Cancer Genes and Genomics Forced Dimerization Increases the Activity of DEGFR/EGFRvIII and Enhances Its Oncogenicity

Delta epidermal growth factor receptor (DEGFR), an in-frame deletion mutant of the extracellular ligandbinding domain, which occurs in about 30% of glioblastoma, is a potent oncogene that promotes tumor growth and progression. The signaling of DEGFR 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 DEGFR 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 DEGFR that allows forced dimerization via domains derived from variants of the FKBP12 protein that are brought together by FK506 derivatives. Forced dimerization of chimeric DEGFR significantly increased the intensity of its signal, as measured by receptor phosphorylation levels, suggesting that the naturally occurring DEGFR does not form strong or stable dimers as part of its low level signal. Interestingly, the increased activity of dimerized, chimeric DEGFR did not promote receptor internalization, implying that reduced rate of endocytic downregulation of DEGFR is an inherent characteristic. Significantly, forced dimerization enhanced the oncogenic signal of the receptor, implying that the DEGFR is a potent oncogene despite, not because of its low intensity. Mol Cancer Res; 9(9); 1–10. 2011 AACR.