DIFFERENTIAL-EFFECTS OF A HEPARIN ANTAGONIST (HEXADIMETHRINE) OR CHLORATE ON AMPHIREGULIN, BASIC FIBROBLAST GROWTH-FACTOR, AND HEPARIN-BINDING EGF-LIKE GROWTH-FACTOR ACTIVITY
Pw. Cook et al., DIFFERENTIAL-EFFECTS OF A HEPARIN ANTAGONIST (HEXADIMETHRINE) OR CHLORATE ON AMPHIREGULIN, BASIC FIBROBLAST GROWTH-FACTOR, AND HEPARIN-BINDING EGF-LIKE GROWTH-FACTOR ACTIVITY, Journal of cellular physiology, 163(2), 1995, pp. 418-429
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 recepto
r; however, AR and HB-EGF differ from EGF in that both of these mitoge
ns bind to heparin while EGF does not. To determine whether interactio
ns with heparin-like molecules on the cell surface influence binding o
f AR and HB-EGF with EGF receptors and the subsequent mitogenic activi
ty exerted by these growth factors, murine AKR-2B and Balb/MK-2 cells
were treated with either an inhibitor of proteoglycan sulfation (chlor
ate) or a heparin antagonist (hexadimethrine). As expected, neither tr
eatment significantly altered the specific binding of I-125-EGF on AKR
-2B cells. Interestingly, treatment with either chlorate or hexadimeth
rine inhibited the ability of AR to compete with I-125-EGF for cell su
rface binding and also attenuated AR-mediated DNA synthesis. Thus, as
has been suggested for other heparin-binding growth factors such as ba
sic fibroblast growth factor (bFGF), the interaction of AR with an EGF
-binding receptor appears to be facilitated by interaction with cell-a
ssociated sulfated glycosaminoglycans or proteoglycans. Unexpectedly,
however, neither chlorate nor hexadimethrine treatment caused an inhib
ition of HB-EGF-induced mitogenic activity. Chlorate treatment did not
significantly alter the ability of HB-EGF to compete with I-125-EGF f
or cell surface binding sites, however, heparin and hexadimethrine red
uced the ability of HB-EGF to compete for I-125-EGF binding. These res
ults suggest that, in AKR-2B cells, HB-EGF may mediate its mitogenic r
esponse at least in part through a receptor which appears to be select
ive for HB-EGF and permits HB-EGF-mediated mitogenic responses in the
presence of hexadimethrine or heparin. Finally, hexadimethrine inhibit
ed the specific binding and mitogenic activity of bFGF, suggesting tha
t this cationic polymer can function as an antagonist of heparin-bindi
ng mitogens other than AR. (C) 1995 Wiley-Liss, Inc.