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.

Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells

“…4C). Consistent with our previous work [17], this biphasic behavior reflects one of the unique features of lipid-ligand induced AXL activation, and points to changes in AXL localization giving rise to the effect of the Gas6-PS interaction rather than a conformational change due to PS interaction itself. This behavior is schematically presented in Fig.…”

“…AXL-mediated downstream signaling events resulting in cell migration have been heavily studied [12,27,28], but the AXL activation mechanism responsible for this phenotype has been largely unknown. Localized Gas6 that is bound to PS on extracellular vesicles was previously reported to mediate ligand-dependent AXL activation [17], and the present study demonstrates that this lipid-ligand-induced AXL signaling enhances cell motility. Warfarin, clinically used as an anti-coagulant [29], prevents binding of in situ -produced PS and has been shown to have anti-metastatic effects [30,31].…”

“…This localized concentration promotes binding at the low-affinity site Ig2 of ligands already bound at the high-affinity site Ig1. In conjunction with diffusional transport of unoccupied AXL within the plasma membrane to the sites of localized Gas6 presentation, this asymmetric bi-valent binding process leads to enhanced AXL activation [17]. These findings motivated us to explore the phenotypic consequences of this unique PS-dependent mechanism of receptor activation.…”

Axl Receptor Axis: A New Therapeutic Target in Lung Cancer

“…However, only in the presence of PS is Gas6 capable of fully activating Axl. 15 Upon activation, Axl homodimerizes and tyrosine amino acids are auto-phosphorylated at positions 779, 821 and 866. Their phosphorylation creates binding sites for multiple adaptor proteins, including growth factor receptor-bound proten 2 (Grb2) and phospholipase C (PLC), which in turn result in activation of key intracellular pathways responsible for proliferation and survival, such as Ras/MEK/ERK and PI3K/Akt.…”

Inhibition of type I interferon responses by adenovirus serotype-dependent Gas6 binding

“…The γ-carboxylated Gla domain enables interaction with phosphatidylserine on apoptotic cells and enveloped virions, which are believed to serve as a nucleation force that facilitates cellular tyrosine receptors Axl, Tyro3, and Mer (TAM) oligomerization and enhanced downstream signaling (Meyer et al, 2015; Tsou et al, 2014). The Gla domains of other serum proteins have been found to interact with Adenovirus capsid proteins (Alba et al, 2009; Coughlan et al, 2012; Parker et al, 2006; Waddington et al, 2008).…”