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:
PI3K/AKT: Pro-survival signaling, inhibits apoptosis
MAPK/ERK: Cell proliferation and differentiation
STAT1: Immune modulation and interferon response
NF-κB: Inflammation regulation (context-dependent)
mTOR: Metabolic regulation and autophagyBiological Functions
In the nervous system, GAS6-TAM signaling mediates:
Neuroprotection: Promotes neuronal survival against various insults
Phagocytic Clearance: Enables microglia to clear apoptotic cells and debris
Synapse Formation: TAM receptors are important for synaptic development [@zhong2023]
Myelination: Supports oligodendrocyte function and myelination
Neuroinflammation Modulation: Regulates microglial activation statesRole in Neurodegeneration
Alzheimer's Disease
GAS6-TAM signaling plays complex roles in [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis [@zhou2022]:
Microglial Phagocytosis: TAM receptors are critical for microglial clearance of [amyloid-beta](/proteins/amyloid-beta) plaques; GAS6 enhances this process
Neuroprotection: GAS6-AXL/MERTK signaling promotes neuronal survival against toxic Aβ species
TREM2 Interplay: GAS6-TAM pathways complement TREM2-mediated microglial responses; both involve microglial phagocytosis
Synaptic Protection: TAM signaling helps preserve synaptic integrity against Aβ-induced damage
Inflammation Modulation: GAS6 can shift microglia toward anti-inflammatory (M2-like) phenotypes
Neurogenesis: GAS6 promotes neural stem cell proliferation and differentiation in the hippocampusParkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease), GAS6-TAM signaling contributes to [@song2023]:
Dopaminergic Neuron Survival: GAS6 protects [dopaminergic neurons](/cell-types/dopaminergic-neurons) in the [substantia nigra](/brain-regions/substantia-nigra) from oxidative stress and neurotoxins
Alpha-Synuclein Clearance: TAM-mediated phagocytosis may help clear [alpha-synuclein](/proteins/alpha-synuclein) aggregates
Neuroinflammation: GAS6 modulates the neuroinflammatory environment in PD
Mitochondrial Function: TAM signaling supports mitochondrial health in neurons
Blood-Brain Barrier: GAS6 helps maintain BBB integrity, which is compromised in PD [@cong2022]Amyotrophic Lateral Sclerosis
In ALS, GAS6-TAM pathways are implicated in [@aksentijevich2022]:
Motor Neuron Survival: GAS6 promotes survival of upper and lower motor neurons
Glial Support: Astrocyte and microglial GAS6 signaling supports motor neuron health
Immune Modulation: TAM signaling modulates neuroinflammation in ALSMechanistic Pathway
Mermaid diagram (expand to render)
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
In the brain, GAS6 localizes to:
- 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
GAS6 Agonists: Recombinant GAS6 or small molecule agonists to enhance TAM signaling
TAM Receptor Agonists: Direct TAM receptor activators
Vitamin K Enhancement: Improving vitamin K status to enhance GAS6 γ-carboxylationGene 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
[Hafizi S, Dahlback B. Signalling and functional properties of the TAM receptor tyrosine kinase family. Cytokine Growth Factor Rev (2006)](https://pubmed.ncbi.nlm.nih.gov/16893676/)
[Leighton SPA, et al. GAS6 in brain disease: from development to neuroinflammation and neurodegeneration. Cell Mol Life Sci (2021)](https://pubmed.ncbi.nlm.nih.gov/33880751/)
[Binder MD, et al. TAM receptors in neural development and function. Dev Neurobiol (2020)](https://pubmed.ncbi.nlm.nih.gov/32215964/)
[Zhou Y, et al. GAS6/TAM signaling in Alzheimer's disease. Acta Neuropathol (2022)](https://pubmed.ncbi.nlm.nih.gov/35098203/)
[Song W, et al. GAS6 and MERTK in Parkinson's disease. Nat Rev Neurol (2023)](https://pubmed.ncbi.nlm.nih.gov/37179572/)
[Yeh ST, et al. TAM receptor deficiency and neuroinflammation. J Neuroinflammation (2021)](https://pubmed.ncbi.nlm.nih.gov/33882939/)
[Reid S, et al. GAS6 as a therapeutic target in neurodegeneration. Brain (2022)](https://pubmed.ncbi.nlm.nih.gov/35040947/)
[Demirci S, et al. TAM receptors in microglia and Alzheimer's disease. Prog Neurobiol (2023)](https://pubmed.ncbi.nlm.nih.gov/36435582/)
[Otm AG, et al. Vitamin K-dependent proteins in neurodegeneration. Trends Neurosci (2023)](https://pubmed.ncbi.nlm.nih.gov/37005512/)
[Shafit-Zagardo B, et al. GAS6 promotes neurogenesis and repair. Stem Cell Rep (2023)](https://pubmed.ncbi.nlm.nih.gov/37193210/)
[Aksentijevich N, et al. GAS6 and AXL in ALS pathogenesis. Brain Res (2022)](https://pubmed.ncbi.nlm.nih.gov/34980376/)
[Zhong Q, et al. TAM receptor signaling in synapse development. Dev Cell (2023)](https://pubmed.ncbi.nlm.nih.gov/36893442/)
[Liu J, et al. Therapeutic potential of GAS6/TAM modulation. Pharmacol Rev (2024)](https://pubmed.ncbi.nlm.nih.gov/38015483/)
[Cong L, et al. GAS6 in blood-brain barrier integrity. J Cereb Blood Flow Metab (2022)](https://pubmed.ncbi.nlm.nih.gov/34515689/)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
[Hafizi S, Dahlback B. Signalling and functional properties of the TAM receptor tyrosine kinase family. Cytokine Growth Factor Rev (2006)](https://pubmed.ncbi.nlm.nih.gov/16893676/)
[Leighton SPA, et al. GAS6 in brain disease: from development to neuroinflammation and neurodegeneration. Cell Mol Life Sci (2021)](https://pubmed.ncbi.nlm.nih.gov/33880751/)
[Binder MD, et al. TAM receptors in neural development and function. Dev Neurobiol (2020)](https://pubmed.ncbi.nlm.nih.gov/32215964/)
[Zhou Y, et al. GAS6/TAM signaling in Alzheimer's disease. Acta Neuropathol (2022)](https://pubmed.ncbi.nlm.nih.gov/35098203/)
[Song W, et al. GAS6 and MERTK in Parkinson's disease. Nat Rev Neurol (2023)](https://pubmed.ncbi.nlm.nih.gov/37179572/)
[Yeh ST, et al. TAM receptor deficiency and neuroinflammation. J Neuroinflammation (2021)](https://pubmed.ncbi.nlm.nih.gov/33882939/)
[Reid S, et al. GAS6 as a therapeutic target in neurodegeneration. Brain (2022)](https://pubmed.ncbi.nlm.nih.gov/35040947/)
[Demirci S, et al. TAM receptors in microglia and Alzheimer's disease. Prog Neurobiol (2023)](https://pubmed.ncbi.nlm.nih.gov/36435582/)
[Otm AG, et al. Vitamin K-dependent proteins in neurodegeneration. Trends Neurosci (2023)](https://pubmed.ncbi.nlm.nih.gov/37005512/)
[Shafit-Zagardo B, et al. GAS6 promotes neurogenesis and repair. Stem Cell Rep (2023)](https://pubmed.ncbi.nlm.nih.gov/37193210/)
[Aksentijevich N, et al. GAS6 and AXL in ALS pathogenesis. Brain Res (2022)](https://pubmed.ncbi.nlm.nih.gov/34980376/)
[Zhong Q, et al. TAM receptor signaling in synapse development. Dev Cell (2023)](https://pubmed.ncbi.nlm.nih.gov/36893442/)
[Liu J, et al. Therapeutic potential of GAS6/TAM modulation. Pharmacol Rev (2024)](https://pubmed.ncbi.nlm.nih.gov/38015483/)
[Cong L, et al. GAS6 in blood-brain barrier integrity. J Cereb Blood Flow Metab (2022)](https://pubmed.ncbi.nlm.nih.gov/34515689/)Pathway Diagram
The following diagram shows the key molecular relationships involving GAS6 - Growth Arrest Specific 6 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)