Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor.
The b isoform of fibroblast growth factor receptor 2, FGFR2b/FGFR2-IIIb/Ksam-IIC1/KGFR, a tyrosine kinase receptor, is expressed in a wide variety of epithelia and is downregulated in several human carcinomas including prostate, salivary and urothelial cell carcinomas. FGFR2b has been shown to inhibit growth in tumour cell lines derived from these carcinomas. Here, we investigated the molecular mechanisms underlying the inhibition of human urothelial carcinoma cell growth following FGFR2b expression. Using a nylon DNA array, we analysed the gene expression profile of the T24 bladder tumour cell line, transfected or not with a construct encoding FGFR2b. The expression of FGFR2b in T24 cells decreased insulin-like growth factor (IGF)-II mRNA levels. This decrease was correlated with a decrease in IGF-II secretion and may have been responsible for the observed inhibition of cell growth because the addition of exogenous IGF-II restored growth rates to normal levels. Using SU5402, an inhibitor of FGFR tyrosine kinase activity, and a kinase dead mutant of the receptor, FGFR2b Y659F/Y660F, we also demonstrated that the growth inhibition and decrease in IGF-II secretion induced by FGFR2b did not require tyrosine kinase activity. Finally, we demonstrated the involvement of the distal carboxy-terminal domain of the receptor in decreasing IGF-II expression and inhibiting T24 cell growth, as Ksam-IIC3, a variant of FGFR2b carrying a short carboxy-terminus, neither downregulated IGF-II nor inhibited cell proliferation. Our data suggest that FGFR2b inhibits the growth of bladder carcinoma cells by reducing IGF-II levels via its carboxy-terminal domain, independent of its tyrosine kinase activity.
Bernard-Pierrot
Isabelle
I
UMR144, CNRS Institut Curie, Section de Recherche, 26 rue d'Ulm, 75248 Paris Cedex, France.
Ricol
David
D
Cassidy
Andrew
A
Graham
Alexander
A
Elvin
Paul
P
Caillault
Aurélie
A
Lair
Séverine
S
Broët
Philippe
P
Thiery
Jean-Paul
JP
Radvanyi
François
F
D001483:Base Sequence; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000473:pathology*
D017931:DNA Primers; D017468:Receptors, Fibroblast Growth Factor; D007335:Insulin-Like Growth Factor II; D051497:Receptor, Fibroblast Growth Factor, Type 2