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

Kariolis, Mihalis S.; Miao, Yu Rebecca; Jones, Douglas S.; Kapur, Shiven; Mathews, Irimpan I.; Giaccia, Amato J.; Cochran, Jennifer R.

doi:10.1038/nchembio.1636

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

Journal Article · Sun Sep 21 00:00:00 EDT 2014 · Nature Chemical Biology

DOI:https://doi.org/10.1038/nchembio.1636· OSTI ID:1293893

Kariolis, Mihalis S. ^[1]; Miao, Yu Rebecca ^[2]; Jones, Douglas S. ^[1]; Kapur, Shiven ^[1]; Mathews, Irimpan I. ^[3]; Giaccia, Amato J. ^[2]; Cochran, Jennifer R. ^[4]

Stanford Univ., CA (United States). Dept. of Bioengineering
Stanford Univ., CA (United States). Stanford University School of Medicine, Dept. of Radiation Oncology
SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Stanford Univ., CA (United States). Dept. of Bioengineering; Stanford Univ., CA (United States). Dept. of Chemical Engineering

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 to Gas6 with femtomolar affinity, an 80-fold improvement compared to the wild-type Axl receptor, allowing effective sequestration of Gas6 and specific abrogation of Axl signaling. Additionally, increased Gas6 binding affinity was critical and correlative with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: NIH CA-088480; NIH CA-67166; T32 GM008412-15S1

OSTI ID:: 1293893

Journal Information:: Nature Chemical Biology, Vol. 10, Issue 11; ISSN 1552-4450

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 96 works

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