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Review
. 2014 Oct 31;2(4):275-300.
doi: 10.3390/biomedicines2040275.

HGF-Met Pathway in Regeneration and Drug Discovery

Kunio Matsumoto  1 , Hiroshi Funakoshi  2 , Hisaaki Takahashi  3 , Katsuya Sakai  4
Affiliations
Review

HGF-Met Pathway in Regeneration and Drug Discovery

Kunio Matsumoto et al. Biomedicines. .

Abstract

Hepatocyte growth factor (HGF) is composed of an α-chain and a β-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. Activation of the HGF-Met pathway evokes dynamic biological responses that support morphogenesis (e.g., epithelial tubulogenesis), regeneration, and the survival of cells and tissues. Characterizations of conditional Met knockout mice have indicated that the HGF-Met pathway plays important roles in regeneration, protection, and homeostasis in various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons. Preclinical studies designed to address the therapeutic significance of HGF have been performed on injury/disease models, including acute tissue injury, chronic fibrosis, and cardiovascular and neurodegenerative diseases. The promotion of cell growth, survival, migration, and morphogenesis that is associated with extracellular matrix proteolysis are the biological activities that underlie the therapeutic actions of HGF. Recombinant HGF protein and the expression vectors for HGF are biological drug candidates for the treatment of patients with diseases and injuries that are associated with impaired tissue function. The intravenous/systemic administration of recombinant HGF protein has been well tolerated in phase I/II clinical trials. The phase-I and phase-I/II clinical trials of the intrathecal administration of HGF protein for the treatment of patients with amyotrophic lateral sclerosis and spinal cord injury, respectively, are ongoing.

Keywords: HGF; Met; amyotrophic lateral sclerosis; clinical trial; spinal cord injury.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic structures of HGF (A) and Met (B). A single-chain HGF is cleaved between Arg494 and Val495 by serine proteases and HGF is modified by glycosylation. Domain structure of Met and typical signaling molecules are described.
Figure 2
Figure 2
Signaling mechanisms responsible for promotion of cell survival mediated by HGF–Met pathway.
Figure 3
Figure 3
Two-pronged roles of HGF in tissue regeneration and cancer tissues. HGF is mainly expressed in stromal cells. Cells responding to HGF are conceptually shown in green. Dynamic morphogenesis (e.g., blanching tubulogenesis in renal tubular cells) and promotion of cell survival (e.g., for neurons) mediated by the HGF–Met pathway play roles in tissue regeneration after tissue injury (right part). Dynamic cell movement and survival promoted by Met activation participate in invasion-metastasis and resistance to anticancer drugs in cancer tissues (left part).
Figure 4
Figure 4
Biological responses leading to angiogenesis driven by the HGF–Met pathway.
See this image and copyright information in PMC

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