Fibroblast growth factor receptor 3 interacts with and activates TGFβ-activated kinase 1 tyrosine phosphorylation and NFκB signaling in multiple myeloma and bladder cancer.
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.
Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California, United States of America.
Lisa
L
Salazar
Department of Biological Chemistry, University of California Irvine, Irvine, California, United States of America.
Tamara
T
Kashiwada
Medical 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.
Pavel
P
Krejci
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.
April N
AN
Meyer
Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, United States of America.
Malcolm
M
Casale
Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California, United States of America.
Matthew
M
Hallowell
Medical 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.
William R
WR
Wilcox
Department 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.
Daniel J
DJ
Donoghue
Department 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.
Leslie Michels
LM
Thompson
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D006801:Humans; D047468:Immunoprecipitation; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000099151:MAP Kinase Kinase Kinase 7
D014408:Biomarkers, Tumor; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D010446:Peptide Fragments; D012333:RNA, Messenger; D051498:Receptor, Fibroblast Growth Factor, Type 3; D016212:Transforming Growth Factor beta; D014443:Tyrosine; D000099151:MAP Kinase Kinase Kinase 7; C496365:FGFR3 protein, human