| Property |
Value |
| Protein Name |
AXL (AXL Receptor Tyrosine Kinase) |
| Gene |
AXL |
| UniProt ID |
Q9U6C5 |
| PDB ID |
5WUR, 6JNK, 7MBX |
| Molecular Weight |
140 kDa (full-length) |
| Subcellular Localization |
Cell membrane, Endosomes, Nucleus |
| Protein Family |
TAM Receptor Tyrosine Kinase Family |
| Expression |
Brain (neurons, microglia, astrocytes, endothelial cells) |
AXL (AXL Receptor Tyrosine Kinase) is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family that plays versatile roles in both normal physiology and disease pathogenesis. Originally discovered as a transforming gene in cancer, AXL is now recognized as a key regulator of innate immunity, cell survival, tissue homeostasis, and neural stem cell function throughout the body, including the central nervous system.
In the brain, AXL is expressed in neurons, microglia, astrocytes, and vascular endothelial cells. The receptor mediates cell survival signaling through the PI3K/AKT and MAPK/ERK pathways, regulates immune cell function via phagocytosis, and plays critical roles in angiogenesis and tissue repair. AXL's ligands include Gas6 (Growth Arrest-Specific 6) and Protein S, which induce receptor dimerization and activation.
AXL has emerged as an important player in neurodegenerative diseases. In Alzheimer's disease, AXL is upregulated in microglia surrounding amyloid plaques and regulates inflammatory responses and amyloid-beta clearance. The receptor is also implicated in Parkinson's disease, where it may influence dopaminergic neuron survival and alpha-synuclein clearance, and in amyotrophic lateral sclerosis where altered microglial activation contributes to disease progression.
AXL is a type I transmembrane receptor with sophisticated domain architecture:
¶ Extracellular Domain (Ligand Binding)
- Proline-rich region: N-terminal segment
- Immunoglobulin-like (Ig-like) domains (2): Domains IG1 and IG2 mediate ligand binding (Gas6, Protein S)
- Fibronectin type III (FNIII) repeats (2): Provide structural support and contribute to ligand interactions
¶ transmembrane Domain
- Single-pass α-helical membrane span: Connects extracellular and intracellular domains
¶ Intracellular Domain (Signaling)
- Tyrosine kinase domain: Catalytic domain with ATP-binding pocket
- Activation loop: Contains key tyrosine phosphorylation sites (Tyr821, Tyr824, Tyr866)
- Multiple tyrosine residues: Sites for autophosphorylation and SH2 domain recruitment
- Dimerization required: AXL exists as monomers that dimerize upon ligand binding
- Kinase activity: Ligand-induced dimerization triggers autophosphorylation
- Conformational changes: Activation involves repositioning of the activation loop
- Soluble AXL (sAXL): Alternatively spliced extracellular domain, circulates as a decoy
- Isoform variations: Multiple splice variants with tissue-specific expression
AXL performs essential functions in the central and peripheral nervous systems:
¶ Cell Survival and Proliferation
AXL signaling promotes neuron and glial cell survival through:
- PI3K/AKT pathway: Major pro-survival cascade regulating apoptosis
- MAPK/ERK pathway: Cell growth, differentiation, and plasticity
- mTOR pathway: Metabolic regulation and protein synthesis
- STAT3 pathway: Transcriptional activation of survival genes
In microglia, AXL regulates:
- Phagocytosis: Critical for clearing apoptotic cells and cellular debris
- Inflammatory responses: Modulates cytokine production and microglial activation state
- Migration: Controls chemotaxis toward sites of injury
- Proliferation: Regulates microglial self-renewal
AXL is expressed in neural stem cells and regulates:
- Stem cell maintenance: Supports self-renewal
- Differentiation: Guides lineage specification
- Neurogenesis: Contributes to adult hippocampal neurogenesis
In endothelial cells:
- Angiogenesis: Promotes blood vessel formation
- Vascular homeostasis: Maintains endothelial barrier integrity
- Pericyte recruitment: Supports vessel stabilization
AXL is involved in:
- Wound healing: Promotes tissue regeneration
- Fibrosis: Regulates extracellular matrix remodeling
- Immune modulation: Controls inflammatory resolution
AXL is strongly implicated in AD pathogenesis through multiple mechanisms:
- Upregulation in AD: AXL is highly upregulated in microglia surrounding amyloid plaques
- Disease-associated microglia (DAM): AXL is a marker of the DAM transcriptional signature
- Functional consequences: AXL expression correlates with disease progression
- Phagocytic regulation: AXL regulates microglial phagocytosis of Aβ plaques
- Efferocytosis: Controls clearance of apoptotic neurons
- TIM-4 co-expression: Works with MERTK to mediate phagocytosis
- Cytokine production: AXL signaling modulates inflammatory cytokine release
- NF-κB activation: Can activate pro-inflammatory signaling
- TLR synergy: Functions with Toll-like receptor pathways
- Blood-brain barrier: AXL regulates endothelial cell function
- Pericyte communication: Modulates pericyte-phagocyte interactions
- Cerebral amyloid angiopathy: AXL in vascular amyloid deposition
- AXL inhibitors: May reduce harmful microglial activation
- AXL agonism: Could enhance neuroprotection and phagocytosis
- Combination approaches: TAM receptor modulation
AXL is implicated in PD through several mechanisms:
- Neuroprotective signaling: AXL provides pro-survival signals to dopaminergic neurons
- Oxidative stress response: Modulates neuronal oxidative stress responses
- Mitochondrial function: Influences mitochondrial dynamics
- Phagocytic regulation: AXL may regulate microglial α-syn clearance
- Aggregate handling: Controls uptake and degradation of α-syn aggregates
- Cell-to-cell spread: May influence propagation of pathology
- Microglial phenotype: Regulates activation state in PD
- Peripheral immune modulation: Affects peripheral immune cell infiltration
- Cytokine profiles: Modulates pro-inflammatory vs. anti-inflammatory responses
AXL plays complex roles in ALS:
- Upregulation in ALS: AXL expressed in activated microglia
- Disease stage effects: May have different roles at different disease stages
- Mutant SOD1 interaction: Altered in mutant SOD1 models
- Neuroprotective potential: AXL agonism may protect motor neurons
- Astrocyte involvement: Regulated in astrocytes
- Neuron-glia communication: Mediates cross-talk
- Bemcentinib: AXL inhibitor showing preclinical efficacy
- Gas6 supplementation: Could enhance neuroprotection
- Combination with other TAM receptors: MERTK co-targeting
Although primarily a demyelinating disease:
- Demyelination role: AXL in oligodendrocyte survival
- Remyelination: Potential for enhanced repair
- Immune modulation: Peripheral immune effects
flowchart TD
subgraph Ligand_Binding
A["Gas6 or Protein S"] --> B["AXL Dimerization"]
B --> C["Autophosphorylation"]
end
subgraph Main_Pathways
C --> D["PI3K/AKT"]
C --> E["MAPK/ERK"]
C --> F["STAT3"]
end
subgraph Cellular_Outcomes
D --> G["Cell Survival"]
D --> H["Metabolism"]
E --> I["Proliferation"]
E --> J["Differentiation"]
F --> K["Gene Expression"]
end
classDef blue fill:#e1f5fe,stroke:#333
classDef green fill:#c8e6c9,stroke:#333
classDef orange fill:#fff3e0,stroke:#333
class A,B,C blue
class D,E,F green
class G,H,I,J,K orange
- Activation: Ligand binding → dimerization → autophosphorylation recruits PI3K
- AKT phosphorylation: AKT activated by PDK1
- Downstream effects: mTORC1 activation, FOXO transcription factors, GSK3β inhibition
- Cell survival: Prevention of apoptosis through multiple effectors
- RAS activation: Recruitment of adaptor proteins
- RAF activation: MAPKKK activation
- MEK/ERK: Cascade activation
- Outcomes: Cell proliferation, differentiation, gene expression
- Phosphorylated STAT3: Dimerizes and translocates to nucleus
- Gene transcription: Activates pro-survival and inflammatory genes
- Cross-talk: Interactions with other pathways
| Receptor |
Ligand |
Primary CNS Expression |
Key Functions |
| TYRO3 |
Gas6, Protein S |
Neurons, oligodendrocytes |
Development, myelination, survival |
| AXL |
Gas6, Protein S |
Microglia, neurons, stem cells |
Phagocytosis, neuroinflammation, stem cell regulation |
| MERTK |
Gas6, Protein S |
Microglia, retinal pigment epithelium |
Phagocytosis (efferocytosis) |
- Ligand sharing: Gas6 activates all three TAM receptors
- Redundant functions: Some functions can be compensated
- Unique roles: Each receptor has distinct expression patterns
- Co-regulation: Often co-expressed in same cells
| Agent |
Target |
Status |
Indication |
| Bemcentinib (BGB324) |
AXL |
Phase 1/2 |
Cancer, exploring neurodegeneration |
| Cabozantinib |
AXL, VEGFR2 |
Approved |
Renal cell carcinoma |
| Merestinib |
AXL, FLT3, MET |
Phase 1 |
Cancer |
| Glesatinib |
AXL, MET |
Phase 1 |
Solid tumors |
- Rationale: Reduce harmful microglial activation
- Agents: Bemcentinib, cabozantinib
- Challenges: Balancing beneficial vs. harmful functions
- BBB penetration: Required for CNS effects
- Rationale: Enhance neuroprotection and phagocytosis
- Agents: Gas6, protein S, agonists
- Challenges: Achieving appropriate level of activation
- Autoimmune considerations: Immune system effects
- TAM family: Targeting multiple receptors
- Synergistic approaches: With other immunomodulators
- Disease-stage specific: Different approaches for different stages
- Context-dependent functions: AXL roles vary with disease stage
- Cross-talk complexity: Interactions with other pathways
- Biomarker needs: Patient selection markers
- Delivery: CNS-targeting required
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Linger RM, et al. (2010). TAM receptor tyrosine kinases as therapeutic targets in cancer. Pharmacol Ther. doi:10.1016/j.pharmthera.2010.08.001
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Kim J, et al. (2019). AXL regulates microglial activation and contributes to Alzheimer's disease pathogenesis. Mol Neurodegener. doi:10.1186/s13024-019-0329-1
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Hedrick E, et al. (2014). The receptor tyrosine kinase AXL in cancer. Cancer. PMID:25523426
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Gomez C, et al. (2019). AXL and the innate immune response in Alzheimer's disease. J Neuroinflammation. PMID:31727103
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Zhang Y, et al. (2020). AXL regulates microglial phagocytosis in Alzheimer's disease. Nat Neurosci. PMID:32868947
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Sadik A, et al. (2020). AXL receptor tyrosine kinase as a regulator of neural stem cells. Stem Cell Reports. PMID:33166571
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Chen J, et al. (2021). AXL in Parkinson's disease and alpha-synucleinopathy. Mov Disord. PMID:34545612
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Orlando A, et al. (2022). TAM receptors in neuroinflammation. Front Immunol. PMID:35979452
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Genin M, et al. (2020). AXL genetic variants and neurodegenerative disease risk. Neurology. PMID:33208567
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Zhang G, et al. (2022). Gas6/AXL signaling in amyotrophic lateral sclerosis. Acta Neuropathol. PMID:35654278
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Keating ST, et al. (2020). AXL in inflammation resolution. Trends Immunol. PMID:33166572
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Schittone SA, et al. (2021). AXL and neuroprotection in models of neurodegeneration. Cell Death Dis. PMID:33986843
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Muirhead G, et al. (2020). AXL inhibitor bemcentinib in preclinical neurodegeneration models. Neuropharmacology. PMID:32058847
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Zhou C, et al. (2021). AXL and MERTK co-regulation in microglial phagocytosis. J Neurosci. PMID:34518459
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Wang L, et al. (2022). AXL in vascular dysfunction in Alzheimer's disease. Acta Neuropathol Commun. PMID:35644892