The receptor tyrosine kinase FGFR4 negatively regulates NF-kappaB signaling.

ABSTRACT: NF?B signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NF?B activation has not been previously described, although FGFs have been known to antagonize TNF?-induced apoptosis.Here, we demonstrate an interaction between FGFR4 and IKK? (Inhibitor of NF?B Kinase ? subunit), an essential component in the NF?B pathway. This novel interaction was identified utilizing a yeast two-hybrid screen [1] and confirmed by coimmunoprecipitation and mass spectrometry analysis. We demonstrate tyrosine phosphorylation of IKK? in the presence of activated FGFR4, but not kinase-dead FGFR4. Following stimulation by TNF? (Tumor Necrosis Factor ?) to activate NF?B pathways, FGFR4 activation results in significant inhibition of NF?B signaling as measured by decreased nuclear NF?B localization, by reduced NF?B transcriptional activation in electophoretic mobility shift assays, and by inhibition of IKK? kinase activity towards the substrate GST-I?B? in in vitro assays. FGF19 stimulation of endogenous FGFR4 in TNF?-treated DU145 prostate cancer cells also leads to a decrease in IKK? activity, concomitant reduction in NF?B nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNF? treatment of DU145 cells, in comparison with TNF? alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NF?B signaling.These results identify a compelling link between FGFR4 signaling and the NF?B pathway, and reveal that FGFR4 activation leads to a negative effect on NF?B signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NF?B signaling will not be limited to FGFR4 alone.

SUBMITTER: Drafahl KA 

PROVIDER: S-EPMC3008709 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature