The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

Abstract

BackgroundNFκB 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 NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis.Methodology/Principal FindingsHere, we demonstrate an interaction between FGFR4 and IKKβ (Inhibitor of NFκB Kinase β subunit), an essential component in the NFκB 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 IKKβ in the presence of activated FGFR4, but not kinase-dead FGFR4. Following stimulation by TNFα (Tumor Necrosis Factor α) to activate NFκB pathways, FGFR4 activation results in significant inhibition of NFκB signaling as measured by decreased nuclear NFκB localization, by reduced NFκB transcriptional activation in electophoretic mobility shift assays, and by inhibition of IKKβ kinase activity towards the substrate GST-IκBα in in vitro assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling.Conclusions/SignificanceThese results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone.

MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis

“…Given that both adiponectin and Fgf15 exhibited potent anti-inflammatory properties (15,16,(45)(46)(47), elevation of circulating adiponectin and Fgf15 in the ethanol-fed mNTKO mice might also synergistically or additively trigger an anti-inflammation signaling network and protected mNTKO mice from ethanol-induced liver injury.…”

“…Conceivably, the normalized hepatic and serum bile acids in the ethanol-fed mNTKO mice might limit accumulation of toxic bile acids such as deoxycholic acid in liver and ultimately ameliorated ethanolinduced liver damage. Fgf15 also has the ability to directly suppress inflammation via signaling through its receptor Fgfr4 (47). Given that hepatocytes are the only cell type in liver that expresses the Fgf15 receptor complex Fgfr4-␤Kl, it is logical to speculate that increased Fgf15 in ethanol-fed mNTKO mice might exert anti-inflammatory effects by targeting hepatocytes (49).…”

Combination of the FGFR4 inhibitor PD173074 and 5-fluorouracil reduces proliferation and promotes apoptosis in gastric cancer

“…This indicates that PD may increase the apoptosis of GC by inhibiting the FGF19/FGFR4 pathway. Furthermore, Drafahl et al (19) found that activation of FGFR4 may lead to a negative effect on the NF-κB pathway, suggesting that NF-κB may be one of the signal pathways influencing apoptosis.…”

Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

“…The reduced proliferation in Hnf1b-deficient pancreata could also be attributed to a decreased FGF signaling via downregulation of Fgfr4. Although the pancreatic phenotype of Fgfr4 −/− embryos was not analyzed (Weinstein et al, 1998), several recent studies showed that Fgfr4 positively regulates proliferation and has anti-apoptotic effects in models of liver, prostate and gastric cancer (Drafahl et al, 2010;Ho et al, 2009;Miura et al, 2012;Ye et al, 2011). Interestingly, both Fgfr2b and Fgfr4 were downregulated in Sox9-deficient pancreas , raising the possibility that they might serve partially redundant functions in MPC proliferation.…”