RT Journal Article
SR Electronic
T1 Epidermal Growth Factor-Urogastrone: Biological Activity and Receptor Binding of Derivatives
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 314
OP 320
VO 17
IS 3
A1 MORLEY D. HOLLENBERG
A1 HAROLD GREGORY
YR 1980
UL http://molpharm.aspetjournals.org/content/17/3/314.abstract
AB We have examined the receptor binding (cultured human fibroblasts) and biological activities (stimulation of human fibroblast thymidine incorporation; inhibition of canine gastric acid secretion) of both human and mouse epidermal growth factor-urogastrone (EGF-URO) and of derivatives of these 53 amino acid polypeptides lacking up to six of the C-terminal amino acid residues. Both the human and the mouse polypeptides are biologically equipotent, although human EGF-URO possesses a two- to threefold higher human fibroblast receptor affinity than does mouse EGF-URO; binding kinetic methods designed to assess the receptor affinity of the unlabeled peptides indicate that the 125I-labeled peptides exhibit a lower fibroblast receptor affinity compared with native peptides. Whereas the shortened peptides (EGF-URO 1-47) are equipotent with the intact molecule (EGF-URO 1-53) in inhibiting gastric acid secretion, both mouse and human EGF-URO 1-47 are only one-tenth as potent as EGF-URO 1-53 in stimulating fibroblast thymidine incorporation; human EGF-URO 1-52 is equipotent with the intact peptide. Neither the human C-terminal hexapeptide (EGF-URO 48-53) nor the 48-52 pentapeptide interacts with the receptor. The reduced carboxamidated intact polypeptide is likewise inactive. In the presence of an excess of the C-terminal EGF-URO 48-53, EGF-URO 1-47 does not exhibit an increased biological potency. The reduced biological potencies of the shortened derivatives (EGF-URO 1-47) in fibroblasts are paralleled by reduced fibroblast receptor affinities, compared with the intact peptides. The data demonstrate the importance of the C-terminal sequence for the enhancement of receptor binding and biological activity in fibroblasts. Further, it appears that the structural requirements (and thus the receptor) related to the acid inhibitory activity differ from those related to the mitogenic activity of these polypeptides. ACKNOWLEDGMENT The incomparable technical assistance of W. H. Shackelford is gratefully acknowledged.