Engineered AXL‑ECD‑Fc variants that abolish the AXL/Gas6 interaction suppress tumor cell migration

  • Authors:
    • Yanting Duan
    • Bo Hu
    • Chunxia Qiao
    • Longlong Luo
    • Xinying Li
    • Jing Wang
    • Hao Liu
    • Tingting Zhou
    • Beifen Shen
    • Ming Lv
    • Jiannan Feng
  • View Affiliations

  • Published online on: April 15, 2019     https://doi.org/10.3892/ol.2019.10255
  • Pages: 5784-5792
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Abstract

AXL receptor tyrosine kinase ligand (AXL), a tyrosine kinase receptor that is commonly overexpressed in numerous types of cancer, significantly promotes drug resistance and metastasis in tumor cells. Inhibition of the AXL/growth arrest‑specific 6 (Gas6) signaling pathway is emerging as a potential anticancer therapeutic strategy. In the present study, on the basis of the three‑dimensional complex structure of AXL/Gas6, the critical residues (E56, E59 and T77) in AXL binding to Gas6 were determined using computer graphics analysis and the distance geometry method. Subsequently, four‑variant AXL‑ECD‑Fc‑M1 (G32S, D87G, V92A and G127R) and AXL‑ECD‑Fc‑M2 (G32A, D87A, V92A and G127A) were predicted as high‑affinity mutants; AXL‑ECD‑Fc‑M3 (E56R and T77R) and AXL‑ECD‑Fc‑M4 (E59R and T77R) were predicted as low‑affinity mutants. The results of the present study revealed that the half‑maximal effect concentrations of AXL‑ECD‑Fc‑M1 and AXL‑ECD‑Fc‑M2 were ~0.141 and 0.375 µg/ml, respectively, whereas that of the wild‑type protein (AXL‑ECD‑Fc‑WT) was 0.514 µg/ml. Furthermore, adding the high‑affinity mutants into culture medium to capture free Gas6 significantly inhibited AXL/Gas6 binding and thus blocked the downstream signaling pathway. In addition, the high‑affinity mutants effectively suppressed the migration and metastasis of SKOV3 and A549 cells. Conversely, compared with AXL‑ECD‑Fc‑WT, the low‑affinity AXL mutants AXL‑ECD‑Fc‑M3 and AXL‑ECD‑Fc‑M4 lost all inhibitory activities. These findings highlight AXL as a potential therapeutic target and demonstrated that the key residues E56, E59 and T77 may be crucial sites for abolishing the activity of the AXL/Gas6 pathway in cancer therapy.
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June 2019
Volume 17 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

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APA
Duan, Y., Hu, B., Qiao, C., Luo, L., Li, X., Wang, J. ... Feng, J. (2019). Engineered AXL‑ECD‑Fc variants that abolish the AXL/Gas6 interaction suppress tumor cell migration. Oncology Letters, 17, 5784-5792. https://doi.org/10.3892/ol.2019.10255
MLA
Duan, Y., Hu, B., Qiao, C., Luo, L., Li, X., Wang, J., Liu, H., Zhou, T., Shen, B., Lv, M., Feng, J."Engineered AXL‑ECD‑Fc variants that abolish the AXL/Gas6 interaction suppress tumor cell migration". Oncology Letters 17.6 (2019): 5784-5792.
Chicago
Duan, Y., Hu, B., Qiao, C., Luo, L., Li, X., Wang, J., Liu, H., Zhou, T., Shen, B., Lv, M., Feng, J."Engineered AXL‑ECD‑Fc variants that abolish the AXL/Gas6 interaction suppress tumor cell migration". Oncology Letters 17, no. 6 (2019): 5784-5792. https://doi.org/10.3892/ol.2019.10255