Activity and cellular localization of an oncogenic glioblastoma multiforme-associated EGF receptor mutant possessing a duplicated kinase domain.

Oncogene
B H OzerP J Bertics

Abstract

A mutation of the epidermal growth factor receptor (EGFR) that results in a tandem kinase domain duplication (TKD-EGFR) has been described in glioblastoma multiforme biopsies and cell lines. Although the TKD-EGFR confers tumorigenicity, little is known about the molecular underpinnings of receptor dysregulation. Therefore, we transfected B82L mouse fibroblast cells devoid of endogenous EGFR to determine the molecular mechanisms of receptor activation when expressed in cells as well as the contribution of each duplicated kinase domain to receptor phosphorylation. The TKD-EGFR displayed chronically elevated basal autophosphorylation at five known phosphotyrosine sites. The chronically phosphorylated TKD-EGFR was also resistant to competitive inhibition of ligand-binding compared with wild-type EGFR (WT-EGFR) and showed undetectable levels of basal dimerization, suggesting the TKD-EGFR escapes known mechanisms of receptor downregulation. Immunofluorescence analyses revealed a substantial portion of the TKD-EGFR resides in the cytosol in an activated state, although surface-localized subsets of the receptor retain ligand responsiveness. Kinase activity-deficient knockouts of the N-terminal or the C-terminal kinase domains generated...Continue Reading

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Citations

Sep 24, 2015·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Christina S BaikColin C Pritchard
Nov 29, 2014·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Shaoyi LiYunhui Liu
Apr 29, 2014·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Jin ChenFeng Wang
Feb 22, 2014·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Shaoyi LiYunhui Liu
Jul 19, 2012·Biochemistry. Biokhimii︠a︡·O L PolanovskiS M Deyev
Dec 18, 2010·Oncotarget·Zhenfeng ZhangBalazs Halmos
Jul 22, 2020·Annual Review of Cell and Developmental Biology·Aneta Koseska, Philippe I H Bastiaens
May 5, 2021·Cancer Research and Treatment : Official Journal of Korean Cancer Association·Chaelin LeeDae Seog Heo

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Methods Mentioned

BETA
biopsy
transfection
transfections
biopsies

Software Mentioned

Nikon Elements

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