title: Forced dimerization increases the activity of ΔEGFR/EGFRvIII and enhances its oncogenicity.
abstract: Delta epidermal growth factor receptor (ΔEGFR), an in-frame deletion mutant of the extracellular ligand-binding domain, which occurs in about 30% of glioblastoma, is a potent oncogene that promotes tumor growth and progression. The signaling of ΔEGFR is ligand-independent and low intensity, allowing it to evade the normal mechanisms of internalization and degradation by the endocytic machinery and hence is persistent. The basis of the oncogenic potential of ΔEGFR remains incompletely understood, including whether dimerization plays an important role in its signal and whether its oncogenic potential is dependent on its relatively low intensity, when compared with the acutely activated wild-type receptor. To examine these two important questions, we have generated a chimeric ΔEGFR that allows forced dimerization via domains derived from variants of the FKBP12 protein that are brought together by FK506 derivatives. Forced dimerization of chimeric ΔEGFR significantly increased the intensity of its signal, as measured by receptor phosphorylation levels, suggesting that the naturally occurring ΔEGFR does not form strong or stable dimers as part of its low level signal. Interestingly, the increased activity of dimerized, chimeric ΔEGFR did not promote receptor internalization, implying that reduced rate of endocytic downregulation of ΔEGFR is an inherent characteristic. Significantly, forced dimerization enhanced the oncogenic signal of the receptor, implying that the ΔEGFR is a potent oncogene despite, not because of its low intensity.
authors.affiliation: Department of Neurosurgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Yeohyeon
authors.initials: Y
authors.lastname: Hwang
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Chumbalkar
authors.forename: Khatri
authors.initials: K
authors.lastname: Latha
authors.forename: Oliver
authors.initials: O
authors.lastname: Bogler
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D015533:Transcriptional Activation; D014945:Wound Healing
chemical_list: D011993:Recombinant Fusion Proteins; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D022061:Tacrolimus Binding Protein 1A