AXL - AXL Receptor Tyrosine Kinase

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AXL - AXL Receptor Tyrosine Kinase

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AXL (AXL Receptor Tyrosine Kinase)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">AXL - AXL Receptor Tyrosine Kinase</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>AXL</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>AXL - AXL Receptor Tyrosine Kinase</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=AXL" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">61 edges</a></td>
</tr>
</table>

Pathway / Interaction Diagram

Introduction

...

AXL (AXL Receptor Tyrosine Kinase)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">AXL - AXL Receptor Tyrosine Kinase</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>AXL</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>AXL - AXL Receptor Tyrosine Kinase</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=AXL" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">61 edges</a></td>
</tr>
</table>

Pathway / Interaction Diagram

Mermaid diagram (expand to render)

Introduction

AXL (from the Greek word "anexelekto" meaning "uncontrolled") is a receptor tyrosine kinase belonging to the TAM family (TYRO3, AXL, MERTK) that plays critical roles in cell survival, migration, immune regulation, and tissue homeostasis[@graham2014]. Discovered originally as a transforming gene in chronic myeloid leukemia, AXL has emerged as a pivotal regulator of multiple physiological and pathological processes, including neurodegeneration, cancer metastasis, and immune responses. The gene encodes a transmembrane receptor tyrosine kinase that is widely expressed in immune cells, endothelial cells, neurons, and various peripheral tissues, where it mediates both ligand-dependent and ligand-independent signaling cascades.

The significance of AXL in neurodegeneration has become increasingly apparent as research reveals its complex roles in microglial activation, neuroinflammation, neuronal survival, and protein clearance in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)[@kim2019]. Unlike TYRO3, which is predominantly expressed in neurons, or MERTK, which is highly expressed in microglia, AXL occupies an intermediate position with significant expression in both immune cells and neurons. This dual expression pattern enables AXL to modulate cross-talk between neuronal and immune compartments in the brain.

This comprehensive examination explores AXL's structure, signaling mechanisms, expression patterns, disease associations, and therapeutic potential in neurodegenerative disorders. Understanding the multifaceted roles of AXL provides insights into disease mechanisms and identifies potential therapeutic targets for intervention in progressive neurological conditions.

Gene Structure and Protein Architecture

Genomic Organization

The AXL gene (NCBI Gene ID: 55768, Ensembl ID: ENSG00000167601) is located on chromosome 19q13.2, spanning approximately 50 kilobases of genomic DNA. The gene consists of 20 exons encoding a full-length receptor tyrosine kinase of 1,985 amino acids[@graham2014]. The chromosomal region 19q13.2 contains multiple members of the TAM family cluster, suggesting coordinated regulation.

The AXL promoter contains several transcription factor binding sites including SP1, AP-2, NF-κB, and HIF-1α response elements, enabling regulation by inflammatory cytokines, hypoxia, and growth factors. Polymorphisms in the AXL promoter and coding regions have been associated with modified risk of Alzheimer's disease[@wilson2018].

Protein Domain Structure

The AXL protein (UniProt ID: Q9U6C5, OMIM: 607175) possesses a complex domain architecture enabling its diverse functions:

Extracellular Domain (1-500 amino acids): The N-terminal extracellular region contains two immunoglobulin-like (Ig-like) domains (D1 and D2) and two fibronectin type III (FNIII) domains. The Ig-like domains mediate ligand binding, particularly recognition of Gas6 and Protein S with high affinity[@graham2014]. The FNIII domains contribute to receptor dimerization and stability at the cell membrane.

Transmembrane Domain (501-525 amino acids): A single-pass transmembrane helix anchors the receptor in the lipid bilayer, facilitating proper localization and enabling signal transduction across the membrane.

Cytoplasmic Kinase Domain (526-985 amino acids): The intracellular portion contains the catalytic tyrosine kinase domain responsible for autophosphorylation and downstream signaling. The kinase domain shares structural homology with other TAM family members but exhibits unique regulatory features. Key tyrosine residues (Y779, Y783, Y784, Y821, Y866) serve as phosphorylation sites mediating interaction with adaptor proteins including GRB2, PLCγ, and phosphatidylinositol 3-kinase (PI3K).

Isoforms and Alternative Splicing

Multiple AXL isoforms have been identified through alternative splicing:

Full-length AXL (fl-AXL): The canonical transmembrane receptor (1,985 amino acids) expressed predominantly in immune cells and neurons
Soluble AXL (s-AXL): Generated through proteolytic cleavage (ectodomain shedding) or alternative splicing, containing the extracellular domain without the transmembrane and kinase regions. Soluble AXL can function as a decoy receptor, antagonizing ligand binding to membrane-bound receptor
AXL-ΔK: A variant isoform with truncation in the kinase domain, potentially functioning as a dominant-negative regulator

The balance between membrane-bound and soluble AXL forms influences signaling activity and may be dysregulated in neurodegenerative diseases.

TAM Receptor Family

Family Members and Evolution

The TAM receptor family comprises three related receptor tyrosine kinases: TYRO3, AXL, and MERTK. These receptors share common structural features and ligand recognition patterns, having evolved from a common ancestor with distinct but overlapping functions[@graham2014].

TYRO3 is the founding member, primarily expressed in neurons and oligodendrocytes, regulating synaptic function and myelination.

AXL was discovered as a transforming gene in chronic myeloid leukemia. It is widely expressed in immune cells, endothelial cells, and various tissues, playing roles in cell survival, migration, and innate immunity.

MERTK is predominantly expressed in cells of the myeloid lineage, especially macrophages and microglia, where it mediates phagocytosis.

Shared Ligand System: Gas6 and Protein S

Both Gas6 (Growth Arrest Specific 6) and Protein S serve as shared ligands for all three TAM receptors:

Gas6: Binds all three TAM receptors with highest affinity for TYRO3, intermediate for AXL, and lowest for MERTK[@graham2014]. Gas6 contains an N-terminal gamma-carboxyglutamic acid (Gla) domain that enables calcium-dependent binding to phosphatidylserine.
Protein S: Primarily a cofactor for activated protein C in coagulation, Protein S also functions as a TAM ligand with binding preference for TYRO3 and MERTK.

Signaling Pathways and Molecular Mechanisms

Activation Mechanisms

AXL activation occurs through multiple mechanisms:

Ligand-Dependent Activation: Binding of Gas6 or Protein S to the extracellular domain induces receptor dimerization and autophosphorylation on key tyrosine residues. The Gla domain of these ligands bridges apoptotic cells bearing phosphatidylserine to AXL on phagocytes[@zhou2019].

Ligand-Independent Activation: AXL can also be activated through:

Heterodimerization with other TAM receptors
Interaction with integrins and other cell surface proteins
Mechanical stress
Oxidative modification

Constitutive Activity: Some AXL mutations associated with cancer result in constitutive kinase activity.

Downstream Signaling Cascades

Activated AXL triggers multiple downstream signaling pathways:

PI3K/AKT Pathway: AXL activates PI3K leading to AKT phosphorylation. The PI3K/AKT pathway promotes:

Cell survival through phosphorylation of BAD and caspase-9
Metabolic regulation through mTOR activation
Protein synthesis and cellular growth
Anti-apoptotic gene expression

MAPK/ERK Pathway: Through RAS/RAF/MEK/ERK signaling, AXL regulates:

Cell proliferation and differentiation
Transcriptional activation of immediate-early genes
Cytoskeletal reorganization for migration

JAK/STAT Pathway: AXL can activate STAT proteins, particularly STAT3, leading to:

Expression of anti-inflammatory genes
Regulation of microglial activation states
Modulation of adaptive immune responses

NF-κB Pathway: AXL signaling can modulate NF-κB activity, with complex context-dependent effects:

In resting cells, AXL can suppress pro-inflammatory NF-κB signaling
Upon activation, AXL may contribute to inflammatory gene expression

PLCγ and Calcium Signaling: Phospholipase C gamma (PLCγ) activation leads to:

Inositol trisphosphate (IP3) production
Calcium release from intracellular stores
Calmodulin activation and downstream effects

Immune Regulatory Functions

AXL plays crucial roles in immune regulation:

Phagocytosis: AXL mediates phagocytosis of apoptotic cells through phosphatidylserine recognition[@ko2020].

Anti-Inflammatory Signaling: AXL activation promotes anti-inflammatory (M2-like) microglial phenotype, suppressing production of pro-inflammatory cytokines while enhancing anti-inflammatory mediators.

Immune Cell Activation: AXL modulates activation states of macrophages, dendritic cells, and other immune cells.

Expression Patterns

Central Nervous System Expression

Within the CNS, AXL is expressed in multiple cell types:

Microglial Expression: AXL is expressed in microglia, where it regulates phagocytic activity and inflammatory responses[@kim2019]. Microglial AXL expression is dynamic, increasing in response to injury or disease.

Neuronal Expression: AXL is expressed in neurons throughout the brain, with highest levels in:

Hippocampus (CA1-CA3 regions)
Cerebral cortex
[Cerebellum](/brain-regions/cerebellum)
Substantia nigra (dopaminergic neurons)

Endothelial Expression: AXL is expressed in cerebral endothelial cells, where it contributes to blood-brain barrier integrity[@park2021].

Astrocyte Expression: Lower levels of AXL are expressed in astrocytes.

Peripheral Expression

AXL is expressed in various peripheral tissues:

Immune Cells: High expression in macrophages, dendritic cells, and monocytes
Endothelial Cells: Expression in vascular endothelial cells throughout the body
Reproductive Tissues: Expression in testis and ovary
Lung: Expression in epithelial cells

Disease Associations

Alzheimer's Disease

AXL plays complex and multifaceted roles in Alzheimer's disease pathogenesis[@kim2019]:

Microglial Activation: AXL regulates microglial activation states. In AD, AXL expression is often upregulated in microglia surrounding amyloid plaques, where it may modulate inflammatory responses.

Phagocytosis: AXL-mediated phagocytosis contributes to clearance of amyloid-beta plaques. However, in AD, this function is often impaired, leading to accumulation of pathological aggregates.

Neuroinflammation: AXL signaling modulates neuroinflammation in AD. Resting microglia express AXL that suppresses pro-inflammatory responses; upon activation, AXL expression can be downregulated, shifting microglia toward a pro-inflammatory phenotype.

Neuronal Survival: AXL signaling provides trophic support to neurons, protecting them from various toxic insults.

Genetic Associations: Polymorphisms in the AXL gene have been associated with Alzheimer's disease risk[@wilson2018].

Parkinson's Disease

In Parkinson's disease, AXL is implicated in multiple pathogenic processes[@chen2020]:

Dopaminergic Neuron Survival: AXL signaling provides trophic support to dopaminergic neurons in the substantia nigra. Loss of AXL function may contribute to increased neuronal vulnerability.

Alpha-Synuclein Clearance: Microglial AXL may contribute to clearance of alpha-synuclein aggregates.

Neuroinflammation: Similar to AD, AXL modulates microglial activation in PD.

Mitochondrial Function: AXL may influence mitochondrial function in neurons and glia.

Amyotrophic Lateral Sclerosis (ALS)

AXL is implicated in ALS through several mechanisms[@zhang2021]:

Microglial Activation: In ALS, microglia adopt a primarily pro-inflammatory phenotype. AXL downregulation in microglia may contribute to this shift.

Neuronal Debris Clearance: AXL-mediated phagocytosis is important for clearing debris from dying motor neurons.

Astrocyte Involvement: Reactive astrocytes in ALS may have altered AXL expression.

Cancer

AXL is frequently overexpressed in various cancers and promotes[@linger2010]:

Tumor cell survival
Metastasis
Angiogenesis
Therapy resistance

This has led to development of AXL inhibitors for cancer therapy.

Therapeutic Implications

AXL Inhibitors

Multiple AXL inhibitors are in development for cancer and may have applications in neurodegeneration[@xu2020]:

Bemcentinib (BGB324): Selective AXL inhibitor Cabozantinib: Multi-kinase inhibitor including AXL Merestinib (LY2801653): Multi-kinase inhibitor

In neurodegeneration, AXL inhibitors may:

Reduce neuroinflammation
Modulate microglial activation

AXL Agonists

Activating AXL signaling could provide therapeutic benefits:

Mechanism: Agonists would enhance:

Clearance of pathological protein aggregates
Anti-inflammatory microglial polarization
Neuronal survival signaling

Development Status: Several approaches are explored:

Recombinant Gas6 administration
Small molecule AXL activators
Gene therapy approaches

TAM Receptor Agonists

Gas6 or Protein S mimetics could activate AXL for therapeutic benefit in neurodegeneration[@tang2022].

Research Directions

Unresolved Questions

Several key questions remain:

Cell Type-Specific Effects: What are the differential roles of neuronal versus microglial AXL?

Therapeutic Window: What is the optimal level of AXL activation for therapeutic benefit?

Biomarkers: Can AXL-related measurements predict disease progression?

Emerging Research Areas

Single-Cell Analysis: Single-cell RNA sequencing is revealing cell type-specific AXL expression patterns.

Structural Biology: Crystal structures of AXL domains are enabling rational drug design.

Molecular Mechanisms of Neuroprotection

Anti-Apoptotic Signaling

AXL-mediated neuroprotection operates through multiple anti-apoptotic mechanisms:

BAD Phosphorylation: Activated AXL signals through PI3K/AKT to phosphorylate BAD, preventing it from inhibiting anti-apoptotic BCL-2 proteins. This promotes neuronal survival under conditions of apoptotic stress.

Caspase Inhibition: AXL signaling can inhibit caspase-9 and caspase-3 activation, blocking the apoptotic cascade at key points.

Mitochondrial Protection: AXL helps maintain mitochondrial integrity by promoting BCL-2 expression and inhibiting mitochondrial permeability transition.

Oxidative Stress Response

AXL protects neurons from oxidative stress through:

Antioxidant Gene Expression: AXL/STAT3 signaling promotes expression of antioxidant enzymes including superoxide dismutase (SOD) and catalase.

NADPH Oxidase Regulation: AXL inhibits NADPH oxidase activity in microglia, reducing production of reactive oxygen species (ROS).

Glutathione Regulation: AXL signaling influences glutathione metabolism, enhancing cellular capacity to neutralize ROS.

Protein Homeostasis

AXL plays roles in protein quality control:

Autophagy Regulation: AXL signaling activates autophagy pathways that clear damaged proteins and organelles.

Proteasomal Function: AXL modulates proteasome activity and protein degradation.

Aggregate Clearance: AXL-mediated phagocytosis can clear protein aggregates including amyloid-beta and alpha-synuclein.

Comparative Biology with Other TAM Receptors

Functional Specialization

While sharing ligands and signaling pathways, TAM receptors exhibit functional specialization:

AXL: Intermediate position between TYRO3 and MERTK. Significant expression in both immune cells and neurons. Functions in both phagocytosis and neuronal survival.

TYRO3: Primary role in neuronal survival, synaptic function, and myelination. Highest affinity for Gas6.

MERTK: Primary role in phagocytosis. Highest expression in microglia and macrophages.

Redundancy and Compensation

TAM receptors can compensate for each other:

Developmental Redundancy: During development, loss of one TAM receptor can be partially compensated by others.

Adult Tissue Specificity: In adults, each TAM receptor has more distinct functions.

Disease Context: In disease states, compensation may be insufficient, leading to distinct phenotypes.

Clinical Implications

Diagnostic Applications

AXL as a biomarker:

Soluble AXL: Levels in cerebrospinal fluid (CSF) may reflect microglial activation status.

Gas6: CSF Gas6 levels correlate with disease severity in some neurodegenerative conditions.

Imaging: PET ligands targeting AXL could visualize neuroinflammation.

Therapeutic Targeting

AXL modulators in development:

Agonists: Small molecule AXL agonists are in preclinical development for AD and PD.

Inhibitors: Primarily developed for cancer, may reduce neuroinflammation.

Gene Therapy: AAV-mediated AXL delivery is being explored.

Animal Models

Genetic Knockout Models

AXL knockout mice exhibit:

Increased embryonic lethality
Defective fertility
Impaired immune responses
Increased tumor susceptibility

Disease Models

AXL in animal models of disease:

Alzheimer's Models: AXL overexpression protects against amyloid-beta toxicity in mouse models.

Parkinson's Models: AXL agonists protect dopaminergic neurons in MPTP models.

ALS Models: AXL deficiency accelerates disease progression in SOD1 models.

Future Directions

Research Priorities

Key areas for future research:

Cell-Type Specific Function: Conditional knockout models

Biomarker Development: Validated AXL-based biomarkers

Clinical Translation: Early-phase clinical trials of AXL modulators

Combination Therapies: Synergistic approaches with other targets

Therapeutic Challenges

Challenges to overcome:

Achieving sufficient CNS penetration
Balancing receptor activation to avoid side effects
Patient selection based on AXL expression
Combination with disease-modifying therapies

Conclusion

AXL represents a critical member of the TAM receptor family with complex roles in both immune regulation and neuronal survival. Its dual expression in microglia and neurons positions it as a key modulator of neuroinflammation and neurodegeneration. Understanding the cell-type specific functions and signaling mechanisms of AXL provides insights into disease pathogenesis and identifies potential therapeutic targets for neurodegenerative disorders.

References

[Linger et al., TAM receptor tyrosine kinases as therapeutic targets in cancer (2010)](https://doi.org/10.1016/j.pharmthera.2010.08.001)

[Kim et al., AXL regulates microglial activation in AD (2019)](https://doi.org/10.1186/s13024-019-0329-1)

[Graham et al., The TAM family: phosphatidylserine-sensing receptor tyrosine kinases (2014)](https://doi.org/10.1016/j.cytogfr.2014.03.003)

[Zhou et al., AXL-mediated signaling in microglia (2019)](https://doi.org/10.3389/fncel.2019.00427)

[Chen et al., AXL in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32044168/)

[Zhang et al., AXL in ALS models (2021)](https://pubmed.ncbi.nlm.nih.gov/33581456/)

[Wang et al., Targeting AXL in neurodegenerative diseases (2022)](https://pubmed.ncbi.nlm.nih.gov/35062291/)

[Morant et al., Structure-function analysis of AXL (2021)](https://pubmed.ncbi.nlm.nih.gov/34252318/)

[Shen et al., Gas6/AXL signaling in neural stem cells (2018)](https://pubmed.ncbi.nlm.nih.gov/29872891/)

[Liu et al., AXL as therapeutic target in ALS (2019)](https://pubmed.ncbi.nlm.nih.gov/31241156/)

[Yang et al., AXL in retinal degeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/33068723/)

[Feng et al., AXL deficiency in microglia (2021)](https://pubmed.ncbi.nlm.nih.gov/33985504/)

[Ko et al., AXL-mediated phagocytosis (2020)](https://pubmed.ncbi.nlm.nih.gov/32847921/)

[Park et al., AXL in blood-brain barrier (2021)](https://pubmed.ncbi.nlm.nih.gov/33962093/)

[Xu et al., AXL inhibitors in cancer therapy (2020)](https://pubmed.ncbi.nlm.nih.gov/32669354/)

[Brown et al., TAM receptor-mediated phagocytosis (2019)](https://pubmed.ncbi.nlm.nih.gov/31789376/)

[Tang et al., AXL modulators in neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/35063891/)

[Lewis et al., AXL in synapse elimination (2020)](https://pubmed.ncbi.nlm.nih.gov/32804123/)

[Wilson et al., AXL polymorphisms and AD risk (2018)](https://pubmed.ncbi.nlm.nih.gov/29485219/)

[Liu et al., AXL activation promotes neurogenesis (2021)](https://pubmed.ncbi.nlm.nih.gov/33734456/)

Pathway Diagram

The following diagram shows the key molecular relationships involving AXL - AXL Receptor Tyrosine Kinase discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

AXL

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-axl
kg_node_id	AXL
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-ef6e3ff26570
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-axl'}
_schema_version	1

📊 Evidence Profile Foundational

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Certainty

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Debates

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Outgoing

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0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

AXL - AXL Receptor Tyrosine Kinase

AXL (AXL Receptor Tyrosine Kinase)

Pathway / Interaction Diagram

Introduction

AXL (AXL Receptor Tyrosine Kinase)

Pathway / Interaction Diagram

Introduction

Gene Structure and Protein Architecture

Genomic Organization

Protein Domain Structure

Isoforms and Alternative Splicing

TAM Receptor Family

Family Members and Evolution

Shared Ligand System: Gas6 and Protein S

Signaling Pathways and Molecular Mechanisms

Activation Mechanisms

Downstream Signaling Cascades

Immune Regulatory Functions

Expression Patterns

Central Nervous System Expression

Peripheral Expression

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Cancer

Therapeutic Implications

AXL Inhibitors

AXL Agonists

TAM Receptor Agonists

Research Directions

Unresolved Questions

Emerging Research Areas

See Also

Molecular Mechanisms of Neuroprotection

Anti-Apoptotic Signaling

Oxidative Stress Response

Protein Homeostasis

Comparative Biology with Other TAM Receptors

Functional Specialization

Redundancy and Compensation

Clinical Implications

Diagnostic Applications

Therapeutic Targeting

Animal Models

Genetic Knockout Models

Disease Models

Future Directions

Research Priorities

Therapeutic Challenges

Conclusion

See Also

References

Pathway Diagram

💬 Discussion