Fig. 1

Structure and activation mechanisms of the TYRO3, AXL, and MERTK (TAM) receptors. a The TAM receptors and ligands share closely related structures. The structure of growth arrest-specific protein 6 (GAS6) and vitamin K-dependent protein S (PROS1) comprises a γ-carboxyglutamic acid (GLA) domain, a loop region, four epidermal growth factor-like (EGF-like) repeats, and two C-terminal globular laminin G-like (LG) domains. TAM receptors consist of two immunoglobulin-like (Ig) domains, two fibronectin III (FNIII) repeat domains, and a kinase domain. GAS6 binds to all three receptors, while PROS1 binds to MERTK and TYRO3, but not to AXL. The decreasing width of the arrows indicates a reduction in receptor activation strength by the ligands, reflecting their relative affinities. b Ligand-Dependent Activation: Binding of GAS6 to AXL leads to receptor activation. Optimal activation requires PtdSer (phosphatidylserine) on the opposed cell membrane, which binds to the GLA domain of the ligand. c Ligand-Independent Activation: Various factors in the tumor microenvironment can activate AXL in a ligand-independent manner. d Homophilic Interaction: Activation can occur through interaction between AXL monomers on neighboring cells. e Heterophilic Activation: AXL can also be activated heterophilically with non-TAM receptors. Activation of AXL through these mechanisms results in autophosphorylation of intracellular tyrosine residues, initiating signaling pathways that promote tumor proliferation, invasion, migration, angiogenesis, drug resistance, and immune evasion