Induction of anchorage-independent growth by amphiregulin.
We have previously shown that the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AR) exhibits low potency as a result of its C-terminal truncation. This led us to investigate whether its inability to promote anchorage-independent growth (AIG) of normal cells arose because of its compromised interaction with EGFR. Wild type AR(1-84) was tested in AIG and mitogenesis assays using NRK-49F or NR6/HER fibroblasts. In contrast to NR6/HER cells, the response of NRK-49F fibroblasts to AR was much lower than expected. As the effect of AR was heparin-insensitive, contributions from heparan sulphate proteoglycan interactions could not explain the differing sensitivities of the cells. Comparison of the effects of AR on two additional cell lines indicated that low EGFR number correlated with AR insensitivity: this suggested that the low potency of AR precluded activation of sufficient receptors to elicit a response. Consistent with this proposal, a modified form of AR (AR[1-90(leu86)]) with enhanced potency was able to induce AIG of NRK-49F fibroblasts. Thus, the ability of AR to promote AIG is determined both by ligand potency and the EGFR complement of cells.
Adam
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RM
Chamberlin
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SG
Davies
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D066258:Amphiregulin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D006583:Hexadimethrine Bromide / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D051381:Rats
C587848:AREG protein, human; D066258:Amphiregulin; D000970:Antineoplastic Agents; C587849:Areg protein, mouse; C587850:Areg protein, rat; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016222:Fibroblast Growth Factor 2; D006583:Hexadimethrine Bromide; D004815:Epidermal Growth Factor; D006493:Heparin; D066246:ErbB Receptors