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FGFR Kinase Activity Leads to Decreased NFkB Activity in Prostate Cancer

Kristy Drafahl

Appointment Period: 2006-2009, Grant Years: [22,23,24]

Kristy DrafahlNFkappaB 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.

In my work, I demonstrated an interaction between FGFR4 and IKKbeta (Inhibitor of NFkappaB Kinase beta subunit), an essential component in the NFkappaB pathway. We demonstrate tyrosine phosphorylation of IKKbeta in the presence of activated FGFR4, but not kinase-dead FGFR4. Following stimulation by TNFalpha to activate NFkappaB pathways, FGFR4 activation results in significant inhibition of NFkappaB signaling as measured by decreased nuclear NFkappaB localization, by reduced NFkappaB transcriptional activation in electophoretic mobility shift assays, and by inhibition of IKKbeta kinase activity towards the substrate GST-IkappaBalpha in in vitro assays. Microarray analysis demonstrates that FGF19 + TNFalpha treatment of DU145 cells, in comparison with TNFalpha alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFkappaB signaling. These results identify a compelling link between FGFR4 signaling and the NFkappaB pathway, and reveal that FGFR4 activation leads to a negative effect on NFkappaB signaling including an inhibitory effect on proapoptotic signaling.

Drafahl, K. A., C. W. McAndrew, D. J. Donoghue. Signaling from fibroblast growth factor receptors in development and disease. (2009). In "Handbook of Cell Signaling", Second Edition (R. Bradshaw & E. Dennis, Eds.) Oxford:Academic Press, pp. 1939-1948.

Drafahl KA, McAndrew CW, Meyer AN, Haas M, Donoghue DJ. The receptor tyrosine kinase FGFR4 negatively regulates NF-kappaB signaling. PLoS One. (2010) 5:e14412. PMID: 21203561; PMCID: PMC3008709.