Differential effects of a heparin antagonist (hexadimethrine) or chlorate on amphiregulin, basic fibroblast growth factor, and heparin-binding EGF-like growth factor activity.
Amphiregulin (AR) and heparin-binding EGF-like growth factor (HB-EGF) are two recently identified members of the EGF family. Both AR and HB-EGF share with EGF the ability to interact with the type-1 EGF receptor; however, AR and HB-EGF differ from EGF in that both of these mitogens bind to heparin while EGF does not. To determine whether interactions with heparin-like molecules on the cell surface influence binding of AR and HB-EGF with EGF receptors and the subsequent mitogenic activity exerted by these growth factors, murine AKR-2B and Balb/MK-2 cells were treated with either an inhibitor of proteoglycan sulfation (chlorate) or a heparin antagonist (hexadimethrine). As expected, neither treatment significantly altered the specific binding of 125I-EGF on AKR-2B cells. Interestingly, treatment with either chlorate or hexadimethrine inhibited the ability of AR to compete with 125I-EGF for cell surface binding and also attenuated AR-mediated DNA synthesis. Thus, as has been suggested for other heparin-binding growth factors such as basic fibroblast growth factor (bFGF), the interaction of AR with an EGF-binding receptor appears to be facilitated by interaction with cell-associated sulfated glycosaminoglycans or proteoglycans. Unexpectedly, however, neither chlorate nor hexadimethrine treatment caused an inhibition of HB-EGF-induced mitogenic activity. Chlorate treatment did not significantly alter the ability of HB-EGF to compete with 125I-EGF for cell surface binding sites, however, heparin and hexadimethrine reduced the ability of HB-EGF to compete for 125I-EGF binding. These results suggest that, in AKR-2B cells, HB-EGF may mediate its mitogenic response at least in part through a receptor which appears to be selective for HB-EGF and permits HB-EGF-mediated mitogenic responses in the presence of hexadimethrine or heparin. Finally, hexadimethrine inhibited the specific binding and mitogenic activity of bFGF, suggesting that this cationic polymer can function as an antagonist of heparin-binding mitogens other than AR.
Cook
P W
PW
Scios Nova Inc., Mountain View, California 94043, USA.
Ashton
N M
NM
Karkaria
C E
CE
Siess
D C
DC
Shipley
G D
GD
D066258:Amphiregulin; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002704:Chlorates / Q000494:pharmacology*; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism* / Q000494:pharmacology; D006494:Heparin Antagonists / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D006583:Hexadimethrine Bromide / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008934:Mitogens / Q000494:pharmacology
D066258:Amphiregulin; C587849:Areg protein, mouse; D002704:Chlorates; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; C587884:Hbegf protein, mouse; D006494:Heparin Antagonists; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D016222:Fibroblast Growth Factor 2; D006583:Hexadimethrine Bromide; D004815:Epidermal Growth Factor; D004247:DNA