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An EGFR wild type–EGFRvIII–HB-EGF feed-forward loop regulates the activation of EGFRvIII

Oncogene volume 33, pages 4253–4264 (2014)Cite this article

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Abstract

EGFRvIII is a key oncogene in glioblastoma (GBM). EGFRvIII results from an in-frame deletion in the extracellular domain of EGFR, does not bind ligand and is thought to be constitutively active. Although EGFRvIII dimerization is known to activate EGFRvIII, the factors that drive EGFRvIII dimerization and activation are not well understood. Here we present a new model of EGFRvIII activation and propose that oncogenic activation of EGFRvIII in glioma cells is driven by co-expressed activated EGFR wild type (EGFRwt). Increasing EGFRwt leads to a striking increase in EGFRvIII tyrosine phosphorylation and activation while silencing EGFRwt inhibits EGFRvIII activation. Both the dimerization arm and the kinase activity of EGFRwt are required for EGFRvIII activation. EGFRwt activates EGFRvIII by facilitating EGFRvIII dimerization. We have previously identified HB-EGF, a ligand for EGFRwt, as a gene induced specifically by EGFRvIII. In this study, we show that HB-EGF is induced by EGFRvIII only when EGFRwt is present. Remarkably, altering HB-EGF recapitulates the effect of EGFRwt on EGFRvIII activation. Thus, increasing HB-EGF leads to a striking increase in EGFRvIII tyrosine phosphorylation while silencing HB-EGF attenuates EGFRvIII phosphorylation, suggesting that an EGFRvIII–HB-EGF–EGFRwt feed-forward loop regulates EGFRvIII activation. Silencing EGFRwt or HB-EGF leads to a striking inhibition of EGFRvIII-induced tumorigenicity, while increasing EGFRwt or HB-EGF levels resulted in accelerated EGFRvIII-mediated oncogenicity in an orthotopic mouse model. Furthermore, we demonstrate the existence of this loop in human GBM. Thus, our data demonstrate that oncogenic activation of EGFRvIII in GBM is likely maintained by a continuous EGFRwt–EGFRvIII–HB-EGF loop, potentially an attractive target for therapeutic intervention.

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Acknowledgements

We thank Dr Mien-Chie Hung (MD Anderson Cancer Center) for the EGFRwt-Myc plasmid and Dr James Van Brocklyn (Ohio State University) for GBM9 cells. This work was supported in part by NIH grant RO1NS062080 to AH and by RO1 CA139217 to DAB. SB is supported by grants from the National Institutes of Health (RO1 CA149461), National Aeronautics and Space Administration (NNX13AI13G) and the Cancer Prevention and Research Institute of Texas (RP100644).

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Author notes

  1. L Li and S Chakraborty: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA

    L Li, S Chakraborty, V T Puliyappadamba, A Rehman, A J Jiwani & A A Habib

  2. Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    C-R Yang, D A Boothman & A A Habib

  3. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    K J Hatanpaa & J Raisanen

  4. College of Nursing, University of Texas at Arlington, Arlington, TX, USA

    D J Cipher

  5. Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, TX, USA

    B Mickey & C Madden

  6. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    S Burma & D Saha

  7. Department of Cell Biology, University of Alberta, Edmonton, Canada

    Z Wang

  8. Department of Neurosciences, Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, CA, USA

    S C Pingle & S Kesari

  9. VA North Texas Health Care System, Dallas, TX, USA

    A A Habib

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Correspondence to A A Habib.

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Li, L., Chakraborty, S., Yang, CR. et al. An EGFR wild type–EGFRvIII–HB-EGF feed-forward loop regulates the activation of EGFRvIII. Oncogene 33, 4253–4264 (2014). https://doi.org/10.1038/onc.2013.400

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