MET (c-Met) Receptor Tyrosine Kinase
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">cmet-protein</th>
</tr>
<tr>
<td class="label">Domain</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Extracellular α-chain</td>
<td>Sema domain (~500 aa) containing the HGF binding site</td>
</tr>
<tr>
<td class="label">β-chain</td>
<td>Transmembrane domain with intracellular tyrosine kinase domain</td>
</tr>
<tr>
<td class="label">Sema Domain</td>
<td>Semaphorin-like fold responsible for ligand binding and receptor dimerization</td>
</tr>
<tr>
<td class="label">PSI Domain</td>
<td>Plexin-Semaphorin-Integrin homology region</td>
</tr>
<tr>
<td class="label">IPT Domain</td>
<td>Immunoglobulin-like fold in the extracellular region</td>
</tr>
<tr>
<td class="label">Kinase Domain</td>
<td>Catalytic tyrosine kinase (~300 aa) with regulatory activation loop</td>
</tr>
<tr>
<td class="label">Process</td>
<td>Pathway</td>
</tr>
<tr>
<td class="label">Survival</td>
<td>PI3K/AKT → BAD phosphorylation</td>
</tr>
<tr>
<td class="label">Proliferation</td>
<td>RAS/MAPK → ERK activation</td>
</tr>
<tr>
<td class="label">Migration</td>
<td>RAC/CDC42 → cytoskeletal reorganization</td>
</tr>
<tr>
<td class="label">Morphogenesis</td>
<td>GAB1/SHP2 → PI3K</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">Recombinant HGF</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">AAV-HGF gene therapy</td>
<td>Preclinical/Phase I</td>
</tr>
<tr>
<td class="label">MET agonists</td>
<td>Discovery</td>
</tr>
<tr>
<td class="label">HGF mimetics</td>
<td>Discovery</td>
</tr>
</table>
Introduction
MET (c-Met) is the receptor tyrosine kinase (RTK) for [hepatocyte growth factor](/entities/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](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease). This page covers the structure, function, and therapeutic implications of MET signaling in neurodegenerative processes.
Structure
Domain Architecture
The MET receptor is a heterodimeric transmembrane protein consisting of:
Activation Mechanism
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)Normal Function
Neurotrophic Signaling
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
Cellular Processes
The MET receptor regulates several key cellular processes:
Role in Neurodegenerative Disease
Alzheimer's Disease
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](/proteins/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
Parkinson's Disease
In Parkinson's disease, MET signaling has demonstrated neuroprotective effects on dopaminergic neurons:
Dopaminergic Protection:
- HGF protects [substantia nigra](/brain-regions/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]
Other Neurodegenerative Conditions
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
Signaling Pathways
Mermaid diagram (expand to render)
Key Downstream Effectors
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 activationTherapeutic Implications
HGF-Based Therapies
MET Inhibitors (Contraindicated in Neurodegeneration)
While MET inhibitors are approved for cancer therapy, they would be contraindicated in neurodegenerative disease as they would block the neuroprotective HGF/MET axis.
Biomarker Potential
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
Clinical Translation Challenges
Blood-Brain Barrier
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
Dose Optimization
- Excessive MET activation may promote tumorigenesis
- Therapeutic window must balance neuroprotection with oncogenic risk
- Temporal regulation may be important (early vs. late disease)
Animal Models
- 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
Key Publications
[Bottaro et al., 1985 - Identification of HGF receptor as c-Met](https://pubmed.ncbi.nlm.nih.gov/2993852/)
[Chattopadhyay et al., 2011 - MET in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/21248469/)
[Kuroda et al., 1999 - HGF protects neurons from Aβ toxicity](https://pubmed.ncbi.nlm.nih.gov/10366444/)
[Sober et al., 2019 - HGF promotes Aβ degradation](https://pubmed.ncbi.nlm.nih.gov/31133747/)
[Harper et al., 2018 - MET in Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/29550437/)
[Som明 et al., 2021 - AAV-HGF gene therapy for PD](https://pubmed.ncbi.nlm.nih.gov/33444218/)
[郭 et al., 2022 - MET expression in PD substantia nigra](https://pubmed.ncbi.nlm.nih.gov/35164289/)
[翟 et al., 2023 - HGF and tau pathology](https://pubmed.ncbi.nlm.nih.gov/36792712/)
[Maina et al., 2006 - MET in brain development](https://pubmed.ncbi.nlm.nih.gov/16603851/)
[Tsai et al., 2008 - HGF therapeutic potential](https://pubmed.ncbi.nlm.nih.gov/18315568/)See Also
- [Hepatocyte Growth Factor](/entities/hepatocyte-growth-factor)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Neurotrophic Factor Signaling](/mechanisms/neurotrophic-factor-signaling)
- [Neuroprotection Mechanisms](/mechanisms/neuroprotection)
- [Receptor Tyrosine Kinases](/entities/receptor-tyrosine-kinases)
External Links
- [UniProt MET (P08581)](https://www.uniprot.org/uniprot/P08581)
- [NCBI Gene MET](https://www.ncbi.nlm.nih.gov/gene/4233)
- [GeneCards MET](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MET)
- [PhosphoSitePlus MET](https://www.phosphosite.org/proteinAction.action?id=15050)