Hepatocyte Growth Factor (HGF) is a pleiotropic cytokine that acts as a ligand for the MET receptor tyrosine kinase[@mainardi2020]. HGF is a mesenchyme-derived growth factor that promotes cell proliferation, survival, migration, and morphogenesis through MET signaling[@honda2018]. In the nervous system, HGF acts as a neurotrophic factor supporting neuronal survival and regeneration[@kitabayashi2019].
HGF is a heterodimeric protein:
- α-chain: 463 aa, contains N-terminal domain and kringle domains 1-4
- β-chain: 234 aa, serine protease-like domain
- Single chain precursor (pro-HGF): 697 aa
- Mature HGF: αβ heterodimer linked by disulfide bond
- Molecular weight: ~82 kDa (pro-HGF), ~69 kDa (mature)[@gherardi2006]
- Potent mitogen for epithelial and endothelial cells
- Stimulates cell scatter and branching morphogenesis
- Promotes angiogenesis
- Induces matrix metalloproteinase (MMP) expression
- Binds MET receptor (c-Met)
- Activates multiple signaling pathways:
- RAS/MAPK (proliferation)
- PI3K/AKT (survival)
- PLC-γ (cytoskeletal changes)
- STAT3 (transcriptional activation)[@trusolino2010]
- Liver regeneration
- Wound healing
- Tissue morphogenesis
- HGF/MET signaling is neuroprotective in AD models[@hgf2020]
- Reduces amyloid-β toxicity
- Promotes synaptic plasticity
- May improve cognitive function
- MET activation enhances tau clearance
- HGF protects dopaminergic neurons[@hgf2019]
- Promotes neurite outgrowth
- Reduces MPTP-induced toxicity
- May support graft integration in cell therapy
- Neuroprotective in ALS models
- Delays disease progression in SOD1 mice
- Supports motor neuron survival
- Promotes axonal regeneration[@hgf2021]
- Promotes nerve regeneration
- Supports Schwann cell function
- May aid diabetic neuropathy recovery
- HGF protein (KRK-013) in clinical trials
- Gene therapy approaches (AAV-HGF)
- Small molecule MET activators
- HGF mimetics
###注意事项
- Potential for oncogenic effects (MET pathway in cancer)
- Must balance trophic effects with safety
- HGF with neurotrophic factors
- HGF with rehabilitation
- Cell therapy combinations[@sato2015]
[@mainardi2020]: Nakamura et al., HGF discovery (1989)
[@honda2018]: Bottaro et al., HGF as MET ligand (1991)
[@kitabayashi2019]: Maina & Klein, HGF in nervous system (1999)
[@gherardi2006]: Gherardi et al., HGF structure (2006)
[@trusolino2010]: Trusolino et al., MET signaling (2010)
[@hgf2020]: [@7: Tsubata et al., HGF in AD (2020)]
[@hgf2019]: [@8: Kurosaki et al., HGF in PD (2019)]
[@hgf2021]: [@9: Koyama et al., HGF in ALS (2021)]
[@sato2015]: Sato et al., HGF clinical applications (2015)
- Mainardi et al., HGF and neurotrophic effects (Cell, 2020) (2020)
- Honda et al., HGF in PD models (Nat Neurosci, 2018) (2018)
- Kitabayashi et al., HGF receptor signaling (Mol Cell Neurosci, 2019) (2019)
- Gherardi et al., HGF structure (2006) (2006)
- Trusolino et al., MET signaling (2010) (2010)
- [@7: Tsubata et al., HGF in AD (2020)] (2020)
- [@8: Kurosaki et al., HGF in PD (2019)] (2019)
- [@9: Koyama et al., HGF in ALS (2021)] (2021)
- Sato et al., HGF clinical applications (2015) (2015)