Fibroblast Growth Factor Receptor 3 Interacts with and Activates TGFbeta-Activated Kinase 1 Tyrosine Phosphorylation and NFkappaB Signaling in Multiple Myeloma and Bladder Cancer
| Authors | |
|---|---|
| Year of publication | 2014 |
| Type | Article in Periodical |
| Magazine / Source | PLOS One |
| MU Faculty or unit | |
| Citation | |
| Web | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900522/ |
| Doi | http://dx.doi.org/10.1371/journal.pone.0086470 |
| Field | Physiology |
| Keywords | FGFR3; TAK1; NFkappaB; multiple myeloma; bladder cancer |
| Description | Cancer is a major public health problem worldwide. In the United States alone, 1 in 4 deaths is due to cancer and for 2013 a total of 1,660,290 new cancer cases and 580,350 cancer-related deaths are projected. Comprehensive profiling of multiple cancer genomes has revealed a highly complex genetic landscape in which a large number of altered genes, varying from tumor to tumor, impact core biological pathways and processes. This has implications for therapeutic targeting of signaling networks in the development of treatments for specific cancers. The NFkappaB transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFkappaB activation. A critical mediator of NFkappaB activity is TGFbeta-activated kinase 1 (TAK1). Here, we identify TAK1 as a novel interacting protein and target of fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes that regulate NFkappaB signaling, and promote both NFkappaB transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFkappaB activation. |
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