PMID- 21775422 OWN - NLM STAT- MEDLINE DCOM- 20120112 LR - 20211020 IS - 1557-3125 (Electronic) IS - 1541-7786 (Print) IS - 1541-7786 (Linking) VI - 9 IP - 9 DP - 2011 Sep TI - Forced dimerization increases the activity of DeltaEGFR/EGFRvIII and enhances its oncogenicity. PG - 1199-208 LID - 10.1158/1541-7786.MCR-11-0229 [doi] AB - Delta epidermal growth factor receptor (DeltaEGFR), 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 DeltaEGFR 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 DeltaEGFR 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 DeltaEGFR that allows forced dimerization via domains derived from variants of the FKBP12 protein that are brought together by FK506 derivatives. Forced dimerization of chimeric DeltaEGFR significantly increased the intensity of its signal, as measured by receptor phosphorylation levels, suggesting that the naturally occurring DeltaEGFR does not form strong or stable dimers as part of its low level signal. Interestingly, the increased activity of dimerized, chimeric DeltaEGFR did not promote receptor internalization, implying that reduced rate of endocytic downregulation of DeltaEGFR is an inherent characteristic. Significantly, forced dimerization enhanced the oncogenic signal of the receptor, implying that the DeltaEGFR is a potent oncogene despite, not because of its low intensity. CI - (c)2011 AACR. FAU - Hwang, Yeohyeon AU - Hwang Y AD - Department of Neurosurgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. FAU - Chumbalkar, Vaibhav AU - Chumbalkar V FAU - Latha, Khatri AU - Latha K FAU - Bogler, Oliver AU - Bogler O LA - eng GR - R01 CA108500/CA/NCI NIH HHS/United States GR - R01CA108500/CA/NCI NIH HHS/United States GR - CA016672/CA/NCI NIH HHS/United States GR - P50CA127001/CA/NCI NIH HHS/United States GR - P30 CA016672-36/CA/NCI NIH HHS/United States GR - P50 CA127001-04/CA/NCI NIH HHS/United States GR - P30 CA016672/CA/NCI NIH HHS/United States GR - R01 CA108500-06/CA/NCI NIH HHS/United States GR - P50 CA127001/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20110720 PL - United States TA - Mol Cancer Res JT - Molecular cancer research : MCR JID - 101150042 RN - 0 (Recombinant Fusion Proteins) RN - 0 (epidermal growth factor receptor VIII) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 5.2.1.- (Tacrolimus Binding Protein 1A) SB - IM MH - Animals MH - Cell Line, Tumor MH - ErbB Receptors/genetics/*metabolism MH - Gene Expression Regulation, Neoplastic MH - Glioma/genetics/*metabolism MH - Humans MH - Mice MH - Mice, Nude MH - Phosphorylation MH - Protein Multimerization MH - Protein Structure, Tertiary MH - Recombinant Fusion Proteins/genetics/metabolism MH - Sequence Deletion MH - Signal Transduction MH - Tacrolimus Binding Protein 1A/metabolism MH - Transcriptional Activation MH - Wound Healing PMC - PMC3175255 MID - NIHMS313774 COIS- Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed. EDAT- 2011/07/22 06:00 MHDA- 2012/01/13 06:00 PMCR- 2012/09/01 CRDT- 2011/07/22 06:00 PHST- 2011/07/22 06:00 [entrez] PHST- 2011/07/22 06:00 [pubmed] PHST- 2012/01/13 06:00 [medline] PHST- 2012/09/01 00:00 [pmc-release] AID - 1541-7786.MCR-11-0229 [pii] AID - 10.1158/1541-7786.MCR-11-0229 [doi] PST - ppublish SO - Mol Cancer Res. 2011 Sep;9(9):1199-208. doi: 10.1158/1541-7786.MCR-11-0229. Epub 2011 Jul 20.