ALTERNATIVE SPLICING IN FIBROBLAST GROWTH-FACTOR RECEPTOR-2 IS ASSOCIATED WITH INDUCED EPITHELIAL-MESENCHYMAL TRANSITION IN RAT BLADDER-CARCINOMA CELLS

We described previously that acidic fibroblast growth factor (aFGF), b ut not basic fibroblast growth factor (bFGF), can induce the rat carci noma cell line NBT-II to undergo a rapid and reversible transition fro m epithelial to mesenchymal phenotype (EMT). We now find that NBT-II E MT is stimulated by keratinocyte growth factor (KGF) in cells grown at low density. Accordingly, a high-affinity receptor showing 98% homolo gy to mouse FGF receptor 2b/KGF receptor was cloned and sequenced from NBT-II cells. Northern analysis indicated that mRNA for FGF receptor 2b/KGF receptor was drastically down-regulated within 1 wk in aFGF-ind uced mesenchymal NBT-II cells. This decrease coincided with an up-regu lation of FGF receptor 2c/Bek, a KGF-insensitive, alternatively splice d form of FGF receptor 2b/KGF receptor. Functional studies confirmed t hat KGF could not maintain EMT induction on mesenchymal NBT-II cells. FGF receptor 1 and FGF receptor 2c/Bek could also support EMT inductio n when transfected into NBT-II cells in response to aFGF or bFGF. Such transfected cells could bind bFGF as well as aFGF. Therefore, EMT can be induced through different FGF receptors, but EMT may also regulate FGF receptor expression itself.