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PLoS One. 2014 Jan 23;9(1):e86470. doi: 10.1371/journal.pone.0086470. eCollection 2014.

Fibroblast growth factor receptor 3 interacts with and activates TGFβ-activated kinase 1 tyrosine phosphorylation and NFκB signaling in multiple myeloma and bladder cancer.

Author information

  • 1Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California, United States of America.
  • 2Department of Biological Chemistry, University of California Irvine, Irvine, California, United States of America.
  • 3Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America ; Institute of Experimental Biology, Masaryk University and Department of Cytokinetics, Institute of Biophysics AS CR, v.v.i., Brno, Czech Republic ; Department of Pediatrics, UCLA School of Medicine, Los Angeles, California, United States of America.
  • 4Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
  • 5Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, United States of America.
  • 6Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America ; Department of Pediatrics, UCLA School of Medicine, Los Angeles, California, United States of America.
  • 7Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America ; Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
  • 8Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California, United States of America ; Department of Biological Chemistry, University of California Irvine, Irvine, California, United States of America ; Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, United States of America ; Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California, United States of America.

Abstract

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 NFκB transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFκB activation. A critical mediator of NFκB activity is TGFβ-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 NFκB signaling, and promote both NFκB 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 NFκB activation.

PMID:
24466111
[PubMed - indexed for MEDLINE]
PMCID:
PMC3900522
Free PMC Article
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