C-terminal fragment of fibroblast growth factor 23 improves heart function in murine models of high intact fibroblast growth factor 23.

Cardiovascular disease (CVD) is the major cause of death in chronic kidney disease (CKD) and is associated with high circulating fibroblast growth factor (FGF)23 levels. It is unresolved whether high circulating FGF23 is a mere biomarker or pathogenically contributes to cardiomyopathy. It is also unknown whether the C-terminal FGF23 peptide (cFGF23), a natural FGF23 antagonist proteolyzed from intact FGF23 (iFGF23), retards CKD progression and improves cardiomyopathy.

Structural basis for FGF hormone signalling.

α/βKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23) and their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine FGF-FGFR complex. However, these hormones still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation and hence elicit their essential metabolic activities. To reveal the molecular mechanism underpinning the coreceptor role of HS, we solved cryo-electron microscopy structures of three distinct 1:2:1:1 FGF23-FGFR-αKlotho-HS quaternary complexes featuring the 'c' splice isoforms of FGFR1 (FGFR1c), FGFR3 (FGFR3c) or FGFR4 as the receptor component.

Sustained remission of type 2 diabetes in rodents by centrally administered fibroblast growth factor 4.

Type 2 diabetes (T2D) is a major health and economic burden worldwide. Despite the availability of multiple drugs for short-term management, sustained remission of T2D is currently not achievable pharmacologically. Intracerebroventricular administration of fibroblast growth factor 1 (icvFGF1) induces sustained remission in T2D rodents, propelling intense research efforts to understand its mechanism of action.

Gatekeeper mutations activate FGF receptor tyrosine kinases by destabilizing the autoinhibited state.

Many types of human cancers are being treated with small molecule ATP-competitive inhibitors targeting the kinase domain of receptor tyrosine kinases. Despite initial successful remission, long-term treatment almost inevitably leads to the emergence of drug resistance mutations at the gatekeeper residue hindering the access of the inhibitor to a hydrophobic pocket at the back of the ATP-binding cleft. In addition to reducing drug efficacy, gatekeeper mutations elevate the intrinsic activity of the tyrosine kinase domain leading to more aggressive types of cancer.

In vitro reconstitution reveals cooperative mechanisms of adapter protein-mediated activation of phospholipase C-γ1 in T cells.

Activation of T cells upon engagement of the T cell antigen receptor rapidly leads to a number of phosphorylation and plasma membrane recruitment events. For example, translocation of phospholipase-Cγ1 (PLC-γ1) to the plasma membrane and its association with the transmembrane adapter protein LAT and two other adapter proteins, Gads and SLP-76, are critical events in the early T cell activation process. We have previously characterized the formation of a tetrameric LAT-Gads-SLP-76-PLC-γ1 complex by reconstitution in vitro and have also characterized the thermodynamics of tetramer formation.

Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects.

Several members of the FGF family have been identified as potential regulators of glucose homeostasis. We previously reported that a low threshold of FGF-induced FGF receptor 1c (FGFR1c) dimerization and activity is sufficient to evoke a glucose lowering activity. We therefore reasoned that ligand identity may not matter, and that besides paracrine FGF1 and endocrine FGF21, other cognate paracrine FGFs of FGFR1c might possess such activity.

Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling.

Background: Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes.

Curtailing FGF19's mitogenicity by suppressing its receptor dimerization ability.

As a physiological regulator of bile acid homeostasis, FGF19 is also a potent insulin sensitizer capable of normalizing plasma glucose concentration, improving lipid profile, ameliorating fatty liver disease, and causing weight loss in both diabetic and diet-induced obesity mice. There is therefore a major interest in developing FGF19 as a therapeutic agent for treating type 2 diabetes and cholestatic liver disease. However, the known tumorigenic risk associated with prolonged FGF19 administration is a major hurdle in realizing its clinical potential.

Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice.

Background And Aims: Fibroblast growth factor (FGF) 1 demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic and obese mice by an uncertain mechanism. This study investigated the therapeutic activity and mechanism of a nonmitogenic FGF1 variant carrying 3 substitutions of heparin-binding sites (FGF1 ) against NAFLD.

Approach And Results: FGF1 administration was effective in 9-month-old diabetic mice carrying a homozygous mutation in the leptin receptor gene (db/db) with NAFLD; liver weight, lipid deposition, and inflammation declined and liver injury decreased.

Fibroblast growth factor signalling in osteoarthritis and cartilage repair.

Regulated fibroblast growth factor (FGF) signalling is a prerequisite for the correct development and homeostasis of articular cartilage, as evidenced by the fact that aberrant FGF signalling contributes to the maldevelopment of joints and to the onset and progression of osteoarthritis. Of the four FGF receptors (FGFRs 1-4), FGFR1 and FGFR3 are strongly implicated in osteoarthritis, and FGFR1 antagonists, as well as agonists of FGFR3, have shown therapeutic efficacy in mouse models of spontaneous and surgically induced osteoarthritis. FGF18, a high affinity ligand for FGFR3, is the only FGF-based drug currently in clinical trials for osteoarthritis.

C-FGF23 peptide alleviates hypoferremia during acute inflammation.

Hypoferremia results as an acute phase response to infection and inflammation aiming to reduce iron availability to pathogens. Activation of toll-like receptors (TLRs), the key sensors of the innate immune system, induces hypoferremia mainly through the rise of the iron hormone hepcidin. Conversely, stimulation of erythropoiesis suppresses hepcidin expression via induction of the erythropoietin-responsive hormone erythroferrone.

FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis.

Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription.

Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation.

A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer.

Paracrine-endocrine FGF chimeras as potent therapeutics for metabolic diseases.

Background: The development of a clinically useful fibroblast growth factor 21 (FGF21) hormone has been impeded by its inherent instability and weak FGF receptor (FGFR) binding affinity. There is an urgent need for innovative approaches to overcome these limitations.

Methods: We devised a structure-based chimerisation strategy in which we substituted the thermally labile and low receptor affinity core of FGF21 with an HS binding deficient endocrinised core derived from a stable and high receptor affinity paracrine FGF1 (FGF1).

A G protein-coupled, IP3/protein kinase C pathway controlling the synthesis of phosphaturic hormone FGF23.

Dysregulated actions of bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) result in several inherited diseases, such as X-linked hypophosphatemia (XLH), and contribute substantially to the mortality in kidney failure. Mechanisms governing FGF23 production are poorly defined. We herein found that ablation of the Gq/11α-like, extralarge Gα subunit (XLαs), a product of GNAS, exhibits FGF23 deficiency and hyperphosphatemia in early postnatal mice (XLKO).

A Conserved Allosteric Pathway in Tyrosine Kinase Regulation.

An autoinhibitory network of hydrogen bonds located at the kinase hinge (referred to as the "molecular brake") regulates the activity of several receptor tyrosine kinases. The mechanism whereby mutational disengagement of the brake allosterically activates the kinase in human disease is incompletely understood. We used a combination of NMR, bioinformatics, and molecular dynamics simulation to show that mutational disruption of the molecular brake triggers localized conformational perturbations that propagate to the active site.

Structural Biology of the FGF7 Subfamily.

Mammalian fibroblast growth factor (FGF) signaling is intricately regulated via selective binding interactions between 18 FGF ligands and four FGF receptors (FGFR1-4), three of which (FGFR1-3) are expressed as either epithelial ("b") or mesenchymal ("c") splice isoforms. The FGF7 subfamily, consisting of FGF3, FGF7, FGF10, and FGF22, is unique among FGFs in that its members are secreted exclusively by the mesenchyme, and specifically activate the "b" isoforms of FGFR1 (FGFR1b) and FGFR2 (FGFR2b) present in the overlying epithelium. This unidirectional mesenchyme-to-epithelium signaling contributes to the development of essentially all organs, glands, and limbs.

Fibroblast Growth Factor Binding Protein 3 (FGFBP3) impacts carbohydrate and lipid metabolism.

Secreted FGF binding proteins (FGFBP) mobilize locally-acting paracrine FGFs from their extracellular storage. Here, we report that FGFBP3 (BP3) modulates fat and glucose metabolism in mouse models of metabolic syndrome. BP3 knockout mice exhibited altered lipid metabolism pathways with reduced hepatic and serum triglycerides.

A threshold model for receptor tyrosine kinase signaling specificity and cell fate determination.

Upon ligand engagement, the single-pass transmembrane receptor tyrosine kinases (RTKs) dimerize to transmit qualitatively and quantitatively different intracellular signals that alter the transcriptional landscape and thereby determine the cellular response. The molecular mechanisms underlying these fundamental events are not well understood. Considering recent insights into the structural biology of fibroblast growth factor signaling, we propose a threshold model for RTK signaling specificity in which quantitative differences in the strength/longevity of ligand-induced receptor dimers on the cell surface lead to quantitative differences in the phosphorylation of activation loop (A-loop) tyrosines as well as qualitative differences in the phosphorylation of tyrosines mediating substrate recruitment.

Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia.

Severe anemia and iron deficiency are common complications in chronic kidney disease. The cause of renal anemia is multifactorial and includes decreased erythropoietin (Epo) production, iron deficiency, and inflammation, and it is currently treated with injections of synthetic Epo. However, the use of recombinant Epo has several adverse effects.

α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.

The ageing suppressor α-klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown.

A novel fibroblast growth factor-1 ligand with reduced heparin binding protects the heart against ischemia-reperfusion injury in the presence of heparin co-administration.

Aims: Fibroblast growth factor 1 (FGF1), a heparin/heparan sulfate-binding growth factor, is a potent cardioprotective agent against myocardial infarction (MI). The impact of heparin, the standard of care for MI patients entering the emergency room, on cardioprotective effects of FGF1 is unknown, however.

Methods And Results: To address this, a rat model of MI was employed to compare cardioprotective potentials (lower infarct size and improve post-ischemic function) of native FGF1 and an engineered FGF1 (FGF1ΔHBS) with reduced heparin-binding affinity when given at the onset of reperfusion in the absence or presence of heparin.

Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability.

The recent discovery of metabolic roles for fibroblast growth factor 1 (FGF1) in glucose homeostasis has expanded the functions of this classically known mitogen. To dissect the molecular basis for this functional pleiotropy, we engineered an FGF1 partial agonist carrying triple mutations (FGF1) that diminished its ability to induce heparan sulfate (HS)-assisted FGF receptor (FGFR) dimerization and activation. FGF1 exhibited a severely reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1 in vitro and in vivo.

Regulation of Receptor Binding Specificity of FGF9 by an Autoinhibitory Homodimerization.

The epithelial fibroblast growth factor 9 (FGF9) subfamily specifically binds and activates the mesenchymal "c" splice isoform of FGF receptors 1-3 (FGFR1-3) to regulate organogenesis and tissue homeostasis. The unique N and C termini of FGF9 subfamily ligands mediate a reversible homodimerization that occludes major receptor binding sites within the ligand core region. Here we provide compelling X-ray crystallographic, biophysical, and biochemical data showing that homodimerization controls receptor binding specificity of the FGF9 subfamily by keeping the concentration of active FGF9 monomers at a level, which is sufficient for a normal FGFR "c" isoform binding/signaling, but is insufficient for an illegitimate FGFR "b" isoform binding/signaling.

, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 () is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH mutation (p.