A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling.
Epidermal growth factor (EGF) and type alpha transforming growth factor (TGF-alpha) bind to a specific region in subdomain III of the extracellular portion of the EGF receptor (EGFR). Binding leads to receptor dimerization, auto-and transphosphorylation on intracellular tyrosine residues, and activation of signal transduction pathways. We compared the binding and biological actions of EGF and TGF-alpha in Chinese hamster ovary (CHO) cells expressing either wild-type human EGFR (HER497R) or a variant EGFR that has an arginine-to-lysine substitution in the extracellular domain at codon 497 (HER497K) within subdomain IV of EGFR. Both receptors exhibited two orders of binding sites with radioiodinated EGF (125I-EGF). Similar results were obtained with 125I-TGF-alpha in cells expressing HER497R. In contrast, only one order of low-affinity binding sites was seen with 125I-TGF-alpha in the case of HER497K. Although EGF and TGF-alpha enhanced tyrosine phosphorylation of both receptors, CHO cells expressing HER497K exhibited an attenuated growth response to EGF and TGF-alpha and a reduced induction of the protooncogenes FOS, JUN, and MYC. Moreover, high concentrations of TGF-alpha (5 nM) inhibited growth in these cells but not in cells expressing HER497R. These findings indicate that a region in subdomain IV of EGFR regulates signal transduction across the cell membrane and selectively modulates that binding characteristics of TGF-alpha.
Moriai
T
T
Department of Medicine, University of California, Irvine 92717.
Kobrin
M S
MS
Hope
C
C
Speck
L
L
Korc
M
M
D000818:Animals; D001120:Arginine; D001665:Binding Sites; D015152:Blotting, Northern; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D003001:Cloning, Molecular; D003062:Codon; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D016758:Genes, jun; D016259:Genes, myc; D014644:Genetic Variation; D006801:Humans; D007700:Kinetics; D008239:Lysine; D051379:Mice; D010766:Phosphorylation; D017354:Point Mutation; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000378:metabolism* / Q000494:pharmacology*
D003062:Codon; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D004247:DNA; D001120:Arginine; D066246:ErbB Receptors; D008239:Lysine