An EGFR wild type-EGFRvIII-HB-EGF feed-forward loop regulates the activation of EGFRvIII.
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.
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Li
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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S
Chakraborty
Simmons Comprehensive Cancer Center, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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CR
Yang
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
K J
KJ
Hatanpaa
College of Nursing, University of Texas at Arlington, Arlington, TX, USA.
D J
DJ
Cipher
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
V T
VT
Puliyappadamba
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
A
A
Rehman
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
A J
AJ
Jiwani
Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
B
B
Mickey
Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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C
Madden
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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J
Raisanen
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
S
S
Burma
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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D
Saha
Department of Cell Biology, University of Alberta, Edmonton, Canada.
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Z
Wang
Department of Neurosciences, Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, CA, USA.
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SC
Pingle
Department of Neurosciences, Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, CA, USA.
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S
Kesari
Simmons Comprehensive Cancer Center, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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DA
Boothman
1] Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Simmons Comprehensive Cancer Center, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA [3] VA North Texas Health Care System, Dallas, TX, USA.
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Habib
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D015533:Transcriptional Activation
C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors