; S-S, disulfide bond; SEMA, semaphorin; PSI, plexin, semaphorin, integrin cysteine-rich domain; IPT, immunoglobulin-like regions in plexins and transcription factors; Gab1, Grb2-associated protein 1; shp2, Src homology region 2 domain-containing phosphatase-2; Grb2, growth factor receptor-bound protein 2; Stat3, signal transducer and activation of transcription-3; PI3K, phosphoinositide 3-kinase; Cdc42, cell division control protein 42 homolog; Raf1, Raf-1 proto-oncogene, serine/threonine kinase; Rac1, Rac family small GTPase 1; MEK, mitogen-activated protein kinase kinase; mTOR, mechanistic target of rapamycin; ERK, extracellular signal-regulated kinases.