PMID- 9210410 OWN - NLM STAT- MEDLINE DCOM- 19970728 LR - 20220225 IS - 0264-6021 (Print) IS - 1470-8728 (Electronic) IS - 0264-6021 (Linking) VI - 324 ( Pt 3) IP - Pt 3 DP - 1997 Jun 15 TI - Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). PG - 855-61 AB - The type-III deletion variant of the epidermal growth factor receptor (EGFRvIII) is frequently found in glioblastomas and other malignant human tumours. Although EGFRvIII confers ligand-independent oncogenic transformation of cell lines, the mechanism by which it promotes aberrant cellular proliferation is unknown. Using cell lines expressing comparable numbers of either wild-type receptor (EGFRwt) or EGFRvIII, we compared several parameters of receptor activation: dimerization, tyrosine phosphorylation and activation of intracellular signalling proteins. Like activated EGFRwt, EGFRvIII was phosphorylated and bound constitutively to the Shc adapter protein. Indeed, EGFRvIII-associated Shc had a higher phosphotyrosine content than Shc associated with stimulated EGFRwt. EGFRwt dimerized in response to either EGF or transforming growth factor alpha. Higher cross-linker concentrations and incubation at higher temperatures (37 degrees C) allowed detection of EGFRwt dimers even in the absence of exogenous ligand. In contrast, EGFRvIII failed to dimerize under any conditions studied. Moreover, neither mitogen-activated protein kinase nor phospholipase Cgamma were phosphorylated in EGFRvIII-expressing cells. We conclude that the deletion of 267 amino acids from the 621-amino-acid N-terminal domain of EGFR does not result simply in a constitutively activated receptor, but alters the spectrum of signalling cascades utilized. Furthermore the ligand-independent transforming activity of EGFRvIII is independent of receptor dimerization. FAU - Chu, C T AU - Chu CT AD - Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA. FAU - Everiss, K D AU - Everiss KD FAU - Wikstrand, C J AU - Wikstrand CJ FAU - Batra, S K AU - Batra SK FAU - Kung, H J AU - Kung HJ FAU - Bigner, D D AU - Bigner DD LA - eng GR - 5T32-NS-07-304-09/NS/NINDS NIH HHS/United States GR - CA 11898/CA/NCI NIH HHS/United States GR - NS 20023/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PL - England TA - Biochem J JT - The Biochemical journal JID - 2984726R RN - 0 (Receptors, Cell Surface) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Dimerization MH - ErbB Receptors/genetics/*metabolism MH - Humans MH - Receptors, Cell Surface/metabolism MH - *Signal Transduction MH - Tumor Cells, Cultured PMC - PMC1218502 EDAT- 1997/06/15 00:00 MHDA- 1997/06/15 00:01 PMCR- 1997/12/15 CRDT- 1997/06/15 00:00 PHST- 1997/06/15 00:00 [pubmed] PHST- 1997/06/15 00:01 [medline] PHST- 1997/06/15 00:00 [entrez] PHST- 1997/12/15 00:00 [pmc-release] AID - 10.1042/bj3240855 [doi] PST - ppublish SO - Biochem J. 1997 Jun 15;324 ( Pt 3)(Pt 3):855-61. doi: 10.1042/bj3240855.