Analysis of mammalian fibroblast transformation by normal and mutated human EGF receptors.
Activation of the EGF receptor (c-erbB) tyrosine kinase has been implicated in tumorigenesis, either by overexpression of the normal receptor in the presence of EGF, or through expression of a truncated receptor lacking the EGF binding domain as in the viral oncogene v-erbB. Here, normal and truncated human EGF receptors expressed in Rat1 fibroblasts were analysed for receptor tyrosine kinase activity and several transformation parameters in comparison with polyoma middle T and EJ-ras. Expression of a truncated EGF receptor lacking the extracellular ligand binding domain induced transformation of immortalized rodent fibroblasts and appears to activate the intrinsic tyrosine kinase. The transformed phenotype becomes enhanced by further truncation of the C-terminal domain containing the tyrosine autophosphorylation sites P1 and P2. Over expression of EGF receptors with an intact extracellular region in transfected Rat1 cells shows EGF dependent transformation, which is reduced by C-terminal truncation. Transformation is dependent on the cellular receptor concentration and can be selected as a stable phenotype. We conclude that expression of receptors with a truncated EGF-binding domain alone is sufficient to transform mammalian fibroblasts, in contrast to chick fibroblasts transformed by v-erbB where additional deletion of C-terminal receptor sequences appears to be an absolute requirement.
Haley
J D
JD
Ludwig Institute for Cancer Research, London, UK.
Hsuan
J J
JJ
Waterfield
M D
MD
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000503:physiopathology*; D004252:DNA Mutational Analysis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D051379:Mice; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases