Daniel J. Donoghue
Professor of Chemistry/Biochemistry
Ph.D., Massachusetts Institute of Technology
FGFRs in Human Cancer
We are studying the significance of Fibroblast Growth Factor Receptors (FGFRs), which are receptor tyrosine kinases in several human cancers, specifically the interaction of FGFRs with the NFkappaB inflammatory signaling pathway. Our published work reveals an interaction between FGFR4 and IKKbeta, an important regulatory protein of the NFkappaB pathway. This interaction negatively regulates NFkappaB signaling activated by its ligand, TNFalpha. More recently, we have also demonstrated that FGFR2 phosphorylates IKKbeta in human breast cancer cells.
We have demonstrated that the receptor tyrosine kinases FRFG2 and FGFR4 induce tyrosine phosphorylation of IKKbeta. We are using mass spectrometry to identify these phosphorylation sites, and have recently identified multiple novel sites of Tyr phosphorylation as well as novel sites of Ser/Thr phosphorylation on IKKbeta. Mutant forms of IKKbeta are being constructed that incorporate mutations in these Tyr phosphorylation sites, and the effects of these single and multiple mutations are being studied with regards to NFkappaB signaling, IKKbeta stability and turnover, and nuclear versus cytoplasmic localization of key components of these pathways. Tyrosine phosphoryation of IKKbeta has not been previously reported or characterized, and we believe a global approach to understanding the role of these novel phosphorylation events will reveal important information about the interactions between growth factor signaling pathways and inflammatory signaling.
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