GAS6 - Growth Arrest Specific 6

GAS6 — Growth Arrest Specific 6

Overview

The GAS6 gene encodes GAS6 (Growth Arrest-Specific 6), a vitamin K-dependent growth factor and the principal ligand for the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases. GAS6 is a multifunctional protein involved in cell survival, proliferation, migration, phagocytosis, and immunomodulation. In the [central nervous system](/brain-regions/), GAS6 plays critical roles in [neuronal](/entities/neurons) survival, [microglial](/entities/microglia) phagocytosis, synaptic function, and neuroprotection, making it highly relevant to [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and amyotrophic lateral sclerosis [@leighton2021].

GAS6 — Growth Arrest Specific 6

Overview

The GAS6 gene encodes GAS6 (Growth Arrest-Specific 6), a vitamin K-dependent growth factor and the principal ligand for the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases. GAS6 is a multifunctional protein involved in cell survival, proliferation, migration, phagocytosis, and immunomodulation. In the [central nervous system](/brain-regions/), GAS6 plays critical roles in [neuronal](/entities/neurons) survival, [microglial](/entities/microglia) phagocytosis, synaptic function, and neuroprotection, making it highly relevant to [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and amyotrophic lateral sclerosis [@leighton2021].

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">GAS6 Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>GAS6</td></tr>
<tr><td><strong>Full Name</strong></td><td>Growth Arrest-Specific 6</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>13q34</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[2621](https://www.ncbi.nlm.nih.gov/gene/2621)</td></tr>
<tr><td><strong>OMIM</strong></td><td>600441</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000111321</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P14384](https://www.uniprot.org/uniprot/P14384)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), ALS, Cancer, Autoimmune Disease</td></tr>
</table>
</div>

Function

Protein Structure

GAS6 is a vitamin K-dependent protein with structural homology to protein S, another TAM ligand [@hafizi2006]:

| Domain | Function |
|--------|----------|
| Gla Domain | γ-carboxylated glutamic acid residues enable calcium-dependent membrane binding |
| Loop 1 | Contains growth factor-like domain with receptor binding sites |
| Loop 2 | Additional receptor interaction region |
| Loop 3 | Heparin-binding site for cell surface proteoglycan interaction |
| C-terminal Region | Contains sex hormone-binding globulin (SHBG)-like domain |

The Gla domain requires vitamin K for γ-carboxylation, linking GAS6 biology to vitamin K metabolism and its potential role in neurodegeneration [@otm2023].

TAM Receptor Activation

GAS6 binds to and activates all three TAM receptors [@binder2020]:

| Receptor | Expression Pattern | Primary Functions |
|----------|-------------------|-------------------|
| TYRO3 | Neurons, astrocytes, oligodendrocytes | Development, synaptic function |
| AXL | Microglia, neurons, Schwann cells | Phagocytosis, cell survival |
| MERTK | Microglia, macrophages | Apoptotic cell clearance, phagocytosis |

Signaling Pathways

GAS6-TAM receptor activation triggers multiple downstream pathways:

Biological Functions

In the nervous system, GAS6-TAM signaling mediates:

Role in Neurodegeneration

Alzheimer's Disease

GAS6-TAM signaling plays complex roles in [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis [@zhou2022]:

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), GAS6-TAM signaling contributes to [@song2023]:

Amyotrophic Lateral Sclerosis

In ALS, GAS6-TAM pathways are implicated in [@aksentijevich2022]:

Mechanistic Pathway

Expression Patterns

GAS6 exhibits specific expression in the [central nervous system](/brain-regions/) [@leighton2021]:

• Neuronal Expression: High in cortical neurons, hippocampal pyramidal cells, cerebellar Purkinje cells
• Glial Expression: Micro astrocytes and some microglia express GAS6; expression increases with activation
• Development: Important during neurodevelopment for synaptic formation and myelination
• Aging: GAS6 expression decreases with age, potentially contributing to age-related neurodegeneration

• Neuronal cell bodies and dendrites
• Synaptic compartments
• Astrocyte processes
• Microglial cells (lower baseline, increases with activation)

Therapeutic Implications

Biomarker Potential

GAS6 levels in cerebrospinal fluid (CSF) or blood may serve as:

• Biomarker for neurodegenerative disease progression
• Indicator of microglial activation status
• Therapeutic response marker for TAM-targeting interventions

Drug Development Targets

Gene Therapy Approaches

• AAV-mediated GAS6 delivery to neurons
• AAV-mediated MERTK or AXL delivery to enhance TAM signaling
• CRISPR-based approaches to enhance endogenous GAS6 expression

Combination Strategies

GAS6-TAM modulation may synergize with:

• [TREM2-targeting therapies](/entities/trem2)
• Anti-amyloid immunotherapies
• Anti-inflammatory treatments

Clinical Connections

Vitamin K and Neurodegeneration

GAS6's vitamin K dependency links it to nutritional status in neurodegeneration [@otm2023]:

• Vitamin K deficiency is associated with cognitive decline
• Vitamin K antagonists (warfarin) may increase neurodegeneration risk
• Vitamin K supplementation may support GAS6 function

Cancer Therapy Connections

AXL and MERTK are oncogenic in some cancers:

• GAS6/AXL axis promotes tumor cell survival and metastasis
• AXL inhibitors are in cancer clinical trials
• Lessons from oncology may inform neurodegenerative disease approaches

Autoimmune Diseases

TAM receptor deficiencies are linked to autoimmune conditions:

• Double knockout mice develop autoimmunity
• Relevance to neuroinflammation in degeneration

Key Publications

See Also

• [AXL Gene](/genes/axl) — TAM receptor, GAS6 ligand
• [MERTK Gene](/genes/merkt) — TAM receptor, GAS6 ligand
• [TYRO3 Gene](/genes/tyro3) — TAM receptor, GAS6 ligand
• [TREM2](/proteins/trem2) — Microglial receptor, complementary to TAM pathways
• [Microglial Phagocytosis](/mechanisms/microglial-phagocytosis-neurodegeneration) — Clearance pathways
• [Alzheimer's Disease](/diseases/alzheimers-disease) — Disease context
• [Parkinson's Disease](/diseases/parkinsons-disease) — Disease context

References

Pathway Diagram

The following diagram shows the key molecular relationships involving GAS6 - Growth Arrest Specific 6 discovered through SciDEX knowledge graph analysis: