The AXL Receptor Is a Sensor of Ligand Spatial Heterogeneity

• Main Authors: Meyer, Aaron Samuel (Contributor), Zweemer, Jacomina M. (Contributor), Lauffenburger, Douglas A (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2017-02-15T21:31:26Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Institutes of Health (U.S.) (Grants U54-CA112967 and DP5-OD019815)
United States. Army Research Office (Institute for Collaborative Biotechnologies. Grant W911NF-09-0001)
National Cancer Institute (David H. Koch Institute for Integrative Cancer Research at MIT. Core Support Grant P30-CA14051)