|The AXL Receptor is a Sensor of Ligand Spatial Heterogeneity.
|Year of Publication
|Meyer, AS, Zweemer, AJM, Lauffenburger, DA
|2015 Jul 29
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 envisioned design of AXL-targeted therapeutic intervention.
|PubMed Central ID
|DP5 OD019815 / OD / NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States