Biological roles of hepatocyte growth factor‑Met signaling from genetically modified animals (Review)

Abstract

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. IntroductionHepatocyte growth factor (HGF). HGF was cloned as a growth factor for hepatocytes (1,2), is identical to scatter factor (SF) and was originally discovered as a fibroblast-derived cell motility factor for epithelial cells (3). HGF is located at 7q21, which spans >70 kb in length and consists of 18 exons. It encodes the inactive pre-pro-HGF, a single chain of 728 amino acids (83 kDa), which includes a signal sequence (1-31), a heavy α chain (69 kDa), and a light β chain (34 kDa). The exons encode the α chain, with four kringle structures (highly conserved triple disulfide loop structures), a short spacer region between the α and β chains, and the β chain (Fig. 1A) (4-6).HGF is produced and secreted by adjacent stromal and mesenchymal cells, it contributes to the development of epithelial organs in a paracrine fashion, exerts regenerative effects on epithelia in the liver, kidney, lung, and other tissues, and promotes the regression of fibrosis in numerous organs (7,8). Various growth factors, cytokines, and prostaglandins upregulate HGF gene expression, including basic fibroblast growth factor, oncostatin M, hypoxia-inducible factor 1α and nuclear factor-κB (NF-κB) (9). By contrast, transforming growth factor (TGF)-β1 was demonstrated to markedly downregulate HGF gene expression (10,11).HGF forms a family with HGF-like protein (HLP), a unique protein with a domain structure similar to that of HGF (12). Macrophage stimulating protein (MSP) was discovered as a serum protein that promoted mouse macrophage motility (13) Abbreviatio...

HGF-induced activation of NEPHRIN and NEPH1 serves as a novel mechanism for recovery of podocytes from injury

“…3B). While the systemic deletion of HGF in mice induces early embryonic lethality [44,45], the podocyte-specific knockout of its receptor c-MET did not result in any structural or physiological loss of renal function [46]. Importantly, we did not find any involvement of MET receptor in HGF-induced NEPHRIN and NEPH1 phosphorylation.…”

“…MET receptor is not required for HGF-induced phosphorylation of NEPHRIN and NEPH1: Since HGF is also a potent activator of MET receptor [12,13], it is possible that MET may be directly or indirectly involved in NEPHRIN and NEPH1 phosphorylation. To test this, we constructed a stable knockdown of MET receptor in HEK293 cells overexpressing NEPHRIN or NEPH1 and performed similar HGF-induced phosphorylation.…”

“…Similar to SHP-2, its activator HGF, which is highly elevated in response to injury conditions [12,13], is also known to induce protective effects in multiple organs, including kidney [14,15]; however, the mechanism for this protection in podocytes remains unknown. Since our results demonstrate that HGF can induce phosphorylation of NEPHRIN and NEPH1 via a direct interaction, we hypothesize that HGF is the primary regulator of NEPH1 and NEPHRIN signaling, which participates in inducing podocyte recovery from glomerular injury.…”

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

“…The binding of the HGF and c-Met promotes different cellular signaling pathways, which is involved in the regulation of tissue homeostasis under physiological conditions. Additionally, tissue hypoxia activates c-Met transcription, consequently leading to amplified HGF signaling [55]. The effects exerted by HGF stimulation of vascular endothelial cells include proliferation, migration, invasion, branching morphogenesis, protease production, and capillary tubes organization [56].…”

Noncoding microdeletion in mouseHgfdisrupts neural crest migration into the stria vascularis, reduces the endocochlear potential and suggests the neuropathology for human nonsyndromic deafness DFNB39

“…Homozygous knockout of mouse Hgf results in embryonic lethality (Kato, 2017). However, we reported that a conditional deficiency in HGF in the ear results in viable deaf mice with thinning of the stria vascularis (SV) in the cochlea (Schultz et al, 2009).…”