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[1]. 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)[2]. 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.
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[1:1]. 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[3].
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[1:2]. 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).
Multiple AXL isoforms have been identified through alternative splicing:
The balance between membrane-bound and soluble AXL forms influences signaling activity and may be dysregulated in neurodegenerative diseases.
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[1:3].
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.
Both Gas6 (Growth Arrest Specific 6) and Protein S serve as shared ligands for all three TAM receptors:
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[4].
Ligand-Independent Activation: AXL can also be activated through:
Constitutive Activity: Some AXL mutations associated with cancer result in constitutive kinase activity.
Activated AXL triggers multiple downstream signaling pathways:
PI3K/AKT Pathway: AXL activates PI3K leading to AKT phosphorylation. The PI3K/AKT pathway promotes:
MAPK/ERK Pathway: Through RAS/RAF/MEK/ERK signaling, AXL regulates:
JAK/STAT Pathway: AXL can activate STAT proteins, particularly STAT3, leading to:
NF-κB Pathway: AXL signaling can modulate NF-κB activity, with complex context-dependent effects:
PLCγ and Calcium Signaling: Phospholipase C gamma (PLCγ) activation leads to:
AXL plays crucial roles in immune regulation:
Phagocytosis: AXL mediates phagocytosis of apoptotic cells through phosphatidylserine recognition[5].
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.
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[2:1]. 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:
Endothelial Expression: AXL is expressed in cerebral endothelial cells, where it contributes to blood-brain barrier integrity[6].
Astrocyte Expression: Lower levels of AXL are expressed in astrocytes.
AXL is expressed in various peripheral tissues:
AXL plays complex and multifaceted roles in Alzheimer's disease pathogenesis[2:2]:
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[3:1].
In Parkinson's disease, AXL is implicated in multiple pathogenic processes[7]:
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.
AXL is implicated in ALS through several mechanisms[8]:
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.
AXL is frequently overexpressed in various cancers and promotes[9]:
This has led to development of AXL inhibitors for cancer therapy.
Multiple AXL inhibitors are in development for cancer and may have applications in neurodegeneration[10]:
Bemcentinib (BGB324): Selective AXL inhibitor
Cabozantinib: Multi-kinase inhibitor including AXL
Merestinib (LY2801653): Multi-kinase inhibitor
In neurodegeneration, AXL inhibitors may:
Activating AXL signaling could provide therapeutic benefits:
Mechanism: Agonists would enhance:
Development Status: Several approaches are explored:
Gas6 or Protein S mimetics could activate AXL for therapeutic benefit in neurodegeneration[11].
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?
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.
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.
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.
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.
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.
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.
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.
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.
AXL knockout mice exhibit:
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.
Key areas for future research:
Challenges to overcome:
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.
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