Canonical Fibroblast Growth Factors Research Articles

Canonical fibroblast growth factors in viral infection.

Fibroblast growth factors (FGFs) are a family of proteins that play a crucial role in the development and maintenance of various tissues in the body. There are three function-al groups of FGFs: canonical FGFs (cFGFs), intracellularly retained FGFs, and metabolic (also called endocrine) FGFs. cFGFs are secreted and act in an autocrine/paracrine fashion to regulate differentiation during foetal development, as well as tissue repair in adults. Recent studies have also begun to unravel the role of cFGFs during viral infections, suggesting that FGF-2 and other canonical FGFs may have an important virus-specific role, also by the regulation of the immune response. Because dysregulation in the FGF pathways is pivotal in cancer development, FGFs are the target of many anticancer drugs. These drugs may be repurposed to treat viral infection, since dysregulation of FGF signalling has been implicated in the pathogenesis of viral infections, such as hepatitis C. Overall, the role of cFGFs during viral infection is an underrepresented area of current research. This review focuses on overviewing the effects of canonical FGFs during infection by different viruses. Many studies highlight that the effects of FGFs during viral infection may be complex and context-dependent. While there is evidence to suggest that FGFs may have a beneficial impact on the immune response and tissue repair during viral infection, further studies are needed to fully understand the mechanisms underlying these effects and to determine in what cases FGFs could be targeted as a therapeutic approach for viral infection.

New developments in the biology of fibroblast growth factors.

The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltage-gated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology Congenital Diseases > Stem Cells and Development Cancer > Stem Cells and Development.

The FGF/FGFR system in the physiopathology of the prostate gland.

Fibroblast growth factors (FGFs) are a family of proteins possessing paracrine, autocrine, or endocrine functions in a variety of biological processes, including embryonic development, angiogenesis, tissue homeostasis, wound repair, and cancer. Canonical FGFs bind and activate tyrosine kinase FGF receptors (FGFRs), triggering intracellular signaling cascades that mediate their biological activity. Experimental evidence indicates that FGFs play a complex role in the physiopathology of the prostate gland that ranges from essential functions during embryonic development to modulation of neoplastic transformation. The use of ligand- and receptor-deleted mouse models has highlighted the requirement for FGF signaling in the normal development of the prostate gland. In adult prostate, the maintenance of a functional FGF/FGFR signaling axis is critical for organ homeostasis and function, as its disruption leads to prostate hyperplasia and may contribute to cancer progression and metastatic dissemination. Dissection of the molecular landscape modulated by the FGF family will facilitate ongoing translational efforts directed toward prostate cancer therapy.

Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells.

It is a well-documented event that fibroblast growth factors (FGFs) regulate liver development and homeostasis in autocrine, paracrine, and endocrine manners via binding and activating FGF receptors (FGFRs) tyrosine kinase in hepatocytes. Recent research reveals that hepatic stellate cells (HSCs) play a fundamental role in liver immunology. However, how FGF signaling in HSCs regulates liver inflammation remains unclear. Here, we report that FGF promoted NF-κB signaling, an inflammatory pathway, in human HSCs, which was associated with FGFR1 expression. Both FGF and NF-κB signaling in HSCs were compromised by FGFR1 tyrosine kinase inhibitor. After stimulating HSCs with proinflammatory cytokines, expression of multiple FGF ligands was significantly increased. However, disruption of FGF signaling with FGFR inhibitors prominently reduced the apoptosis, inflammatory response, NF-κB nuclear translocation, and expression of matrix metalloproteinase-9 (MMP-9) induced by TNFα in HSCs. Interestingly, FGF21 significantly alleviated the inflammation responses in the concanavalin A (Con A)-induced acutely injured liver. Unlike canonic FGFs that elicit signals through activating the FGFR–heparan sulfate complex, FGF21 activates the FGFR–KLB complex and elicits a different set of signals. Therefore, the finding here indicates the urgency of developing pathway-specific inhibitors that only suppress canonical FGF, but not non-canonical FGF21, signaling for alleviating inflammation in the liver, which is presented in all stages of diseased liver.

FHF1 is a bona fide fibroblast growth factor that activates cellular signaling in FGFR-dependent manner

Fibroblast growth factors (FGFs) via their receptors (FGFRs) transduce signals from the extracellular space to the cell interior, modulating pivotal cellular processes such as cell proliferation, motility, metabolism and death. FGF superfamily includes a group of fibroblast growth factor homologous factors (FHFs), proteins whose function is still largely unknown. Since FHFs lack the signal sequence for secretion and are unable to induce FGFR-dependent cell proliferation, these proteins were considered as intracellular proteins that are not involved in signal transduction via FGFRs. Here we demonstrate for the first time that FHF1 directly interacts with all four major FGFRs. FHF1 binding causes efficient FGFR activation and initiation of receptor-dependent signaling cascades. However, the biological effect of FHF1 differs from the one elicited by canonical FGFs, as extracellular FHF1 protects cells from apoptosis, but is unable to stimulate cell division. Our data define FHF1 as a FGFR ligand, emphasizing much greater similarity between FHFs and canonical FGFs than previously indicated.81CmN2k-d47mwAPaQtumJyVideo . (MP4 38460 kb)Graphical abstract

Heparan Sulfate Sulfation by Hs2st Restricts Astroglial Precursor Somal Translocation in Developing Mouse Forebrain by a Non-Cell-Autonomous Mechanism.

Heparan sulfate (HS) is a cell surface and extracellular matrix carbohydrate extensively modified by differential sulfation. HS interacts physically with canonical fibroblast growth factor (FGF) proteins that signal through the extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK) pathway. At the embryonic mouse telencephalic midline, FGF/ERK signaling drives astroglial precursor somal translocation from the ventricular zone of the corticoseptal boundary (CSB) to the induseum griseum (IG), producing a focus of Slit2-expressing astroglial guidepost cells essential for interhemispheric corpus callosum (CC) axon navigation. Here, we investigated the cell and molecular function of a specific form of HS sulfation, 2-O HS sulfation catalyzed by the enzyme Hs2st, in midline astroglial development and in regulating FGF protein levels and interaction with HS. Hs2st−/− embryos of either sex exhibit a grossly enlarged IG due to precocious astroglial translocation and conditional Hs2st mutagenesis and ex vivo culture experiments show that Hs2st is not required cell autonomously by CC axons or by the IG astroglial cell lineage, but rather acts non-cell autonomously to suppress the transmission of translocation signals to astroglial precursors. Rescue of the Hs2st−/− astroglial translocation phenotype by pharmacologically inhibiting FGF signaling shows that the normal role of Hs2st is to suppress FGF-mediated astroglial translocation. We demonstrate a selective action of Hs2st on FGF protein by showing that Hs2st (but not Hs6st1) normally suppresses the levels of Fgf17 protein in the CSB region in vivo and use a biochemical assay to show that Hs2st (but not Hs6st1) facilitates a physical interaction between the Fgf17 protein and HS.SIGNIFICANCE STATEMENT We report a novel non-cell-autonomous mechanism regulating cell signaling in developing brain. Using the developing mouse telencephalic midline as an exemplar, we show that the specific sulfation modification of the cell surface and extracellular carbohydrate heparan sulfate (HS) performed by Hs2st suppresses the supply of translocation signals to astroglial precursors by a non-cell-autonomous mechanism. We further show that Hs2st modification selectively facilitates a physical interaction between Fgf17 and HS and suppresses Fgf17 protein levels in vivo, strongly suggesting that Hs2st acts selectively on Fgf17 signaling. HS interacts with many signaling proteins potentially encoding numerous selective interactions important in development and disease, so this class of mechanism may apply more broadly to other biological systems.

Structures of β-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling.

Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. Here we describe the crystal structures of free and ligand-bound β-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards β-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. β-Klotho serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs.

Fibroblast Growth Factors in the Gastrointestinal Tract: Twists and Turns.

Fibroblast growth factors (FGFs) are a family of conserved peptides that play an important role in the development, homeostasis, and repair processes of many organ systems, including the gastrointestinal tract. All four FGF receptors and several FGF ligands are present in the intestine. They play important roles in controlling cell proliferation, differentiation, epithelial cell restitution, and stem cell maintenance. Several FGFs have also been proven to be protective against gastrointestinal diseases such as inflammatory bowel diseases or to aid in regeneration after intestinal loss associated with short bowel syndrome. Herein, we review the multifaceted actions of canonical FGFs in intestinal development, homeostasis, and repair in rodents and humans. Developmental Dynamics 246:344-352, 2017. © 2016 Wiley Periodicals, Inc.

Functional diversity of fibroblast growth factors in bone formation.

The functional significance of fibroblast growth factor (FGF) signaling in bone formation has been demonstrated through genetic loss-of-function and gain-of-function approaches. FGFs, comprising 22 family members, are classified into three subfamilies: canonical, hormone-like, and intracellular. The former two subfamilies activate their signaling pathways through FGF receptors (FGFRs). Currently, intracellular FGFs appear to be primarily involved in the nervous system. Canonical FGFs such as FGF2 play significant roles in bone formation, and precise spatiotemporal control of FGFs and FGFRs at the transcriptional and posttranscriptional levels may allow for the functional diversity of FGFs during bone formation. Recently, several research groups, including ours, have shown that FGF23, a member of the hormone-like FGF subfamily, is primarily expressed in osteocytes/osteoblasts. This polypeptide decreases serum phosphate levels by inhibiting renal phosphate reabsorption and vitamin D3 activation, resulting in mineralization defects in the bone. Thus, FGFs are involved in the positive and negative regulation of bone formation. In this review, we focus on the reciprocal roles of FGFs in bone formation in relation to their local versus systemic effects.

Commentary: FGF21 Holds Promises for Treating Obesity-related Insulin Resistance and Hepatosteatosis

Fibroblast growth factor (FGF) 21 is the first cloned and identified member of an atypical subfamily of endocrine fibroblast growth factors lacking the conventional heparin-binding domain and secreted into the circulation as a true hormone (1). FGF21 is widely expressed in multiple peripheral tissues, including liver, skeletal muscle, pancreas, and white and brown adipose tissue (WAT and BAT, respectively). Unlike the classical fibroblast growth factors, FGF21 does not have mitogenic activities but acts as a hormone exerting several autocrine/paracrine effects, such as the control of glucose metabolism, insulin sensitivity, lipid homeostasis, and energy balance in experimental models, and results independently associated with several features of metabolic syndrome in humans (2–4). Circulating FGF21 exerts its activity through the extracellular binding to a canonical FGF receptor (FGFR) and a coreceptor called -Klotho. -Klotho coreceptor is preferentially expressed by cells that produce/release FGF21, such as hepatocytes, adipocytes, and pancreatic cells (5). In addition, mRNA expression analysis by real-time quantitative PCR demonstrated that -Klotho coreceptor was abundantly also in other organs, including gall bladder, colon, and aorta (6). The molecular mechanisms that regulate different cellspecific metabolic effects of FGF21 remain unclear even though several crucial networks have been proposed (7– 9). In fact, on binding to -Klotho coreceptor, FGFRs (particularly FGFR1c) can improve pancreatic cells by activation of downstream ERK1/2 and Akt signaling (7). Moreover, a recent study highlights that although ERK1/2 pathway in adipose tissue may be crucial for the FGF21mediated reduction of fat mass, alternative pathways (ie, peroxisome proliferator-activated receptor) and other secretory factors (ie, adiponectin) seem to be essential to lead obesity-induced impairment in insulin signaling in liver and skeletal muscle (8). Interestingly, recently, Muise et al (9) identified novel FGF21-dependent downstream molecular pathways, such as ubiquitin-protein ligase Mdm2, myosin phosphatase target subunit 1, and Signal transducer, and activator of transcription 3, in adipocytes. The first evidence of FGF21-dependent effects was reported in 2005 when Kharitonenkov et al (2) demonstrated that transgenic mice overexpressing hepatic FGF21 displayed improved insulin sensitivity, glucose clearance, and reduced triglyceride levels and were resistant to high-fat-diet–induced obesity. Moreover, FGF21 plays important roles in other physiological processes, including fasting and feeding, GH axis, and thermogenesis (10). As circulating FGF21 levels increase in human subjects affected by obesity-related diseases, including insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD), the clinical relevance of this factor has substantially increased over the years (11–13). In fact, very recently, a clinical trial demonstrated that the 28-day treatment with LY2405319, a variant of FGF21, may improve dyslipidemia, body weight, and fasting insulin, in human obese adults with type 2 diabetes (14). Furthermore, mice genetically lacking FGF21 presented an increase rather than a reduction of body weight and accumulated triglycerides in the liver in response to ketogenic diets (15). These discrepancies between the pathogenetic role of high levels of FGF21 in obesity-related diseases and

Common Senses

Many of the signaling pathways shared between vertebrates and invertebrates were present in the eumetazoan, the ancestor of all multicellular animals, as evidenced by their presence in the sea anemone Nematostella vectensis . Fibroblast growth factor (FGF) signaling performs varied functions throughout an animal’s lifetime and is required during early embryogenesis for gastrulation and neural cell fate specification, including the specification of sensory structures. Rentzsch et al. suggest that sensory organ specification was one of its ancestral roles. Nematostella has only one larval sensory organ, the apical organ, which forms at the aboral pole of the embryo (opposite the mouth) and allows the animal to find a suitable place for settlement and metamorphosis. Expression analysis revealed that genes encoding two FGF ligands, NvFGFa1 and NvFGFa2 , and one encoding a FGF receptor, NvFGFRa , were expressed at the embryonic apical pole. Knockdown with morpholino oligonucleotides of either NvFGFa1 or NvFGFRa produced larvae that lacked an apical organ and that were able to swim but failed to settle and metamorphose. Conversely, knockdown of NvFGFa2 generated larvae with expanded apical organs. Signaling by NvFGFa1 was required to maintain expression of both NvFGFa1 and NvFGFa2 , thereby establishing both positive and negative feedback mechanisms. Pharmacological experiments suggested that NvFGFa1 signaled through a mitogen-activated protein kinase (MAPK) cascade. The region of the embryo in which NvFGFa1 and NvFGFRa were expressed expanded in the absence of NvFGFa2. Thus, two FGFs antagonize one another to induce the apical organ and at least NvFGFa1 signals through a pathway that is very much like the canonical FGF pathway of more complex animals. Although sea anemones do not have a centralized nervous system, the larval sensory organ is induced by the same pathway that contributes to neural cell fating and sensory organ induction in more complex nervous systems. F. Rentzsch, J. H. Fritzenwanker, C. B. Scholz, U. Technau, FGF signalling controls formation of the apical sensory organ in the cnidarian Nematostella vectensis . Development 135 , 1761-1769 (2008). [Abstract] [Full Text]

Actions and Mode of Actions of FGF19 Subfamily Members

Fibroblast growth factors (FGFs) are humoral factors with diverse biological functions. While most FGFs were shown to work as local factors regulating cell growth and differentiation, recent investigations indicated that FGF19 subfamily members, FGF15/19, FGF21 and FGF23 work as systemic factors. FGF15/19 produced by intestine inhibits bile acid synthesis and FGF21from liver is involved in carbohydrate and lipid metabolism. In addition, FGF23 was shown to be produced by bone and regulate phosphate and vitamin D metabolism. Furthermore, these FGFs require klotho or betaklotho for their actions in addition to canonical FGF receptors. It is possible that these FGFs together with their receptor systems might be targets for novel therapeutic measures in the future.

Functional evolutionary history of the mouse Fgf gene family

Fibroblast Growth Factors (FGFs) are polypeptides with diverse activities in development and physiology. The mammalian Fgf family can be divided into the intracellular Fgf11/12/13/14 subfamily (iFGFs), the hormone-like Fgf15/21/23 subfamily (hFGFs), and the canonical Fgf subfamilies, including Fgf1/2/5, Fgf3/4/6, Fgf7/10/22, Fgf8/17/18, and Fgf9/16/20. However, all Fgfs are evolutionarily related. We propose that an Fgf13-like gene is the ancestor of the iFgf subfamily and the most likely evolutionary ancestor of the entire Fgf family. Potential ancestors of the canonical and hFgf subfamilies, Fgf4-, Fgf5-, Fgf8-, Fgf9-, Fgf10-, and Fgf15-like, appear to have derived from an Fgf13-like ancestral gene. Canonical FGFs function in a paracrine manner, while hFGFs function in an endocrine manner. We conclude that the ancestral Fgfs for these subfamilies acquired this functional diversity before the evolution of vertebrates. During the evolution of early vertebrates, the Fgf subfamilies further expanded to contain three or four members in each subfamily.

Co-receptor Requirements for Fibroblast Growth Factor-19 Signaling

FGF19 is a unique member of the fibroblast growth factor (FGF) family of secreted proteins that regulates bile acid homeostasis and metabolic state in an endocrine fashion. Here we investigate the cell surface receptors required for signaling by FGF19. We show that betaKlotho, a single-pass transmembrane protein highly expressed in liver and fat, induced ERK1/2 phosphorylation in response to FGF19 treatment and significantly increased the interactions between FGF19 and FGFR4. Interestingly, our results show that alphaKlotho, another Klotho family protein related to betaKlotho, also induced ERK1/2 phosphorylation in response to FGF19 treatment and increased FGF19-FGFR4 interactions in vitro, similar to the effects of betaKlotho. In addition, heparin further enhanced the effects of both alphaKlotho and betaKlotho in FGF19 signaling and interaction experiments. These results suggest that a functional FGF19 receptor may consist of FGF receptor (FGFR) and heparan sulfate complexed with either alphaKlotho or betaKlotho.

Klotho converts canonical FGF receptor into a specific receptor for FGF23

FGF23 is a unique member of the fibroblast growth factor (FGF) family because it acts as a hormone that derives from bone and regulates kidney functions, whereas most other family members are thought to regulate various cell functions at a local level. The renotropic activity of circulating FGF23 indicates the possible presence of an FGF23-specific receptor in the kidney. Here we show that a previously undescribed receptor conversion by Klotho, a senescence-related molecule, generates the FGF23 receptor. Using a renal homogenate, we found that Klotho binds to FGF23. Forced expression of Klotho enabled the high-affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wild-type mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signalling, we searched for other components of the FGF23 receptor and found FGFR1(IIIc), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. These findings provide insights into the diversity and specificity of interactions between FGF and FGF receptors.