scholarly journals Fibroblast growth factor receptor 5 (FGFR5) is a co-receptor for FGFR1 that is up-regulated in beta-cells by cytokine-induced inflammation

2018 ◽  
Vol 293 (44) ◽  
pp. 17218-17228 ◽  
Author(s):  
Romario Regeenes ◽  
Pamuditha N. Silva ◽  
Huntley H. Chang ◽  
Edith J. Arany ◽  
Andrey I. Shukalyuk ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Growth Factor ◽  
Beta Cell ◽  
Cell Survival ◽  
Fibroblast Growth Factor ◽  
Beta Cells ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Wide Range

Fibroblast growth factor receptor-1 (FGFR1) activity at the plasma membrane is tightly controlled by the availability of co-receptors and competing receptor isoforms. We have previously shown that FGFR1 activity in pancreatic beta-cells modulates a wide range of processes, including lipid metabolism, insulin processing, and cell survival. More recently, we have revealed that co-expression of FGFR5, a receptor isoform that lacks a tyrosine-kinase domain, influences FGFR1 responses. We therefore hypothesized that FGFR5 is a co-receptor to FGFR1 that modulates responses to ligands by forming a receptor heterocomplex with FGFR1. We first show here increased FGFR5 expression in the pancreatic islets of nonobese diabetic (NOD) mice and also in mouse and human islets treated with proinflammatory cytokines. Using siRNA knockdown, we further report that FGFR5 and FGFR1 expression improves beta-cell survival. Co-immunoprecipitation and quantitative live-cell imaging to measure the molecular interaction between FGFR5 and FGFR1 revealed that FGFR5 forms a mixture of ligand-independent homodimers (∼25%) and homotrimers (∼75%) at the plasma membrane. Interestingly, co-expressed FGFR5 and FGFR1 formed heterocomplexes with a 2:1 ratio and subsequently responded to FGF2 by forming FGFR5/FGFR1 signaling complexes with a 4:2 ratio. Taken together, our findings identify FGFR5 as a co-receptor that is up-regulated by inflammation and promotes FGFR1-induced survival, insights that reveal a potential target for intervention during beta-cell pathogenesis.

scholarly journals Distinct Roles of Fibroblast Growth Factor Receptor 1 and 2 in Regulating Cell Survival and Epithelial-Mesenchymal Transition

2007 ◽  
Vol 21 (4) ◽  
pp. 987-1000 ◽  
Author(s):  
Wa Xian ◽  
Kathryn L. Schwertfeger ◽  
Jeffrey M. Rosen
Keyword(s):  
Growth Factor ◽  
Cell Survival ◽  
Fibroblast Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Fibroblast Growth Factor Receptor ◽  
Three Dimensional ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Mesenchymal Transition ◽  
Downstream Signaling

Abstract Two related receptor tyrosine kinases (RTKs), fibroblast growth factor receptor 1 and 2 (FGFR1 and FGFR2), exert distinct effects during carcinogenesis. To examine FGFR1 and FGFR2 signaling in polarized epithelia, we have developed an in vitro three-dimensional HC11 mouse mammary epithelial cell culture model combined with a chemically inducible FGFR (iFGFR) dimerization system. Although activation of both RTKs led to reinitiation of cell proliferation and loss of cell polarity, only iFGFR1 activation induced cell survival and epithelial to mesenchymal transition. In contrast, iFGFR2 activation induced cell apoptosis even in the cells in direct contact with the extracellular matrix. Activation of iFGFR2, but not iFGFR1, led to rapid receptor down-regulation and transient activation of downstream signaling, which were partially rescued by Cbl small interfering RNA knockdown or the proteasome inhibitor lactacystin. Importantly, inhibition of proteasome activity in iFGFR2-activated structures led to epithelial to mesenchymal transition and invasive phenotypes resembling those observed after iFGFR1 activation. These studies demonstrate, for the first time, that the duration of downstream signaling determines the distinct phenotypes mediated by very homologous RTKs in three-dimensional cultures.

scholarly journals Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Ikuko Takeda Nakamura ◽  
Shinji Kohsaka ◽  
Masachika Ikegami ◽  
Hiroshi Ikeuchi ◽  
Toshihide Ueno ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Functional Assay ◽  
Functional Evaluation ◽  
Fibroblast Growth ◽  
Wide Range

AbstractVarious genetic alterations of the fibroblast growth factor receptor (FGFR) family have been detected across a wide range of cancers. However, inhibition of FGFR signaling by kinase inhibitors demonstrated limited clinical effectiveness. Herein, we evaluated the transforming activity and sensitivity of 160 nonsynonymous FGFR mutations and ten fusion genes to seven FGFR tyrosine kinase inhibitors (TKI) using the mixed-all-nominated-in-one (MANO) method, a high-throughput functional assay. The oncogenicity of 71 mutants was newly discovered in this study. The FGFR TKIs showed anti-proliferative activities against the wild-type FGFRs and their fusions, while several hotspot mutants were relatively resistant to those TKIs. The drug sensitivities assessed with the MANO method were well concordant with those evaluated using in vitro and in vivo assays. Comprehensive analysis of published FGFR structures revealed a possible mechanism through which oncogenic FGFR mutations reduce sensitivity to TKIs. It was further revealed that recurrent compound mutations within FGFRs affect the transforming potential and TKI-sensitivity of corresponding kinases. In conclusion, our study suggests the importance of selecting suitable inhibitors against individual FGFR variants. Moreover, it reveals the necessity to develop next-generation FGFR inhibitors, which are effective against all oncogenic FGFR variants.

The ins and outs of fibroblast growth factor receptor signalling

2014 ◽  
Vol 127 (4) ◽  
pp. 217-231 ◽  
Author(s):  
Stacey J. Coleman ◽  
Charo Bruce ◽  
Athina-Myrto Chioni ◽  
Hemant M. Kocher ◽  
Richard P. Grose
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cancer Progression ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Major Focus ◽  
Receptor Signalling ◽  
Area Of Interest ◽  
Wide Range

FGFR (fibroblast growth factor receptor) signalling plays critical roles in embryogensis, adult physiology, tissue repair and many pathologies. Of particular interest over recent years, it has been implicated in a wide range of cancers, and concerted efforts are underway to target different aspects of FGFR signalling networks. A major focus has been identifying the canonical downstream signalling pathways in cancer cells, and these are now relatively well understood. In the present review, we focus on two distinct but emerging hot topics in FGF biology: its role in stromal cross-talk during cancer progression and the potential roles of FGFR signalling in the nucleus. These neglected areas are proving to be of great interest clinically and are intimately linked, at least in pancreatic cancer. The importance of the stroma in cancer is well accepted, both as a conduit/barrier for treatment and as a target in its own right. Nuclear receptors are less acknowledged as targets, largely due to historical scepticism as to their existence or importance. However, increasing evidence from across the receptor tyrosine kinase field is now strong enough to make the study of nuclear growth factor receptors a major area of interest.

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