TAM receptor signaling refers to signaling through the receptor tyrosine kinases TYRO3, AXL, and MERTK (also written as MER) and their canonical ligands GAS6 (growth arrest-specific 6) and PROS1 (protein S). This signaling system represents a critical regulator of innate immunity, phagocytosis, and tissue homeostasis in the nervous system. In the brain, TAM signaling helps regulate microglial phagocytosis, inflammatory tone, glial homeostasis, and neural stem cell survival and differentiation [1][2].
TYRO3 was the first TAM receptor discovered and is expressed predominantly in the nervous system and reproductive tissues. In the brain, TYRO3 is expressed on neurons, astrocytes, and oligodendrocyte precursor cells. TYRO3 signaling promotes cell survival and regulates synaptic function. Mutations in TYRO3 are associated with rare developmental disorders [3][4].
AXL (also known as TYRO3) is the most widely studied TAM receptor in the context of disease. It is highly expressed on microglia and macrophages, where it mediates phagocytosis of apoptotic cells and cellular debris. AXL is often upregulated in response to injury and inflammation, making it a biomarker for immune activation. Soluble AXL (sAXL) can be detected in cerebrospinal fluid and serves as a disease biomarker [5][6].
MERTK is the central phagocytic receptor for apoptotic cell clearance in the brain. Unlike AXL, which is inducible, MERTK is constitutively expressed on microglia and is essential for efficient phagocytosis of apoptotic neurons and debris. Mutations in MERTK cause retinal degeneration and phagocytic defects in mice and humans. MERTK polymorphisms are associated with increased risk for neurodegenerative diseases [7][8].
Growth arrest-specific 6 (GAS6) is the founding TAM ligand, originally identified as a gene upregulated during cellular senescence. GAS6 is expressed in neurons, astrocytes, and endothelial cells. It functions as a soluble bridge molecule, binding to phosphatidylserine on apoptotic cells via its Gla domain and simultaneously engaging TAM receptors on phagocytes. GAS6 has multiple domains including an LG domain that mediates receptor binding [9][10].
Protein S (PROS1) is best known as a cofactor for anticoagulation, but it also functions as a TAM ligand. Like GAS6, PROS1 binds to phosphatidylserine on apoptotic cells and engages TAM receptors. The relative contributions of GAS6 and PROS1 vary by tissue and context. In the brain, both ligands can support microglial phagocytosis [11][12].
TAM receptors are activated through two main mechanisms: ligand-dependent autophosphorylation and ligand-independent transactivation. Binding of GAS6 or PROS1 induces receptor dimerization and autophosphorylation of tyrosine residues in the cytoplasmic domain. This creates docking sites for downstream signaling proteins containing SH2 domains [13][14].
TAM signaling is subject to negative regulation through multiple mechanisms. Protein tyrosine phosphatases (PTPs) dephosphorylate activated receptors. Suppressors of cytokine signaling (SOCS) proteins inhibit signaling through ubiquitination and degradation. Soluble receptor domains (sTYRO3, sAXL, sMERTK) can act as decoys [15][16].
The primary function of TAM receptors in the brain is to mediate microglial phagocytosis. MERTK is essential for the engulfment of apoptotic neurons, while AXL contributes to debris clearance. Impaired TAM signaling leads to accumulation of apoptotic cells and cellular debris, which can trigger chronic inflammation. This is particularly relevant in neurodegenerative diseases where inefficient clearance contributes to pathology [17][18].
TAM signaling acts as a brake on excessive innate immune activation. GAS6/TAM signaling negatively regulates inflammatory induction of cytokines including GM-CSF, TNF-α, and IL-1β. This anti-inflammatory function is mediated in part through inhibition of NF-κB signaling and promotion of anti-inflammatory cytokine production. Dysregulation of this brake contributes to chronic19][19].
TAM receptors cooperate with TREM2 (triggering receptor expressed on myeloid cells 2) in regulating microglial function. Both pathways are involved in phagocytosis and inflammatory responses. TREM2 variants are major risk factors for Alzheimer's disease, and there is evidence for functional interactions between these two microglial receptor systems [20][21].
In AD, TAM receptor expression is altered in response to amyloid pathology. AXL is upregulated in AD brain and in mouse models of amyloid deposition. GAS6 levels are reduced in AD cerebrospinal fluid, potentially reflecting increased consumption or reduced production. MERTK expression on microglia is reduced in AD, which may contribute to impaired phagocytosis of amyloid plaques and apoptotic cells. Targeting TAM signaling has been proposed as a therapeutic strategy [22][23].
In MS and its animal model EAE, TAM signaling modulates disease severity. GAS6 deficiency worsens clinical scores, while exogenous GAS6 ameliorates disease. The mechanism involves regulation of microglial activation and phagocytic clearance of myelin debris. TAM receptors may also affect remyelination by regulating oligodendrocyte precursor cell function [24][25].
In ALS, TAM receptors are expressed in microglia and astrocytes. Changes in TAM signaling may contribute to the neuroinflammatory environment that surrounds motor neurons. MERTK polymorphisms have been associated with ALS risk in some populations. The role of TAM signaling in ALS is an area of active investigation [26][27].
PD involves progressive loss of dopaminergic neurons in the substantia nigra. Microglial TAM signaling may affect the inflammatory environment surrounding vulnerable neurons. AXL has been detected in microglia in PD brain, and changes in soluble AXL have been reported. The contribution of TAM signaling to PD pathogenesis remains to be fully elucidated [28][29].
TAM receptors play crucial roles in nervous system development:
TREM2 and TAM cooperate in microglia:
TAM receptor signaling (TYRO3, AXL, MERTK) and their ligands (GAS6, PROS1) form a critical regulatory system for neuroinflammation and phagocytosis in the brain. These receptors are essential for microglial clearance of apoptotic cells and debris, and they modulate inflammatory tone through negative regulation of cytokine production. Dysregulated TAM signaling contributes to the pathogenesis of Alzheimer's disease, multiple sclerosis, ALS, and Parkinson's disease. Therapeutic targeting of TAM pathways offers potential for modulating neuroinflammation and enhancing debris clearance in neurodegenerative conditions.
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