Unliganded Fibroblast Growth Factor Receptor 1 Forms Density-independent Dimers

Comps-Agrar, Laëtitia; Dunshee, Diana Ronai; Eaton, Dan; Sonoda, Junichiro

doi:10.1074/jbc.m115.681395

Cited by 26 publications

(19 citation statements)

References 58 publications

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“…Furthermore, FRET studies indicate that FGFR-1c forms dimeric assemblies in the membrane prior to FGF binding (although the structural details of such dimers are unknown, they have non-active tyrosine kinase moieties). 85 The present results are therefore consistent with S116R promoting initial assembly of the FGFR-1c signal transduction complex (as represented by the 3OJV structure) by enhancement of FGF-1/FGFR* dimer interface interactions (for FGFR-1c and FGFR-3c). Such an assembly complex may undergo subsequent structural rearrangement to produce a competent signal transduction assembly (represented by 1FQ9 or 1E0O structures).…”

Section: Discussionsupporting

confidence: 89%

An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities

Xia

Kumru

Blaber

et al. 2016

Journal of Pharmaceutical Sciences

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Fibroblast growth factor-1 (FGF-1), a potent human mitogen and insulin sensitizer, signals through both tyrosine kinase receptoremediated autocrine/paracrine pathways as well as a nuclear intracrine pathway. Phosphorylation of FGF-1 at serine 116 (S116) has been proposed to regulate intracrine signaling. Position S116 is located within a ~17 amino acid C-terminal loop that contains a rich set of functional determinants including heparin\heparan sulfate affinity, thiol reactivity, nuclear localization, pharmacokinetics, functional half-life, nuclear ligand affinity, stability, and structural dynamics. Mutational targeting of specific functionality in this region without perturbing other functional determinants is a design challenge. S116R is a non-phosphorylatable variant present in bovine FGF-1 and other members of the human FGF family. We show that the S116R mutation in human FGF-1 is accommodated with no perturbation of biophysical or structural properties, and is therefore an attractive mutation with which to elucidate the functional role of phosphorylation. Characterization of S116R shows reduction in NIH 3T3 fibroblast mitogenic stimulation, increase in fibroblast growth factor receptor-1c activation, and prolonged duration of glucose lowering in ob/ob hyperglycemic mice. A novel FGF-1/fibroblast growth factor receptor-1c dimerization interaction combined with non-phosphorylatable intracrine signaling is hypothesized to be responsible for these observed functional effects.

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Section: Discussionsupporting

confidence: 89%

An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities

Xia

Kumru

Blaber

et al. 2016

Journal of Pharmaceutical Sciences

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“…These receptor complexes undergo conformational changes upon ligand occupancy (56). To establish directly its cofactor role in FGF23-sensitive phosphate transport, we knocked down ␣Klotho in RPTECs and determined its effect on FGF23 and PTH action on phosphate uptake.…”

Section: Resultsmentioning

confidence: 99%

Convergent Signaling Pathways Regulate Parathyroid Hormone and Fibroblast Growth Factor-23 Action on NPT2A-mediated Phosphate Transport

Sneddon¹,

Ruiz

Gallo

et al. 2016

Journal of Biological Chemistry

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Parathyroid hormone (PTH) and FGF23 are the primary hormones regulating acute phosphate homeostasis. Human renal proximal tubule cells (RPTECs) were used to characterize the mechanism and signaling pathways of PTH and FGF23 on phosphate transport and the role of the PDZ protein NHERF1 in mediating PTH and FGF23 effects. RPTECs express the NPT2A phosphate transporter, ␣Klotho, FGFR1, FGFR3, FGFR4, and the PTH receptor. FGFR1 isoforms are formed from alternate splicing of exon 3 and of exon 8 or 9 in Ir-like loop 3. Exon 3 was absent, but mRNA containing both exons 8 and 9 is present in cytoplasm. Using an FGFR1c-specific antibody together with mass spectrometry analysis, we show that RPTECs express FGFR-␤1C. The data are consistent with regulated FGFR1 splicing involving a novel cytoplasmic mechanism. PTH and FGF23 inhibited phosphate transport in a concentration-dependent manner. At maximally effective concentrations, PTH and FGF23 equivalently decreased phosphate uptake and were not additive, suggesting a shared mechanism of action. Protein kinase A or C blockade prevented PTH but not FGF23 actions. Conversely, inhibiting SGK1, blocking FGFR dimerization, or knocking down Klotho expression disrupted FGF23 actions but did not interfere with PTH effects. C-terminal FGF23(180 -251) competitively and selectively blocked FGF23 action without disrupting PTH effects. However, both PTH and FGF23-sensitive phosphate transport were abolished by NHERF1 shRNA knockdown. Extended treatment with PTH or FGF23 down-regulated NPT2A without affecting NHERF1. We conclude that FGFR1c and PTHR signaling pathways converge on NHERF1 to inhibit PTH-and FGF23-sensitive phosphate transport and down-regulate NPT2A.Parathyroid hormone (PTH) 2 and FGF23 display two remarkable features: 1) PTH and FGF23 exhibit parallel inhibition of renal phosphate transport mediated by NPT2A (sodium-dependent phosphate transporter-2a) but opposing actions on 1,25(OH) 2 -vitamin D; 2) despite being structurally and functionally distinct classes of membrane-delimited receptors, PTH and FGF receptors activate kinases that obligatorily phosphorylate NHERF1 at conserved sites required for their phosphaturic action. Phosphorus is essential for growth and maintenance of the skeleton and for generating high energy phosphate compounds. Evolutionary adaptation in humans and other terrestrial vertebrates to phosphorus-rich diets involves cell and molecular mechanisms ensuring the efficient urinary elimination of excess inorganic phosphate. The renal proximal tubule is the primary site of phosphate homeostasis and hormone-dependent phosphate transport. The NPT2A sodium-dependent phosphate cotransporter (SLC34A1) in proximal tubules is regulated by PTH and FGF23 (1, 2). PTH and FGF23 reduce phosphate uptake by sequestering and down-regulating NPT2A, thereby enhancing urinary phosphate excretion (3, 4). PTH actions are mediated by its cognate G protein-coupled PTH receptor (PTHR) (5, 6). Both PKA and PKC have been implicated in PTH-dependent inhibition of NPT2A (7-12)....

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“…This was first reported for FGF19 in 2002 [12], [13] and soon thereafter for FGF21 [14], [15], [16]. The similarity in the metabolic effects of FGF21 and FGF19 was further substantiated by the subsequent discovery that they act through common receptors, namely the "c" splice isoform of FGFR1, 2 and 3, bound by the obligatory coreceptor βKlotho (KLB) (Figure 1) [17], [18], [19], [20].…”

Section: Introductionmentioning

confidence: 81%

FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

Sonoda¹,

Chen²,

Baruch

2017

Hormone Molecular Biology and Clinical Investigation

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Abstract:Fibroblast growth factor 21 (FGF21) analogs and FGF21 receptor agonists (FGF21RAs) that mimic FGF21 ligand activity constitute the new "FGF21-class" of anti-obesity and anti-diabetic molecules that improve insulin sensitivity, ameliorate hepatosteatosis and promote weight loss. The metabolic actions of FGF21-class proteins in obese mice are attributed to stimulation of brown fat thermogenesis and increased secretion of adiponectin. The therapeutic utility of this class of molecules is being actively investigated in clinical trials for the treatment of type 2 diabetes and non-alcoholic steatohepatitis (NASH). This review is focused on various FGF21-class molecules, their molecular designs and the preclinical and clinical activities. These molecules include modified FGF21 as well as agonistic antibodies against the receptor for FGF21, namely the complex of FGF receptor 1 (FGFR1) and the obligatory coreceptor βKlotho (KLB). In addition, a novel approach to increase endogenous FGF21 activity by inhibiting the FGF21-degrading protease fibroblast activation protein (FAP) is discussed.

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Unliganded Fibroblast Growth Factor Receptor 1 Forms Density-independent Dimers

Cited by 26 publications

References 58 publications

An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities

An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities

Convergent Signaling Pathways Regulate Parathyroid Hormone and Fibroblast Growth Factor-23 Action on NPT2A-mediated Phosphate Transport

FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

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