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Heparin‐binding epidermal growth factor‐like growth factor functionally antagonizes interstitial cystitis antiproliferative factor via mitogen‐activated protein kinase pathway activation
Author(s) -
Kim Jayoung,
Keay Susan K.,
Freeman Michael R.
Publication year - 2009
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2008.08097.x
Subject(s) - mapk/erk pathway , epidermal growth factor , protein kinase a , growth factor , heparin binding egf like growth factor , kinase , chemistry , microbiology and biotechnology , mitogen activated protein kinase , extracellular , secretion , p38 mitogen activated protein kinases , signal transduction , cell growth , biology , biochemistry , receptor
OBJECTIVE To delineate the mechanism underlying the potential functional relationship between interstitial cystitis antiproliferative factor (APF) and heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), as APF has previously been shown to decrease the proliferation rate of normal bladder epithelial cells and the amount of HB‐EGF produced by these cells. MATERIALS AND METHODS APF‐responsive T24 transitional carcinoma bladder cells were treated with high‐pressure liquid chromatography‐purified native APF with or without HB‐EGF to determine the involvement of signalling pathways and proliferation by Western blot analysis, p38 mitogen‐activated protein kinase (MAPK) and extracellular signal‐regulated kinase (Erk)/MAPK assays, and 3‐(4,5‐dimethylthiazolyl‐2)‐2,5‐diphenyltetrazolium bromide (MTT) assay. RESULTS Cyclic stretch induced the secretion of HB‐EGF from T24 cells overexpressing the HB‐EGF precursor, resulting in enhanced proliferation. T24 cells treated with APF had increased p38MAPK activity and suppressed cell growth, events that were both reversed by treatment with a p38MAPK‐selective inhibitor. Activation of Erk/MAPK by HB‐EGF was inhibited by APF, and APF did not stimulate p38MAPK in the presence of soluble HB‐EGF or when cells overexpressed constitutively secreted HB‐EGF. Lastly, APF inhibitory effects on cell growth were attenuated by HB‐EGF. CONCLUSIONS These results indicate that HB‐EGF and APF are functionally antagonistic and signal through parallel MAPK signalling pathways in bladder cells.