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The intersection of NFkappaB and fibroblast growth factor receptor signaling pathways

  • Author(s): Drafahl, Kristine A.
  • et al.
Abstract

Misregulation of FGFR signaling, or overexpression of the receptors, can lead to uncontrolled downstream signaling associated with a range of developmental syndromes and various forms of cancer. Given the growing evidence on the importance of FGFR4 in cancer progression, we sought to better understand FGFR4 downstream signaling by searching for novel proteins that interact directly with the receptor. Using the intracellular domain of FGFR4 as bait, a yeast two-hybrid assay was performed against a mouse cDNA library. Interestingly, one of the interacting proteins identified was IKK\[beta\], a critical component of NFkappaB signaling. Research has suggested a link between growth factor signaling pathways and activation of NF\[kappa\]B transcriptional activity. The role of NF\[kappa\]B in regulating apoptosis and proliferation in a variety of human cancers, as well as understanding the significance of inflammatory responses in the development of cancer, has been a topic of increasing interest in recent years. In this work, we show tyrosine phosphorylation of IKK\[beta\] resulting from FGFR4 expression, and demonstrate a decrease in NF\[kappa\]B signaling upon FGFR4 activation, which is dependent upon FGFR4 kinase activity. Our research identifies a novel and compelling link between FGFR4 signaling and the NF\[kappa\]B pathway, providing a unique model of NF\[kappa\]B inactivation and implicating FGFR4 as a tumor suppressor in prostate cancer. Evidence exists to implicate FGFR2 signaling in cancer progression as well as protection from inflammatory insults, indicating FGFR2 may play dual roles as a tumor promoter and a tumor suppressor. We found that similar to FGFR4, FGFR2 is also able to interact with IKK\[beta\] and lead to its tyrosine phosphorylation. FGFR2 kinase activity was essential for a decrease in IKK and NF\[kappa\]B activity in breast cancer cells, implicating FGFR2 signaling in the inflammatory response. A somatic mutation was recently identified in the FGFR4 kinase domain in a screen of lung adenocarcinomas. We determined that this mutation is dominant negative and eliminates all kinase activity of the receptor. Additionally, we found that E681K renders FGFR4 incapable of phosphorylating IKK\[beta\] on tyrosine, decreasing IKK activity, and decreasing NF\[kappa\]B activity. This research potentially identifies one mechanism of lung carcinogenesis through inhibition of FGFR4 kinase activity.

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