The AXL Receptor Is a Sensor of Ligand Spatial Heterogeneity

The AXL receptor is a TAM (Tyro3, AXL, MerTK) receptor tyrosine kinase (RTK) important in physiological inflammatory processes such as blood clotting, viral infection, and innate immune-mediated cell clearance. Overexpression of the receptor in a number of solid tumors is increasingly appreciated as a key drug resistance and tumor dissemination mechanism. Although the ligand-receptor (Gas6-AXL) complex structure is known, literature reports on ligand-mediated signaling have provided conflicting conclusions regarding the influence of other factors such as phosphatidylserine binding, and a detailed, mechanistic picture of AXL activation has not emerged. Integrating quantitative experiments with mathematical modeling, we show here that AXL operates to sense local spatial heterogeneity in ligand concentration, a feature consistent with its physiological role in inflammatory cell responses. This effect arises as a result of an intricate reaction-diffusion interaction. Our results demonstrate that AXL functions distinctly from other RTK families, a vital insight for the envisioned design of AXL-targeted therapeutic intervention. [Display omitted] •The dynamics of AXL receptor activation are distinct from those of other RTK families•Spatially heterogeneous presentation of the ligand Gas6 leads to enhanced AXL response•Localization and activation of AXL can arise from Gas6/phosphatidylserine interactions•A diffusion-reaction model can account for the influence of phosphatidylserine Meyer et al. show that complex responses of the AXL receptor to phosphatidylserine and ligand result from asymmetry in receptor-ligand binding affinity and relocalization of receptors driven by local spatial heterogeneity in ligand concentration.