Axl Protein

AXL Protein — AXL Receptor Tyrosine Kinase

<div class="infobox infobox-protein">

| 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) |

</div>

Overview

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[@hedrick2014], 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[@linger2010].

In the brain, AXL is expressed in [neurons](/entities/neurons), [microglia](/cell-types/microglia-neuroinflammation), [astrocytes](/entities/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[@orlando2022].

AXL Protein — AXL Receptor Tyrosine Kinase

<div class="infobox infobox-protein">

| 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) |

</div>

Overview

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[@hedrick2014], 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[@linger2010].

In the brain, AXL is expressed in [neurons](/entities/neurons), [microglia](/cell-types/microglia-neuroinflammation), [astrocytes](/entities/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[@orlando2022].

AXL has emerged as an important player in neurodegenerative diseases. In [Alzheimer's disease](/diseases/alzheimers-disease), AXL is upregulated in microglia surrounding amyloid plaques and regulates inflammatory responses and [amyloid-beta](/proteins/amyloid-beta) clearance[@zhang2020]. The receptor is also implicated in [Parkinson's disease](/diseases/parkinsons-disease), where it may influence dopaminergic neuron survival and [alpha-synuclein](/proteins/alpha-synuclein) clearance[@chen2021], and in [amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) where altered microglial activation contributes to disease progression[@zhang2022].

Structure

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

Structural Insights

• 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

Alternative Splicing

• Soluble AXL (sAXL): Alternatively spliced extracellular domain, circulates as a decoy
• Isoform variations: Multiple splice variants with tissue-specific expression

Normal Function in the Nervous System

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](/mechanisms/mtor-signaling-pathway) pathway: Metabolic regulation and protein synthesis
• STAT3 pathway: Transcriptional activation of survival genes

Microglial Function

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

Neural Stem Cell Regulation

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[@sadik2020]

Vascular Function

In endothelial cells:

• Angiogenesis: Promotes blood vessel formation
• Vascular homeostasis: Maintains endothelial barrier integrity[@wang2022]
• Pericyte recruitment: Supports vessel stabilization

Tissue Repair

AXL is involved in:

• Wound healing: Promotes tissue regeneration
• Fibrosis: Regulates extracellular matrix remodeling
• Immune modulation: Controls inflammatory resolution[@keating2020]

Role in Neurodegenerative Diseases

Alzheimer's Disease

AXL is strongly implicated in AD pathogenesis through multiple mechanisms[@gomez2019]:

Microglial Activation

• 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

Amyloid Clearance

• Phagocytic regulation: AXL regulates microglial phagocytosis of Aβ plaques[@zhang2020]
• Efferocytosis: Controls clearance of apoptotic neurons
• TIM-4 co-expression: Works with MERTK to mediate phagocytosis[@zhou2021]

Neuroinflammation

• Cytokine production: AXL signaling modulates inflammatory cytokine release
• NF-κB activation: Can activate pro-inflammatory signaling
• TLR synergy: Functions with Toll-like receptor pathways

Vascular Dysfunction

• Blood-brain barrier: AXL regulates endothelial cell function[@wang2022]
• Pericyte communication: Modulates pericyte-phagocyte interactions
• Cerebral amyloid angiopathy: AXL in vascular amyloid deposition

Therapeutic Implications

• AXL inhibitors: May reduce harmful microglial activation
• AXL agonism: Could enhance neuroprotection and phagocytosis
• Combination approaches: TAM receptor modulation[@cunningham2023]

Parkinson's Disease

AXL is implicated in PD through several mechanisms[@chen2021]:

Dopaminergic Neuron Protection

• Neuroprotective signaling: AXL provides pro-survival signals to dopaminergic neurons
• Oxidative stress response: Modulates neuronal oxidative stress responses
• Mitochondrial function: Influences mitochondrial dynamics

Alpha-Synuclein Clearance

• 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

Neuroinflammation

• Microglial phenotype: Regulates activation state in PD
• Peripheral immune modulation: Affects peripheral immune cell infiltration
• Cytokine profiles: Modulates pro-inflammatory vs. anti-inflammatory responses

Amyotrophic Lateral Sclerosis

AXL plays complex roles in ALS[@zhang2022]:

Microglial Activation

• 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

Motor Neuron Vulnerability

• Neuroprotective potential: AXL agonism may protect motor neurons
• Astrocyte involvement: Regulated in astrocytes
• Neuron-glia communication: Mediates cross-talk

Therapeutic Targeting

• Bemcentinib: AXL inhibitor showing preclinical efficacy[@muirhead2020]
• Gas6 supplementation: Could enhance neuroprotection
• Combination with other TAM receptors: MERTK co-targeting

Multiple Sclerosis

Although primarily a demyelinating disease:

• Demyelination role: AXL in oligodendrocyte survival
• Remyelination: Potential for enhanced repair
• Immune modulation: Peripheral immune effects

Signaling Pathways

Downstream Signaling Cascades

PI3K/AKT Pathway

• 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

MAPK/ERK Pathway

• RAS activation: Recruitment of adaptor proteins
• RAF activation: MAPKKK activation
• MEK/ERK: Cascade activation
• Outcomes: Cell proliferation, differentiation, gene expression

STAT3 Pathway

• Phosphorylated STAT3: Dimerizes and translocates to nucleus
• Gene transcription: Activates pro-survival and inflammatory genes
• Cross-talk: Interactions with other pathways

TAM Receptor Family

| 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) |

family Interaction

• 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

Therapeutic Targeting

Clinical Development

| 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 |

Strategies for Neurodegeneration

AXL Inhibition

• Rationale: Reduce harmful microglial activation
• Agents: Bemcentinib, cabozantinib
• Challenges: Balancing beneficial vs. harmful functions
• BBB penetration: Required for CNS effects

AXL Agonism

• Rationale: Enhance neuroprotection and phagocytosis
• Agents: Gas6, protein S, agonists
• Challenges: Achieving appropriate level of activation
• Autoimmune considerations: Immune system effects

Combination Approaches

• TAM family: Targeting multiple receptors
• Synergistic approaches: With other immunomodulators
• Disease-stage specific: Different approaches for different stages

Challenges

• 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

Key Publications

Cross-links

• [AXL Gene](/genes/axl) — Gene page for AXL
• [TYRO3](/genes/tyro3) — TYRO3 receptor
• [MERTK](/genes/mertk) — MERTK receptor
• [TAM Receptor Signaling](/mechanisms/tam-receptor-signaling) — TAM pathway
• [Microglia](/cell-types/microglia-neuroinflammation) — Microglia cell type
• [Alzheimer's Disease](/diseases/alzheimers-disease) — AD disease page
• [Parkinson's Disease](/diseases/parkinsons-disease) — PD disease page

External Links

• [Human Protein Atlas: AXL](https://www.proteinatlas.org/ENSG00000167601-AXL)
• [UniProt: AXL](https://www.uniprot.org/uniprotkb/Q9U6C5)
• [NCBI Gene: AXL](https://www.ncbi.nlm.nih.gov/gene/55924)

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Microglia](/cell-types/microglia-neuroinflammation)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [TAM Receptor Signaling](/mechanisms/tam-receptor-signaling)