Altered subcellular location of an activated and tumour-associated epidermal growth factor receptor

A. J. Ekstrand*, L. Liu, J. He, M. L. Hamid, N. Longo, V. P. Collins, C. D. James

*Corresponding author for this work

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

The epidermal growth factor (EGF) receptor is a membrane bound tyrosine kinase whose activity is initiated by ligand binding. The malignant brain tumour glioblastoma frequently shows amplification and rearrangements of the EGF receptor gene that are associated with the synthesis of a constitutively activated tyrosine kinase, lacking amino acids 6-273 near the protein's N-terminus. When expressed in Chinese hamster ovary (CHO) cells, this mutant receptor (p140(EGFR)) displays ligand-independent tyrosine kinase activity, stimulates DNA synthesis, and promotes cell proliferation. Here, we investigate the subcellular location of p140(EGFR) in CHO cell transfectants as well as in human glioblastoma tumours, p140(EGFR) had an intracellular location that contrasted sharply with the plasma membrane location of the wild-type EGF receptor. Endoglycosidase H sensitivity analysis and the pattern of p140(EGFR) inmunoreactivity suggested that the aberrant tyrosine kinase resided primarily in the endoplasmic reticulum. The half-life of p140(EGFR) in the endoplasmic reticulum was extended several-fold over that of the ligand-activated wild-type receptor. The altered subcellular location of p140(EGFR) in combination with its prolonged half-life suggest that this activated tyrosine kinase may escape the regulatory mechanisms utilized for the attenuation of wild-type receptor signaling. Therefore, the previously reported growth stimulatory property of the ligand-independent p140(EGFR) may be attributed to a sustained tyrosine kinase activity resulting from an altered subcellular location.

Original languageEnglish (US)
Pages (from-to)1455-1460
Number of pages6
JournalOncogene
Volume10
Issue number7
StatePublished - Jan 1 1995

Keywords

  • Confocal microscopy
  • EGF binding
  • Endoplasmic reticulum
  • Glio blastoma
  • Oncogene
  • Tyrosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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