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Nat Chem Biol. 2014 Nov;10(11):977-83. doi: 10.1038/nchembio.1636. Epub 2014 Sep 21.

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

Author information

1
Department of Bioengineering, Stanford University, Stanford, California, USA.
2
Department of Radiation Oncology, Stanford University School of Medicine, Stanford University, Stanford, California, USA.
3
Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California, USA.
4
1] Department of Bioengineering, Stanford University, Stanford, California, USA. [2] Department of Chemical Engineering, Stanford University, Stanford, California, USA.

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.

PMID:
25242553
PMCID:
PMC4372605
DOI:
10.1038/nchembio.1636
[Indexed for MEDLINE]
Free PMC Article

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