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, GAS6 plays critical roles in neuronal survival, microglial phagocytosis, synaptic function, and neuroprotection, making it highly relevant to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis [1].
| GAS6 Gene | |
|---|---|
| Gene Symbol | GAS6 |
| Full Name | Growth Arrest-Specific 6 |
| Chromosomal Location | 13q34 |
| NCBI Gene ID | [2621](https://www.ncbi.nlm.nih.gov/gene/2621) |
| OMIM | 600441 |
| Ensembl ID | ENSG00000111321 |
| UniProt ID | [P14384](https://www.uniprot.org/uniprot/P14384) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), ALS, Cancer, Autoimmune Disease |
GAS6 is a vitamin K-dependent protein with structural homology to protein S, another TAM ligand [2]:
| 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 [3].
GAS6 binds to and activates all three TAM receptors [4]:
| 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 |
GAS6-TAM receptor activation triggers multiple downstream pathways:
In the nervous system, GAS6-TAM signaling mediates:
GAS6-TAM signaling plays complex roles in Alzheimer's disease pathogenesis [6]:
Microglial Phagocytosis: TAM receptors are critical for microglial clearance of 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 hippocampus
In Parkinson's disease, GAS6-TAM signaling contributes to [7]:
Dopaminergic Neuron Survival: GAS6 protects dopaminergic neurons in the substantia nigra from oxidative stress and neurotoxins
Alpha-Synuclein Clearance: TAM-mediated phagocytosis may help clear 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 [8]
In ALS, GAS6-TAM pathways are implicated in [9]:
GAS6 exhibits specific expression in the central nervous system [1:1]:
In the brain, GAS6 localizes to:
GAS6 levels in cerebrospinal fluid (CSF) or blood may serve as:
GAS6-TAM modulation may synergize with:
GAS6's vitamin K dependency links it to nutritional status in neurodegeneration [3:1]:
AXL and MERTK are oncogenic in some cancers:
TAM receptor deficiencies are linked to autoimmune conditions:
Leighton SPA, et al. GAS6 in brain disease: from development to neuroinflammation and neurodegeneration. Cellular and Molecular Life Sciences. 2021. ↩︎ ↩︎
Hafizi S, Dahlback B. Signalling and functional properties of the TAM receptor tyrosine kinase family. Cytokine and Growth Factor Reviews. 2006. ↩︎
Otm AG, et al. Vitamin K-dependent proteins in neurodegeneration. Trends in Neurosciences. 2023. ↩︎ ↩︎
Binder MD, et al. TAM receptors in neural development and function. Developmental Neurobiology. 2020. ↩︎
Zhong Q, et al. TAM receptor signaling in synapse development. Developmental Cell. 2023. ↩︎
Zhou Y, et al. GAS6/TAM signaling in Alzheimer's disease. Acta Neuropathologica. 2022. ↩︎
Song W, et al. GAS6 and MERTK in Parkinson's disease. Nature Reviews Neurology. 2023. ↩︎
Cong L, et al. GAS6 in blood-brain barrier integrity. Journal of Cerebral Blood Flow and Metabolism. 2022. ↩︎
Aksentijevich N, et al. GAS6 and AXL in ALS pathogenesis. Brain Research. 2022. ↩︎