Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII).
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.
Chu
C T
CT
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Everiss
K D
KD
Wikstrand
C J
CJ
Batra
S K
SK
Kung
H J
HJ
Bigner
D D
DD
D019281:Dimerization; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D011956:Receptors, Cell Surface; D066246:ErbB Receptors