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

• Type of Material: Article
• Authors: Lisa Salazar, University of California Irvine; Tamara Kashiwada, University of California Irvine; Pavel Krejci, Cedars-Sinai Medical Center; April N. Meyer, University of California San Diego; Malcolm Casale, University of California Irvine; Matthew Hallowell, University of California Irvine; William R. Wilcox, Emory University; Daniel J. Donoghue, University of California San Diego; Leslie Michels Thompson, University of California Irvine
• Language: English
• Date: 2014-01-23
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Salazar et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0086470
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 1
• Start Page: e86470
• End Page: e86470
• Grant/Funding Information: This work was supported by the Multiple Myeloma Research Foundation, Chao Family Comprehensive Cancer Center at UCI, Elsa U. Pardee Foundation, Ministry of Education, Youth and Sports of the Czech Republic (KONTAKT LH12004), Czech Science Foundation (P305/11/0752).
• Keywords: TAK1; PATHWAYS; Multidisciplinary Sciences; Science & Technology - Other Topics; DOWN-REGULATION; TARGET GENES; FGFR3; URINARY-BLADDER; EXPRESSION; GENE-PRODUCTS; Science & Technology; FACTOR-KAPPA-B; CELL CARCINOMA
• Research Categories: Chemistry, Biochemistry; Health Sciences, Oncology

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.