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An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis.

Kariolis MS, Miao YR, Jones DS, Kapur S, Mathews II, Giaccia AJ, Cochran JR
Nat Chem Biol 10 977-83 (2014)
Cited: 78 times
EuropePMC logo PMID: 25242553

Abstract

Aberrant signaling through the Axl receptor tyrosine kinase has been associated with a myriad of human diseases, most notably metastatic cancer, identifying Axl and its ligand Gas6 as important therapeutic targets. Using rational and combinatorial approaches, we engineered an Axl 'decoy receptor' that binds Gas6 with high affinity and inhibits its function, offering an alternative approach from drug discovery efforts that directly target Axl. Four mutations within this high-affinity Axl variant caused structural alterations in side chains across the Gas6-Axl binding interface, stabilizing a conformational change on Gas6. When reformatted as an Fc fusion, the engineered decoy receptor bound Gas6 with femtomolar affinity, an 80-fold improvement compared to binding of the wild-type Axl receptor, allowing effective sequestration of Gas6 and specific abrogation of Axl signaling. Moreover, increased Gas6 binding affinity was critical and correlative with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo.

Articles - 4ra0 mentioned but not cited (2)

  1. Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. Kariolis MS, Miao YR, Diep A, Nash SE, Olcina MM, Jiang D, Jones DS, Kapur S, Mathews II, Koong AC, Rankin EB, Cochran JR, Giaccia AJ. J Clin Invest 127 183-198 (2017)
  2. Letter Prediction analysis of porcine AXL protein as a potential receptor for SARS-CoV-2. Zeng C, Ye Z, Fu L, Ye Y. J Infect 84 579-613 (2022)


Reviews citing this publication (38)

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