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 .