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

Abstract

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.

Toxocara canis Differentially Affects Hepatic MicroRNA Expression in Beagle Dogs at Different Stages of Infection

“…Furthermore, the IgSF gene FGFR1 was predicted to be regulated by miRNA novel-294 at 12 hpi (Supplementary Table 3). A previous study found that FGFR1 expression improved beta-cell survival in cytokineinduced inflammation (33). Hence, we speculated that the upregulation of the novel-294 in puppies' livers promotes the immune response of puppies to T. canis infection via increasing the expression of FGFR1.…”

FGFR-TKI resistance in cancer: current status and perspectives

“…Unlike the other four members, FGFR5 (known as FGFRL1) lacks a tyrosine kinase domain. It plays a role in regulating excessive activation of the FGF-FGFR1 signaling pathway [ 4 , 5 ]. The signaling axis of FGFRs is primarily activated in a ligand-dependent manner, by binding of fibroblast growth factors (FGFs) and the subsequent receptor dimerization induced intracellular kinase transautophosphorylation events [ 6 ].…”

Dermatologic Adverse Events Associated with Selective Fibroblast Growth Factor Receptor Inhibitors: Overview, Prevention, and Management Guidelines

“…The human FGFR family comprises five members: FGFR1, FGFR2, FGFR3, FGFR4, and FGFR5. FGFRs 1–4 are receptor tyrosine kinases consisting of an extracellular ligand binding domain and a tyrosine kinase domain, which are expressed on the cell membrane [3]. FGFR fusions and other alterations have been reported in a wide range of solid tumors, including cholangiocarcinoma [4], bladder cancer [5], lung cancer [6], and glioblastoma [7].…”