Newman, J.P., Wang, G.Y., Arima, K. et al. Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme. Nat Commun 8, 1913 (2017). https://doi.org/10.1038/s41467-017-01392-9
Abstract:
The interleukin-13 receptor alpha2 (IL-13Rα2) is a cancer-associated receptor overexpressed in human glioblastoma multiforme (GBM). This receptor is undetectable in normal brain which makes it a highly suitable target for diagnostic and therapeutic purposes. However, the pathological role of this receptor in GBM remains to be established. Here we report that IL-13Rα2 alone induces invasiveness of human GBM cells without affecting their proliferation. In contrast, in the presence of the mutant EGFR (EGFRvIII), IL-13Rα2 promotes GBM cell proliferation in vitro and in vivo. Mechanistically, the cytoplasmic domain of IL-13Rα2 specifically binds to EGFRvIII, and this binding upregulates the tyrosine kinase activity of EGFRvIII and activates the RAS/RAF/MEK/ERK and STAT3 pathways. Our findings support the “To Go or To Grow” hypothesis whereby IL-13Rα2 serves as a molecular switch from invasion to proliferation, and suggest that targeting both receptors with STAT3 signaling inhibitor might be a therapeutic approach for the treatment of GBM.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This project was funded by grants from A*Star (07/1/31/19/547), Singhealth Grant Foundation, and institutional center grant from the National Medical Research Council of Singapore awarded to P.Y.P.L. This work was also supported by grant from the National Institute of Health R01AI093718 awarded to T.K. and in part, by a grant awarded to Amyn A Habib from the Department of Veteran’s Affairs (I01BX002559).