title: The AXL Receptor is a Sensor of Ligand Spatial Heterogeneity.
abstract: 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.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge MA 02139 ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge MA 02139.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Meyer
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge MA 02139 ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge MA 02139.
authors.forename: Annelien J M
authors.initials: AJ
authors.lastname: Zweemer
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge MA 02139 ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge MA 02139.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger