Fibroblast Growth Factor Receptor 3 Interacts with and Activates TGFβ-Activated Kinase 1 Tyrosine Phosphorylation and NFκB Signaling in Multiple Myeloma and Bladder Cancer

Lisa Salazar,Malcolm Casale,Tamara Kashiwada,Daniel J Donoghue,William R Wilcox,Leslie Michels Thompson,Pavel Krejci,April N Meyer,Matthew Hallowell,Hari K Koul

doi:10.1371/journal.pone.0086470

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.

Highlights

Cancer is a complex disease arising from the acquisition of somatic mutations that dysregulate signaling pathways central to cell proliferation and survival, angiogenesis, and metastasis
We further determined by Y2H using fibroblast growth factor receptor 3 (FGFR3) domain constructs (Fig. 1A) that the region encompassing the second half of the tyrosine kinase domain of FGFR3, containing the activation loop of the receptor and C-terminal tail of FGFR3, is sufficient for the FGFR3-TGFb-activated kinase 1 (TAK1) interaction
This study describes the identification of a novel interaction between FGFR3 and TAK1, a member of the MAPK signaling pathway, both through molecular interaction and at the level of pathway integration

Summary

Introduction

Cancer is a complex disease arising from the acquisition of somatic mutations that dysregulate signaling pathways central to cell proliferation and survival, angiogenesis, and metastasis. Dysregulation of FGFR3 signaling has been implicated in several cancer types, most notably urothelial cell carcinoma (UC) and multiple myeloma (MM). The acquisition of FGFR3-activating mutations (5–10% of t(4;14) cases) with disease progression indicates a role for FGFR3 in MM pathogenesis, and early studies demonstrate the oncogenic potential of activated mutant FGFR3 [4]. It was more recently demonstrated that wild-type FGFR3, as is expressed in most FGFR3-positive t(4;14) tumors, can contribute to B cell oncogenesis [7]. A wealth of preclinical data demonstrate the effectiveness of receptor tyrosine kinase inhibitors and neutralizing antibody against MM cells expressing FGFR3activating mutations and wild-type receptor (reviewed in [3,4,5]). Inhibition of FGFR3 can induce cell cycle arrest and/or apoptosis in UC [8,9] both in vitro and in vivo, providing validation that FGFR3 and downstream signaling pathways represent potentially relevant therapeutic targets for the treatment of FGFR3-associated cancers

Methods

Results

Conclusion