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

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.
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [2] ;  [4]
  1. Stanford Univ., CA (United States). Dept. of Bioengineering
  2. Stanford Univ., CA (United States). Stanford University School of Medicine, Dept. of Radiation Oncology
  3. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
  4. Stanford Univ., CA (United States). Dept. of Bioengineering; Stanford Univ., CA (United States). Dept. of Chemical Engineering
Publication Date:
OSTI Identifier:
1293893
Grant/Contract Number:
NIH CA-088480; NIH CA-67166; T32 GM008412-15S1
Type:
Accepted Manuscript
Journal Name:
Nature Chemical Biology
Additional Journal Information:
Journal Volume: 10; Journal Issue: 11; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Research Org:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES Cancer therapy; Cell signalling; Combinatorial libraries; Kinases