Stanford University2014-11-18 3:40 PM

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

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 .



Full Article:

http://www.nature.com/nchembio/journal/v10/n11/full/nchembio.1636.html

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