MET (c-Met) is the cell surface receptor for hepatocyte growth factor (HGF), also known as scatter factor. MET is a receptor tyrosine kinase (RTK) that plays crucial roles in embryonic development, tissue regeneration, and adult tissue homeostasis. In the nervous system, the HGF/MET signaling pathway is essential for neuronal development, synaptic plasticity, and neuroprotection. Dysregulated MET signaling has been implicated in neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as in cancer metastasis [1].
The HGF/MET axis has attracted significant interest as a therapeutic target for neurodegenerative disorders due to its neurotrophic and neuroprotective properties. Activation of MET by HGF promotes neuronal survival, stimulates dendritic growth, and modulates synaptic function. Several therapeutic approaches targeting this pathway are under investigation, including HGF analogs, MET agonists, and gene therapy strategies.
The MET gene (Gene ID: 4233) is located on chromosome 7q31.2 in humans. The gene spans approximately 120 kb and contains 21 exons. The MET promoter contains multiple regulatory elements responsive to growth factors, cytokines, and developmental signals. Alternative splicing produces variants with different signaling properties.
Key features:
MET is a heterodimeric receptor tyrosine kinase consisting of two polypeptide chains:
| Domain | Description |
|---|---|
| α-subunit (50 kDa) | Extracellular ligand-binding domain |
| β-subunit (140 kDa) | Transmembrane and intracellular kinase domain |
| Sema domain | N-terminal semaphorin-like domain for ligand binding |
| PSI domain | Plexin-semaphorin-integrin domain |
| IPT domain | Immunoglobulin-like domain in ectodomain |
| Transmembrane helix | Single pass membrane-spanning region |
| Kinase domain | Intracellular tyrosine kinase (catalytic) |
| C-terminal tail | Docking sites for signaling proteins |
The MET receptor undergoes dimerization upon HGF binding, leading to autophosphorylation of tyrosine residues in the intracellular kinase domain and recruitment of downstream signaling adapters.
During embryonic development, HGF/MET signaling is essential for proper nervous system formation: [2]
The HGF/MET axis is particularly important for:
HGF functions as a potent axonal chemoattractant: [3]
HGF/MET provides potent neurotrophic support: [4]
In the adult nervous system, MET continues to play important roles: [5]
HGF binding to MET triggers:
| Pathway | Key Effectors | Cellular Outcomes |
|---|---|---|
| RAS/RAF/MEK/ERK | Ras, Raf, MEK, ERK1/2 | Proliferation, differentiation |
| PI3K/AKT | PI3K, Akt, mTOR | Cell survival, growth |
| STAT | STAT3 | Gene transcription, survival |
| PLC-γ | PLC-γ, PKC | Calcium signaling, migration |
| FAK | FAK, paxillin | Adhesion, migration |
The HGF/MET axis mediates:
HGF/MET signaling is significantly altered in AD: [6]
MET plays important roles in PD: [8]
MET involvement in ALS and related disorders: [10]
| Approach | Mechanism | Development Status |
|---|---|---|
| Recombinant HGF | Direct MET activation | Preclinical |
| HGF gene therapy | Viral vector delivery | Clinical trials |
| HGF mimetics | MET-binding peptides | Preclinical |
Small molecule and antibody-based MET agonists:
| Compound | Type | Status |
|---|---|---|
| MetMAb | Anti-MET antibody | Clinical trials |
| HGF variants | Modified HGF | Preclinical |
| MET-specific agonists | Small molecules | Research |
Used primarily in oncology:
| Compound | Indication | Status |
|---|---|---|
| Crizotinib | MET-amplified cancer | Approved |
| Cabozantinib | Various cancers | Approved |
| Sunitinib | Multiple RTKs | Approved |
MET signalling: principles and functions in development, organ regeneration and cancer. ↩︎
Hepatocyte growth factor, a versatile signal for developing neurons. ↩︎
Hepatocyte growth factor/scatter factor is an axonal chemoattractant and a neurotrophic factor for spinal motor neurons. ↩︎
Neurotrophic effect of hepatocyte growth factor on central nervous system neurons in vitro. ↩︎
Neuroprotective effects of HGF in Alzheimer's disease models. ↩︎