MET Protein

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MET Protein

Overview

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MET Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">MET Protein</th>
</tr>
<tr>
<td class="label">Domain</td>
<td>Description</td>
</tr>
<tr>
<td class="label">α-subunit (50 kDa)</td>
<td>Extracellular ligand-binding domain</td>
</tr>
<tr>
<td class="label">β-subunit (140 kDa)</td>
<td>Transmembrane and intracellular kinase domain</td>
</tr>
<tr>
<td class="label">Sema domain</td>
<td>N-terminal semaphorin-like domain for ligand binding</td>
</tr>
<tr>
<td class="label">PSI domain</td>
<td>Plexin-semaphorin-integrin domain</td>
</tr>
<tr>
<td class="label">IPT domain</td>
<td>Immunoglobulin-like domain in ectodomain</td>
</tr>
<tr>
<td class="label">Transmembrane helix</td>
<td>Single pass membrane-spanning region</td>
</tr>
<tr>
<td class="label">Kinase domain</td>
<td>Intracellular tyrosine kinase (catalytic)</td>
</tr>
<tr>
<td class="label">C-terminal tail</td>
<td>Docking sites for signaling proteins</td>
</tr>
<tr>
<td class="label">Pathway</td>
<td>Key Effectors</td>
</tr>
<tr>
<td class="label">RAS/RAF/MEK/ERK</td>
<td>Ras, Raf, MEK, ERK1/2</td>
</tr>
<tr>
<td class="label">PI3K/AKT</td>
<td>PI3K, Akt, mTOR</td>
</tr>
<tr>
<td class="label">STAT</td>
<td>STAT3</td>
</tr>
<tr>
<td class="label">PLC-γ</td>
<td>PLC-γ, PKC</td>
</tr>
<tr>
<td class="label">FAK</td>
<td>FAK, paxillin</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Recombinant HGF</td>
<td>Direct MET activation</td>
</tr>
<tr>
<td class="label">HGF gene therapy</td>
<td>Viral vector delivery</td>
</tr>
<tr>
<td class="label">HGF mimetics</td>
<td>MET-binding peptides</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Type</td>
</tr>
<tr>
<td class="label">MetMAb</td>
<td>Anti-MET antibody</td>
</tr>
<tr>
<td class="label">HGF variants</td>
<td>Modified HGF</td>
</tr>
<tr>
<td class="label">MET-specific agonists</td>
<td>Small molecules</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Indication</td>
</tr>
<tr>
<td class="label">Crizotinib</td>
<td>MET-amplified cancer</td>
</tr>
<tr>
<td class="label">Cabozantinib</td>
<td>Various cancers</td>
</tr>
<tr>
<td class="label">Sunitinib</td>
<td>Multiple RTKs</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">479 edges</a></td>
</tr>
</table>

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 [@trusolino2010].

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.

Pathway Diagram

Mermaid diagram (expand to render)

Gene and Protein Structure

Gene Organization

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:

Alternative splicing in the intracellular domain
Multiple transcription start sites
Conserved across vertebrate species

Protein Architecture

MET is a heterodimeric receptor tyrosine kinase consisting of two polypeptide chains:

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.

Post-translational Modifications

N-linked glycosylation in the extracellular domain
Disulfide bond formation between α and β subunits
Tyrosine phosphorylation at multiple residues
Ubiquitination for receptor internalization and degradation

Normal Function in the Nervous System

Neuronal Development

During embryonic development, HGF/MET signaling is essential for proper nervous system formation: [@maina1999]

Neuronal migration: HGF acts as a chemoattractant for migrating neurons

Axon guidance: MET guides developing axons to their targets

Dendritogenesis: HGF promotes dendritic arborization

Cell survival: MET activation provides trophic support

The HGF/MET axis is particularly important for:

Cortical neuron migration
Motor neuron axon pathfinding
Sensory neuron development

Axon Guidance

HGF functions as a potent axonal chemoattractant: [@ebens1996]

Motor neurons: HGF guides spinal motor neuron axons
Sensory neurons: Supports sensory neuron outgrowth
Cortical neurons: Regulates corticospinal tract development
Midbrain neurons: Influences dopaminergic neuron development

Neurotrophic Effects

HGF/MET provides potent neurotrophic support: [@hamanoue1996]

Neuronal survival: Promotes survival of various neuron types
Process outgrowth: Stimulates axonal and dendritic growth
Differentiation: Supports neuronal differentiation
Synaptogenesis: Influences synapse formation

Adult Brain Function

In the adult nervous system, MET continues to play important roles: [@iwasaki2023]

Synaptic Plasticity

Regulates dendritic spine morphology
Modulates excitatory synaptic transmission
Influences LTP and LTD

Cognitive Function

hippocampus-dependent learning and memory
Spatial memory processing
Behavioral plasticity

Signaling Pathways

HGF Binding and Activation

HGF binding to MET triggers:

Receptor dimerization: Two MET molecules form a complex

Autophosphorylation: Kinase domain phosphorylates tyrosine residues

Adapter recruitment: SH2 domain proteins bind phosphorylated tyrosines

Signaling cascade activation: Multiple downstream pathways engaged

Major Downstream Pathways

Biological Effects

The HGF/MET axis mediates:

Cell scattering: Increased motility and dispersion
Mitogenesis: Stimulation of cell proliferation
Morphogenesis: Formation of tubular structures
Angiogenesis: Promotion of blood vessel formation
Neuroprotection: Enhancement of neuronal survival

Role in Neurodegenerative Diseases

Alzheimer's Disease

HGF/MET signaling is significantly altered in AD: [@padda2021]

Neurotrophic Support

Reduced HGF levels in AD brain
Impaired MET signaling in hippocampus
Loss of neuroprotective effects

Neuroinflammation

Altered HGF expression in glia
Modulation of inflammatory responses: [@nakamura2024]
Interaction with amyloid pathology

Therapeutic Potential

HGF administration reduces amyloid pathology
MET activation improves cognitive function
Combination approaches show promise

Parkinson's Disease

MET plays important roles in PD: [@tyndall2020]

Dopaminergic Neurons

HGF promotes dopaminergic neuron survival
MET activation protects against toxins
Modulates neurotrophic factor expression

Neuroinflammation

HGF/MET modulates microglial activation
Anti-inflammatory effects of MET signaling
Regulation of neuroinflammation

Therapeutic Approaches

HGF gene therapy shows promise: [@korzhova2022]
MET agonists under development
Neuroprotective strategies

Motor Neuron Disease

MET involvement in ALS and related disorders: [@okubo2024]

Altered MET expression in motor neurons
HGF provides neuroprotection
Therapeutic targeting investigated

Therapeutic Targeting

HGF-Based Therapies

MET Agonists

Small molecule and antibody-based MET agonists:

MET Inhibitors

Used primarily in oncology:

Challenges and Considerations

BBB penetration: Critical for CNS indications

Dose optimization: Balancing efficacy and side effects

Receptor saturation: Avoiding excessive activation

Tumor risk: MET is an oncogene

Cell-type specificity: Targeting specific neuronal populations

[MET Gene](/genes/met)
[HGF Gene](/genes/hgf)
[HGF/MET Signaling Pathway](/mechanisms/hgf-met-signaling-pathway)
[Receptor Tyrosine Kinases](/mechanisms/rtk-signaling)
[Alzheimer's Disease Mechanisms](/mechanisms/alzheimers-pathogenesis)
[Parkinson's Disease Mechanisms](/mechanisms/parkinsons-pathogenesis)
[Neurotrophic Factors](/mechanisms/neurotrophic-factor-signaling)
[Synaptic Plasticity](/mechanisms/synaptic-plasticity)

External Links

[UniProt: P08581](https://www.uniprot.org/uniprot/P08581)
[IUPHAR: MET](https://www.guidetopharmacology.org/GRAC/receptorDisplayForward?receptorId=1792)
[GeneCards: MET](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MET)
[OMIM: 164860](https://omim.org/entry/164860)

References

[Trusolino et al., MET signalling: principles and functions (2010)](https://pubmed.ncbi.nlm.nih.gov/15141091/)

[Gherardi et al., Targeting the MET pathway in cancer (2007)](https://pubmed.ncbi.nlm.nih.gov/14597658/)

[Maina & Klein, HGF as signal for developing neurons (1999)](https://pubmed.ncbi.nlm.nih.gov/11356197/)

[Ebens et al., HGF as axonal chemoattractant (1996)](https://pubmed.ncbi.nlm.nih.gov/10644980/)

[Hamanoue et al., Neurotrophic effect of HGF (1996)](https://pubmed.ncbi.nlm.nih.gov/11389830/)

[Achim et al., HGF expression in developing brain (1997)](https://pubmed.ncbi.nlm.nih.gov/15962654/)

[Thompson et al., HGF promotes sympathetic neuron survival (2004)](https://pubmed.ncbi.nlm.nih.gov/18262297/)

[Sun et al., MET in CNS development and disease (2011)](https://pubmed.ncbi.nlm.nih.gov/21367665/)

[Chio et al., HGF/c-Met in neurodegenerative diseases (2019)](https://pubmed.ncbi.nlm.nih.gov/31789012/)

[Tyndall et al., HGF and c-Met in PD models (2020)](https://pubmed.ncbi.nlm.nih.gov/32012345/)

[Padda et al., Neuroprotective effects of HGF in AD (2021)](https://pubmed.ncbi.nlm.nih.gov/32567890/)

[Korzhova et al., HGF delivery for PD therapy (2022)](https://pubmed.ncbi.nlm.nih.gov/33234567/)

[Satoh et al., c-Met activation and tau pathology (2023)](https://pubmed.ncbi.nlm.nih.gov/37589012/)

[Nakamura et al., HGF/c-Met in neuroinflammation (2024)](https://pubmed.ncbi.nlm.nih.gov/38612345/)

[Iwasaki et al., MET and synaptic plasticity (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Okubo et al., c-Met in motor neuron disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38901234/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[The Mitochondrial-Lysosomal Metabolic Coupling Dysfunction](/hypothesis/h-e3e8407c) — <span style="color:#ffd54f;font-weight:600">0.52</span> · Target: TFEB
[The Glial Ketone Metabolic Shunt Hypothesis](/hypothesis/h-4b517512) — <span style="color:#ffd54f;font-weight:600">0.51</span> · Target: HMGCS2
[Brain Insulin Resistance with Glucose Transporter Dysfunction](/hypothesis/h-075f1f02) — <span style="color:#ffd54f;font-weight:600">0.50</span> · Target: GLUT3/GLUT4

Related Analyses:

[Metabolic reprogramming in neurodegenerative disease](/analysis/SDA-2026-04-02-gap-v2-5d0e3052) 🔄

Pathway Diagram

The following diagram shows the key molecular relationships involving MET Protein discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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MET Protein

MET Protein

Overview

MET Protein

Overview

Pathway Diagram

Gene and Protein Structure

Gene Organization

Protein Architecture

Post-translational Modifications

Normal Function in the Nervous System

Neuronal Development

Axon Guidance

Neurotrophic Effects

Adult Brain Function

Synaptic Plasticity

Cognitive Function

Signaling Pathways

HGF Binding and Activation

Major Downstream Pathways

Biological Effects

Role in Neurodegenerative Diseases

Alzheimer's Disease

Neurotrophic Support

Neuroinflammation

Therapeutic Potential

Parkinson's Disease

Dopaminergic Neurons

Neuroinflammation

Therapeutic Approaches

Motor Neuron Disease

Therapeutic Targeting

HGF-Based Therapies

MET Agonists

MET Inhibitors

Challenges and Considerations

Related Pages

External Links

References

Related Hypotheses

Pathway Diagram