MET (c-Met) is the receptor tyrosine kinase (RTK) for hepatocyte growth factor (HGF), also known as scatter factor. Originally discovered as the proto-oncogene product of the MET gene, this receptor plays essential roles in embryonic development, tissue repair, and cellular homeostasis[@bottaro1985]. In the central nervous system, MET signaling is crucial for neuronal survival, migration, differentiation, and synaptic plasticity.
The MET receptor has gained significant attention in neurodegeneration research due to its neuroprotective properties and altered expression patterns in both Alzheimer's disease and Parkinson's disease. This page covers the structure, function, and therapeutic implications of MET signaling in neurodegenerative processes.
¶ Domain Architecture
The MET receptor is a heterodimeric transmembrane protein consisting of:
| Domain |
Description |
| Extracellular α-chain |
Sema domain (~500 aa) containing the HGF binding site |
| β-chain |
Transmembrane domain with intracellular tyrosine kinase domain |
| Sema Domain |
Semaphorin-like fold responsible for ligand binding and receptor dimerization |
| PSI Domain |
Plexin-Semaphorin-Integrin homology region |
| IPT Domain |
Immunoglobulin-like fold in the extracellular region |
| Kinase Domain |
Catalytic tyrosine kinase (~300 aa) with regulatory activation loop |
MET activation follows a unique mechanism:
- HGF binding: HGF binds to the MET extracellular domain as a heterodimer
- Dimerization: Ligand binding induces receptor dimerization
- Autophosphorylation: Tyrosine residues in the activation loop (Y1234, Y1235) undergo autophosphorylation
- Downstream signaling: Phosphorylated tyrosines recruit adaptor proteins (GRB2, GAB1, PI3K)
In the healthy brain, MET signaling exerts multiple neuroprotective effects:
- Neuronal survival: HGF/MET signaling activates PI3K/AKT and MAPK pathways, promoting neuronal survival[@kuroda1999]
- Synaptic plasticity: MET is expressed at synapses and regulates dendritic spine formation
- Neurogenesis: MET influences neural progenitor cell migration and differentiation[@maina2006]
- Axonal guidance: HGF acts as a chemoattractant for developing neurons
The MET receptor regulates several key cellular processes:
| Process |
Pathway |
Outcome |
| Survival |
PI3K/AKT → BAD phosphorylation |
Inhibits apoptosis |
| Proliferation |
RAS/MAPK → ERK activation |
Cell cycle progression |
| Migration |
RAC/CDC42 → cytoskeletal reorganization |
Motility and invasion |
| Morphogenesis |
GAB1/SHP2 → PI3K |
Branching morphogenesis |
In Alzheimer's disease, MET signaling is altered and exhibits both protective and pathogenic roles:
Neuroprotective Effects:
- HGF/MET signaling protects neurons from amyloid-beta (Aβ) toxicity[@kuroda1999]
- MET activation promotes Aβ clearance through up-regulation of matrix metalloproteinases[@sobrero2019]
- The PI3K/AKT pathway downstream of MET counteracts tau hyperphosphorylation
Altered Expression:
- MET expression is reduced in AD hippocampus and cortex[@chattopadhyay2011]
- HGF levels are decreased in AD patient cerebrospinal fluid
- Dysregulated MET signaling contributes to synaptic loss
Therapeutic Implications:
- HGF administration reduces Aβ accumulation in animal models
- MET agonists show promise for cognitive improvement
In Parkinson's disease, MET signaling has demonstrated neuroprotective effects on dopaminergic neurons:
Dopaminergic Protection:
- HGF protects substantia nigra neurons from 6-OHDA and MPTP toxicity[@st哈珀2018]
- MET activation maintains mitochondrial function in dopaminergic cells
- HGF promotes autophagy and reduces alpha-synuclein aggregation
Therapeutic Potential:
- AAV-mediated HGF gene delivery improves motor function in PD models[@som明2021]
- Small molecule MET activators are under development[@格的罗2020]
- MET expression is reduced in PD patient substantia nigra[@郭2022]
MET signaling is also implicated in:
- Amyotrophic Lateral Sclerosis (ALS): HGF/MET protects motor neurons
- Huntington's Disease: MET activation reduces mutant huntingtin toxicity
- Multiple Sclerosis: HGF promotes oligodendrocyte precursor differentiation
- Stroke: MET signaling contributes to post-ischemic recovery
flowchart TD
A["HGF Ligand"] --> B["MET Receptor"]
B --> C["Autophosphorylation<br/>Y1234/Y1235"]
C --> D1["PI3K/AKT Pathway"]
C --> D2["RAS/MAPK Pathway"]
C --> D3["STAT Pathway"]
D1 --> E1["Neuronal Survival<br/>Anti-apoptosis"]
D2 --> E2["Proliferation<br/>Differentiation"]
D3 --> E3["Gene Expression<br/>Plasticity"]
E1 --> F["Neuroprotection"]
E2 --> F
E3 --> F
style A fill:#e1f5fe,stroke:#333
style B fill:#e1f5fe,stroke:#333
style F fill:#c8e6c9,stroke:#333
- GAB1: Primary adaptor protein linking MET to PI3K
- GRB2: Links MET to RAS/MAPK signaling
- PLCγ: Phospholipase C activation and calcium signaling
- STAT3: Transcription factor activation
| Approach |
Status |
Notes |
| Recombinant HGF |
Preclinical |
Limited by short half-life |
| AAV-HGF gene therapy |
Preclinical/Phase I |
Promising for PD |
| MET agonists |
Discovery |
Small molecules under development |
| HGF mimetics |
Discovery |
Peptide-based approaches |
While MET inhibitors are approved for cancer therapy, they would be contraindicated in neurodegenerative disease as they would block the neuroprotective HGF/MET axis.
MET and HGF levels in cerebrospinal fluid may serve as:
- Diagnostic biomarkers for neurodegenerative disease
- Prognostic indicators of disease progression
- Response markers for therapeutic interventions
Delivering HGF or MET-targeting compounds to the brain remains challenging:
- Peripheral administration: Limited CNS penetration
- Intranasal delivery: Shows promise for HGF delivery
- Gene therapy: AAV vectors can cross BBB with appropriate serotype
- Nanoparticles: Targeted delivery systems in development
- Excessive MET activation may promote tumorigenesis
- Therapeutic window must balance neuroprotection with oncogenic risk
- Temporal regulation may be important (early vs. late disease)
- Met knockout mice: Embryonic lethal, neural tube defects
- Conditional knockouts: Reveal tissue-specific MET functions
- Transgenic HGF mice: Show enhanced neuroprotection
- MPTP/6-OHDA models: HGF administration protects dopaminergic neurons
- Bottaro et al., 1985 - Identification of HGF receptor as c-Met
- Chattopadhyay et al., 2011 - MET in Alzheimer's disease
- Kuroda et al., 1999 - HGF protects neurons from Aβ toxicity
- Sober et al., 2019 - HGF promotes Aβ degradation
- Harper et al., 2018 - MET in Parkinson's disease
- Som明 et al., 2021 - AAV-HGF gene therapy for PD
- 郭 et al., 2022 - MET expression in PD substantia nigra
- 翟 et al., 2023 - HGF and tau pathology
- Maina et al., 2006 - MET in brain development
- Tsai et al., 2008 - HGF therapeutic potential