Biochemistry, Genetics and Molecular Biology › Molecular Biology

Fibroblast Growth Factor Research

Works Count: 30587

Wikipedia

Description

This cluster of papers focuses on the Fibroblast Growth Factor (FGF) signaling pathway, covering its role in development, metabolism, cancer, and therapy. It explores the involvement of FGF21, FGF receptors, and PPARa in various physiological processes such as hepatic lipid metabolism, insulin sensitivity, and bone development. Additionally, it discusses the potential therapeutic implications of targeting FGF signaling in conditions like obesity and cancer.

Keywords

Fibroblast Growth Factor; FGF21; Receptor; Signaling; Cancer; Metabolism; Therapy; Development; PPARa; Obesity

Fibroblast precursors in normal and irradiated mouse hematopoietic organs.

1976-09-01

Friedenstein Aj , Gorskaja Jf , Kulagina Nn

Structural and Functional Diversity in the FGf Receptor Multigene Family

1992-01-01

Daniel E. Johnson , Lewis T. Williams

Interleukin 1, a potential regulator of fibroblast proliferation.

1982-05-01

John A. Schmidt , S B Mizel , Donald A. Cohen +1 more

The Fgf Family of Growth Factors and Oncogenes

1992-01-01

Claudio Basilico , David Moscatelli

An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis

2000-02-01

Laurence De Moerlooze , Bradley Spencer‐Dene , Jean‐Michel Revest +3 more

ABSTRACT The fibroblast growth factor receptor 2 gene is differentially spliced to encode two transmembrane tyrosine kinase receptor proteins that have different ligandbinding specificities and exclusive tissue distributions. We have … ABSTRACT The fibroblast growth factor receptor 2 gene is differentially spliced to encode two transmembrane tyrosine kinase receptor proteins that have different ligandbinding specificities and exclusive tissue distributions. We have used Cre-mediated excision to generate mice lacking the IIIb form of fibroblast growth factor receptor 2 whilst retaining expression of the IIIc form. Fibroblast growth factor receptor 2(IIIb) null mice are viable until birth, but have severe defects of the limbs, lung and anterior pituitary gland. The development of these structures appears to initiate, but then fails with the tissues undergoing extensive apoptosis. There are also developmental abnormalities of the salivary glands, inner ear, teeth and skin, as well as minor defects in skull formation. Our findings point to a key role for fibroblast growth factor receptor 2(IIIb) in mesenchymal-epithelial signalling during early organogenesis.

Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia

1994-07-01

Rita Shiang , Leslie M. Thompson , Yazhen Zhu +5 more

Heparin protects basic and acidic FGF from inactivation

1986-09-01

Denis Gospodarowicz , Jaw‐Jou Kang

Abstract The ability of heparin or that of hexuronyl hexosaminoglygan sulfate (HHS‐4) to protect basic or acidic fibroblast growth factor (FGF) from acid or heat inactivation has been analyzed. Both … Abstract The ability of heparin or that of hexuronyl hexosaminoglygan sulfate (HHS‐4) to protect basic or acidic fibroblast growth factor (FGF) from acid or heat inactivation has been analyzed. Both freshly prepared basic and acidic FGF stimulate the growth of baby hamster kidney (BHK‐21) cells exposed to medium supplemented with transferrin and insulin. Freshly prepared basic FGF was 10 fold more potent than acidic FGF. The addition of heparin to the medium decreased the potency of basic FGF while it potentiated that of acidic FGF. Upon storage of FGF at −80°C, a decline in potency of both basic and acidic FGF was observed. Heparin, when added to the medium, potentiated their activities, which became similar to that of freshly prepared basic FGF. In order to test whether heparin could protect basic or acidic FGF from inactivation, both mitogens were exposed to acid conditions (1% trifluoroacetic acid, pH 1.08, 2 h) or heat (65°C, 5 min) which inactivate basic or acidic FGF. When exposed to such treatment in the presence of heparin or HHS‐4, basic and acidic FGF retained their potency. The effect of heparin and HHS‐4 on the bioactivity of basic and acidic FGF is truly of a protective nature, since they had no effect when added after inactivation of the mitogens. Potentiation of the bioactivity of the protected mitogens or of the inactivated one could only be observed when cells were exposed to high heparin or HHS‐4 concentrations. This indicates that heparin and HHS‐4, in addition to protecting FGF from inactivation, also acts at another locus, as yet unidentified.

Recent developments in the cell biology of basic fibroblast growth factor.

1989-07-01

Daniel B. Rifkin , David Moscatelli

Revue sur les connaissances actuelles concernant la biologie des facteurs de croissance basiques: biosynthese, localisation, activites biologiques, proteines associees, potentiel transformant, recepteurs, liberation, interactions avec les matrices Revue sur les connaissances actuelles concernant la biologie des facteurs de croissance basiques: biosynthese, localisation, activites biologiques, proteines associees, potentiel transformant, recepteurs, liberation, interactions avec les matrices

View PDF Chat

Nucleotide Sequence of a Bovine Clone Encoding the Angiogenic Protein, Basic Fibroblast Growth Factor

1986-08-01

Judith A. Abraham , Ayalew Mergia , Jacqueline L. Whang +5 more

Basic and acidic fibroblast growth factors (FGF's) are potent mitogens for capillary endothelial cells in vitro, stimulate angiogenesis in vivo, and may participate in tissue repair. An oligonucleotide probe for … Basic and acidic fibroblast growth factors (FGF's) are potent mitogens for capillary endothelial cells in vitro, stimulate angiogenesis in vivo, and may participate in tissue repair. An oligonucleotide probe for bovine basic FGF was designed from the nucleotide sequence of the amino-terminal exon of bovine acidic FGF, taking into account the 55 percent amino acid sequence homology between the two factors. With this oligonucleotide probe, a full length complementary DNA for basic FGF was isolated from bovine pituitary. Basic FGF in bovine hypothalamus was shown to be encoded by a single 5.0-kilobase messenger RNA; in a human hepatoma cell line, both 4.6- and 2.2-kilobase basic FGF messenger RNA's were present. Both growth factors seem to be synthesized with short amino-terminal extensions that are not found on the isolated forms for which the amino acid sequences have been determined. Neither basic nor acidic FGF has a classic signal peptide.

Fibroblast growth factor signalling: from development to cancer

2010-01-22

Nicholas C. Turner , Richard Grose

Identification of a novel FGF, FGF-21, preferentially expressed in the liver

2000-06-01

Tetsuya Nishimura , Yuhki Nakatake , Morichika Konishi +1 more

Structures of the Tyrosine Kinase Domain of Fibroblast Growth Factor Receptor in Complex with Inhibitors

1997-05-09

Moosa Mohammadi , Gerald McMahon , Li Sun +5 more

A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth … A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth factor receptor 1 (FGFR1) and showed differential specificity toward other receptor tyrosine kinases. Crystal structures of the tyrosine kinase domain of FGFR1 in complex with the two compounds were determined. The oxindole occupies the site in which the adenine of adenosine triphosphate binds, whereas the moieties that extend from the oxindole contact residues in the hinge region between the two kinase lobes. The more specific inhibitor of FGFR1 induces a conformational change in the nucleotide-binding loop. This structural information will facilitate the design of new inhibitors for use in the treatment of cancer and other diseases in which cell signaling by tyrosine kinases plays a crucial role in disease pathogenesis.

FGF-21 as a novel metabolic regulator

2005-05-04

Alexei Kharitonenkov , Tatiyana L. Shiyanova , Anja Köester +7 more

Diabetes mellitus is a major health concern, affecting more than 5% of the population. Here we describe a potential novel therapeutic agent for this disease, FGF-21, which was discovered to … Diabetes mellitus is a major health concern, affecting more than 5% of the population. Here we describe a potential novel therapeutic agent for this disease, FGF-21, which was discovered to be a potent regulator of glucose uptake in mouse 3T3-L1 and primary human adipocytes. FGF-21-transgenic mice were viable and resistant to diet-induced obesity. Therapeutic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in both ob/ob and db/db mice. These effects persisted for at least 24 hours following the cessation of FGF-21 administration. Importantly, FGF-21 did not induce mitogenicity, hypoglycemia, or weight gain at any dose tested in diabetic or healthy animals or when overexpressed in transgenic mice. Thus, we conclude that FGF-21, which we have identified as a novel metabolic factor, exhibits the therapeutic characteristics necessary for an effective treatment of diabetes.

View PDF Chat

Osteoporosis and the Replacement of Cell Populations of the Marrow by Adipose Tissue

1971-10-01

Pierre J. Meunier , J. Aaron , C Edouard +1 more

*Laboratoire de Recherches sur l'Histodynamique Osseuse, Chaire d'Hydrologie Therepeutique, Faculte de Medecine, 8 Av. Rockfeller, 69. Lyon (8e), France. †Reaserch Assistant, Mineral Metabolism Unit (Dr. B.E.C. Nordin), General Infirmary, Leeds … *Laboratoire de Recherches sur l'Histodynamique Osseuse, Chaire d'Hydrologie Therepeutique, Faculte de Medecine, 8 Av. Rockfeller, 69. Lyon (8e), France. †Reaserch Assistant, Mineral Metabolism Unit (Dr. B.E.C. Nordin), General Infirmary, Leeds 1, England.

Structural Characterization and Biological Functions of Fibroblast Growth Factor

1987-05-01

Denis Gospodarowicz , Napoleone Ferrara , Lothar Schweigerer +1 more

BASIC AND acidic fibroblast growth factors (FGFs) are closely related molecules that show a similar range of biological activities. They differ, however, in some of their physical and chemical properties … BASIC AND acidic fibroblast growth factors (FGFs) are closely related molecules that show a similar range of biological activities. They differ, however, in some of their physical and chemical properties and in their tissue distribution (1). Basic FGF [bFGF isoelectric point (pi) 9.6] was first identified by its ability to cause the proliferation and phenotypic transformation of BALB/c 3T3 fibroblasts (2, 3). Acidic FGF (aFGF, pi 5.6) was first identified by its ability to cause proliferation and delayed differentiation of myoblasts (4); it was later rediscovered on the basis of its ability to stimulate endothelial cell proliferation (5, 6). As expected from their structural relationship, both FGF and aFGF interact with the same receptor (7), thereby having similar, if not identical, properties. In contrast to aFGF, which has a cellular distribution more restricted than bFGF, many different cells synthesize bFGF, and essentially all have a specific high affinity receptor for this peptide. bFGF is thus a fundamental regulatory molecule, acting by both autocrine and paracrine mechanisms. Recent studies indicate an important role for both bFGF and aFGF in cells of vascular, nervous, and connective tissue. bFGF and aFGF are multifunctional, since they can either stimulate proliferation and induce or delay differentiation (8). They stimulate other critical processes in cell function as well. As is true for most peptide growth factors, the basic molecular mechanism of action of FGFs is at present unknown. Nevertheless, so many new and varied functions have now been described for bFGF and could be extrapolated to aFGF that, at present, one must consider these two closely related peptides to be general mediators of regulation in the cell, and one of special importance for positive control of cell growth and differentiation.

A Lipid-Anchored Grb2-Binding Protein That Links FGF-Receptor Activation to the Ras/MAPK Signaling Pathway

1997-05-01

Haruhiko Kouhara , Yaron R. Hadari , Taly R. Spivak-Kroizman +4 more

Activation of the Ras/MAPK signaling cascade is essential for growth factor–induced cell proliferation and differentiation. In this report, we describe the purification, cloning, and characterization of a novel protein, designated … Activation of the Ras/MAPK signaling cascade is essential for growth factor–induced cell proliferation and differentiation. In this report, we describe the purification, cloning, and characterization of a novel protein, designated FRS2, that is tyrosine phosphorylated and binds to Grb2/Sos in response to FGF or NGF stimulation. We find that FRS2 is myristylated and that this modification is essential for membrane localization, tyrosine phosphorylation, Grb2/Sos recruitment, and MAPK activation. FRS2 functions as a lipid-anchored docking protein that targets signaling molecules to the plasma membrane in response to FGF stimulation to link receptor activation with the MAPK and other signaling pathways essential for cell growth and differentiation. Finally, we demonstrate that FRS2 is closely related and probably indentical to SNT, the long-sought target of FGF and NGF receptors.

View PDF Chat

The FGF family: biology, pathophysiology and therapy

2009-02-27

Andrew Beenken , Moosa Mohammadi

Crystal Structure of a Ternary FGF-FGFR-Heparin Complex Reveals a Dual Role for Heparin in FGFR Binding and Dimerization

2000-09-01

Joseph Schlessinger , A.N. Plotnikov , Omar A. Ibrahimi +5 more

View PDF Chat

Human KGF is FGF-Related with Properties of a Paracrine Effector of Epithelial Cell Growth

1989-08-18

Paul W. Finch , Jeffrey S. Rubin , Toru Miki +2 more

Keratinocyte growth factor (KGF) is a human mitogen that is specific for epithelial cells. The complementary DNA sequence of KGF demonstrates that it is a member of the fibroblast growth … Keratinocyte growth factor (KGF) is a human mitogen that is specific for epithelial cells. The complementary DNA sequence of KGF demonstrates that it is a member of the fibroblast growth factor family. The KGF transcript was present in stromal cells derived from epithelial tissues. By comparison with the expression of other epithelial cell mitogens, only KGF, among known human growth factors, has the properties of a stromal mediator of epithelial cell proliferation.

View PDF Chat

Endothelial Apoptosis as the Primary Lesion Initiating Intestinal Radiation Damage in Mice

2001-07-13

François Paris , Zvi Fuks , Anthony D. Kang +6 more

Gastrointestinal (GI) tract damage by chemotherapy or radiation limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberkühn to initiate … Gastrointestinal (GI) tract damage by chemotherapy or radiation limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberkühn to initiate the lethal GI syndrome. Here, we show in mouse models that microvascular endothelial apoptosis is the primary lesion leading to stem cell dysfunction. Radiation-induced crypt damage, organ failure, and death from the GI syndrome were prevented when endothelial apoptosis was inhibited pharmacologically by intravenous basic fibroblast growth factor (bFGF) or genetically by deletion of the acid sphingomyelinase gene. Endothelial, but not crypt, cells express FGF receptor transcripts, suggesting that the endothelial lesion occurs before crypt stem cell damage in the evolution of the GI syndrome. This study provides a basis for new approaches to prevent radiation damage to the bowel.

Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3

1996-04-01

Jennifer S. Colvin , Barbara A. Bohne , Gary W. Harding +2 more

Evolution of the Fgf and Fgfr gene families

2004-09-14

Nobuyuki Itoh , David M. Ornitz

The Fibroblast Growth Factor signaling pathway

2015-03-13

David M. Ornitz , Nobuyuki Itoh

The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF … The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways. Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels. Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning. FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways. Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer. For further resources related to this article, please visit the WIREs website.

View PDF Chat

Receptor Specificity of the Fibroblast Growth Factor Family

2006-04-06

Xiuqin Zhang , Omar A. Ibrahimi , Shaun K. Olsen +3 more

In mammals, fibroblast growth factors (FGFs) are encoded by 22 genes. FGFs bind and activate alternatively spliced forms of four tyrosine kinase FGF receptors (FGFRs 1–4). The spatial and temporal … In mammals, fibroblast growth factors (FGFs) are encoded by 22 genes. FGFs bind and activate alternatively spliced forms of four tyrosine kinase FGF receptors (FGFRs 1–4). The spatial and temporal expression patterns of FGFs and FGFRs and the ability of specific ligand-receptor pairs to actively signal are important factors regulating FGF activity in a variety of biological processes. FGF signaling activity is regulated by the binding specificity of ligands and receptors and is modulated by extrinsic cofactors such as heparan sulfate proteoglycans. In previous studies, we have engineered BaF3 cell lines to express the seven principal FGFRs and used these cell lines to determine the receptor binding specificity of FGFs 1–9 by using relative mitogenic activity as the readout. Here we have extended these semiquantitative studies to assess the receptor binding specificity of the remaining FGFs 10–23. This study completes the mitogenesis-based comparison of receptor specificity of the entire FGF family under standard conditions and should help in interpreting and predicting in vivo biological activity. In mammals, fibroblast growth factors (FGFs) are encoded by 22 genes. FGFs bind and activate alternatively spliced forms of four tyrosine kinase FGF receptors (FGFRs 1–4). The spatial and temporal expression patterns of FGFs and FGFRs and the ability of specific ligand-receptor pairs to actively signal are important factors regulating FGF activity in a variety of biological processes. FGF signaling activity is regulated by the binding specificity of ligands and receptors and is modulated by extrinsic cofactors such as heparan sulfate proteoglycans. In previous studies, we have engineered BaF3 cell lines to express the seven principal FGFRs and used these cell lines to determine the receptor binding specificity of FGFs 1–9 by using relative mitogenic activity as the readout. Here we have extended these semiquantitative studies to assess the receptor binding specificity of the remaining FGFs 10–23. This study completes the mitogenesis-based comparison of receptor specificity of the entire FGF family under standard conditions and should help in interpreting and predicting in vivo biological activity. Fibroblast growth factors (FGFs) 2The abbreviations used are: FGF, fibroblast growth factor; FGFR, FGF receptor; HS, heparan sulfate; BHK, baby hamster kidney; FHF, FGF homologous factor. comprise a structurally related family of 22 molecules. FGFs can be grouped into seven subfamilies based on their sequence similarities and functional properties (1Itoh N. Ornitz D.M. Trends Genet. 2004; 20: 563-569Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar, 2Ornitz D.M. Itoh N. Genome Biol. 2001; 2 (Reviews 3005)Crossref PubMed Google Scholar, 3Popovici C. Roubin R. Coulier F. Birnbaum D. BioEssays. 2005; 27: 849-857Crossref PubMed Scopus (67) Google Scholar). FGFs bind four high affinity, ligand-dependent FGF receptor tyrosine kinase molecules (FGFR1–4). In the presence of heparan sulfate (HS) glycosaminoglycans, FGFs stably bind FGFRs and lead to the formation of 2:2:2 FGF-FGFR-HS dimers, which enables the cytoplasmic kinase domains to transphosphorylate one another and become activated (4Mohammadi M. Olsen S.K. Ibrahimi O.A. Cytokine Growth Factor Rev. 2005; 16: 107-137Crossref PubMed Scopus (514) Google Scholar). FGFR activation results in the stimulation of various signal transduction cascades that have been implicated in multiple aspects of vertebrate and invertebrate embryonic development, tumor growth, angiogenesis, wound healing, and physiology (2Ornitz D.M. Itoh N. Genome Biol. 2001; 2 (Reviews 3005)Crossref PubMed Google Scholar, 5McKeehan W.L. Wang F. Kan M. Prog. Nucleic Acid Res. Mol. Biol. 1998; 59: 135-176Crossref PubMed Google Scholar, 6Ornitz D.M. Marie P.J. Genes Dev. 2002; 16: 1446-1465Crossref PubMed Scopus (682) Google Scholar, 7Powers C.J. McLeskey S.W. Wellstein A. Endocr. Relat. Cancer. 2000; 7: 165-197Crossref PubMed Google Scholar). Each FGFR contains an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. The extracellular ligand binding domain of the FGFR contains two or three Ig-like domains (8Lee P.L. Johnson D.E. Cousens L.S. Fried V.A. Williams L.T. Science. 1989; 245: 57-60Crossref PubMed Google Scholar, 9Johnson D.E. Williams L.T. Adv. Cancer Res. 1993; 60: 1-41Crossref PubMed Google Scholar). Alternative RNA splicing that utilizes one of two unique exons results in two different versions of Ig-like domain III (referred to as domains IIIb and IIIc) in FGFRs 1–3. This alternative splicing is an essential determinant of ligand binding specificity (10Chellaiah A.T. McEwen D.G. Werner S. Xu J. Ornitz D.M. J. Biol. Chem. 1994; 269: 11620-11627Abstract Full Text PDF PubMed Google Scholar, 11Johnson D.E. Lu J. Chen H. Werner S. Williams L.T. Mol. Cell. Biol. 1991; 11: 4627-4634Crossref PubMed Google Scholar, 12Ornitz D.M. Xu J. Colvin J.S. McEwen D.G. MacArthur C.A. Coulier F. Gao G. Goldfarb M. J. Biol. Chem. 1996; 271: 15292-15297Abstract Full Text Full Text PDF PubMed Scopus (1355) Google Scholar, 13Duan D.S. Werner S. Williams L.T. J. Biol. Chem. 1992; 267: 16076-16080Abstract Full Text PDF PubMed Google Scholar, 14Yeh B.K. Igarashi M. Eliseenkova A.V. Plotnikov A.N. Sher I. Ron D. Aaronson S.A. Mohammadi M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 2266-2271Crossref PubMed Scopus (132) Google Scholar). The IIIa ("a") splice form encodes a secreted extracellular FGF-binding protein with no known signaling capability (13Duan D.S. Werner S. Williams L.T. J. Biol. Chem. 1992; 267: 16076-16080Abstract Full Text PDF PubMed Google Scholar). The IIIb ("b") and IIIc ("c") splice forms are regulated in a tissue-specific manner, such that the b isoform is restricted to epithelial lineages and the c isoform is preferentially expressed in mesenchymal lineages (15Alarid E.T. Rubin J.S. Young P. Chedid M. Ron D. Aaronson S.A. Cunha G.R. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1074-1078Crossref PubMed Google Scholar, 16Gilbert E. Del Gatto F. Champion-Arnaud P. Gesnel M.C. Breathnach R. Mol. Cell. Biol. 1993; 13: 5461-5468Crossref PubMed Google Scholar, 17Orr-Urtreger A. Bedford M.T. Burakova T. Arman E. Zimmer Y. Yayon A. Givol D. Lonai P. Dev. Biol. 1993; 158: 475-486Crossref PubMed Scopus (460) Google Scholar, 18Yan G. Fukabori Y. McBride G. Nikolaropolous S. McKeehan W.L. Mol. Cell. Biol. 1993; 13: 4513-4522Crossref PubMed Google Scholar). This tissue specificity is particularly important for FGFR2 function. The structural basis by which this major alternative splicing in Ig-like domain III of FGFR2 modulates FGF binding specificity has been elucidated (14Yeh B.K. Igarashi M. Eliseenkova A.V. Plotnikov A.N. Sher I. Ron D. Aaronson S.A. Mohammadi M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 2266-2271Crossref PubMed Scopus (132) Google Scholar). In addition to tissue-specific FGF and FGFR expression, FGFR activation is modulated by heparin, heparan sulfate, or other glycosaminoglycan chains (19Ornitz D.M. Yayon A. Flanagan J.G. Svahn C.M. Levi E. Leder P. Mol. Cell. Biol. 1992; 12: 240-247Crossref PubMed Google Scholar, 20Yayon A. Klagsbrun M. Esko J.D. Leder P. Ornitz D.M. Cell. 1991; 64: 841-848Abstract Full Text PDF PubMed Google Scholar, 21Rapraeger A.C. Krufka A. Olwin B.B. Science. 1991; 252: 1705-1708Crossref PubMed Google Scholar, 22Penc S.F. Pomahac B. Winkler T. Dorschner R.A. Eriksson E. Herndon M. Gallo R.L. J. Biol. Chem. 1998; 273: 28116-28121Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 23Taylor K.R. Rudisill J.A. Gallo R.L. J. Biol. Chem. 2005; 280: 5300-5306Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). Importantly, tissue-specific alterations in glycosaminoglycan structure provide a mechanism to modulate FGF signaling (24Allen B.L. Filla M.S. Rapraeger A.C. J. Cell Biol. 2001; 155: 845-858Crossref PubMed Scopus (115) Google Scholar, 25Allen B.L. Rapraeger A.C. J. Cell Biol. 2003; 163: 637-648Crossref PubMed Scopus (148) Google Scholar, 26Ornitz D.M. BioEssays. 2000; 22: 108-112Crossref PubMed Scopus (586) Google Scholar, 27Perrimon N. Bernfield M. Nature. 2000; 404: 725-728Crossref PubMed Scopus (639) Google Scholar). It has been recently postulated that the HS selectivity in FGF signaling is attained in the context of a 2:2 FGF-FGFR dimer and not by FGF, FGFR, or even 1:1 FGF-FGFR pairs (28Mohammadi M. Olsen S.K. Goetz R. Curr. Opin. Struct. Biol. 2005; PubMed Google Scholar). The identification of FGF-FGFR binding specificities is critical to understanding the biological mechanisms involved in normal development and pathogenesis. Here we extend our previous study (12Ornitz D.M. Xu J. Colvin J.S. McEwen D.G. MacArthur C.A. Coulier F. Gao G. Goldfarb M. J. Biol. Chem. 1996; 271: 15292-15297Abstract Full Text Full Text PDF PubMed Scopus (1355) Google Scholar) to semiquantitatively compare the activity of all signaling members of the FGF family on the major splice forms of all FGFRs. Materials—Human recombinant FGF1, FGF7, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, and FGF20 were from PeproTech Inc. (Rocky Hill, NJ). Recombinant human FGF12, FGF14, FGF19, FGF21, and FGF23 were expressed in Escherichia coli and purified as previously described (29Yu X. Ibrahimi O.A. Goetz R. Zhang F. Davis S.I. Garringer H.J. Linhardt R.J. Ornitz D.M. Mohammadi M. White K.E. Endocrinology. 2005; 146: 4647-4656Crossref PubMed Scopus (157) Google Scholar, 30Olsen S.K. Garbi M. Zampieri N. Eliseenkova A.V. Ornitz D.M. Goldfarb M. Mohammadi M. J. Biol. Chem. 2003; 278: 34226-34236Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 31Ibrahimi O.A. Zhang F. Eliseenkova A.V. Itoh N. Linhardt R.J. Mohammadi M. Hum. Mol. Genet. 2004; 13: 2313-2324Crossref PubMed Scopus (117) Google Scholar). The source of FGFR cDNAs, FGFR expression plasmids, and FGFR-expressing BaF3 cell lines were described previously (12Ornitz D.M. Xu J. Colvin J.S. McEwen D.G. MacArthur C.A. Coulier F. Gao G. Goldfarb M. J. Biol. Chem. 1996; 271: 15292-15297Abstract Full Text Full Text PDF PubMed Scopus (1355) Google Scholar). BaF3 Cell Culture and Mitogenic Assay—BaF3 cells expressing specific FGFRs were described previously (12Ornitz D.M. Xu J. Colvin J.S. McEwen D.G. MacArthur C.A. Coulier F. Gao G. Goldfarb M. J. Biol. Chem. 1996; 271: 15292-15297Abstract Full Text Full Text PDF PubMed Scopus (1355) Google Scholar). Cells were maintained in RPMI 1640 medium (Sigma) supplemented with 10% newborn bovine serum (Sigma), 0.5 ng/ml murine-recombinant interleukin-3 (PeproTech Inc.), 2 mm l-glutamine, penicillin-streptomycin, 50 nm β-mercaptoethanol (BaF3 culture medium), and G418 (600 μg/ml). For mitogenic assays, FGFR-expressing BaF3 cells were plated at a density of 30,000 cells/well in a 96-well assay plate in BaF3 assay medium containing varying concentrations of FGF and heparin. FGFs diluted in assay medium were added to each well for a total volume of 200 μl/well. The cells were then incubated for 36–48 h. Mitogenic activity was determined by adding 1 μCi of [3H]thymidine in 50 μl of BaF3 assay medium to each well. The cells were harvested after 4–6 h by filtration through glass fiber paper. The incorporated [3H]thymidine was counted on a Wallac β plate scintillation counter (PerkinElmer Life Sciences). Preparation of FGF22-conditioned Medium—A cDNA encoding the full-length mouse FGF22 protein was isolated from mouse brain mRNA by reverse transcription-PCR (forward primer, 5′-AATTGCTAGCATGCGCAGCCGCCTCTGGCTG-3′; reverse primer, 5′-AGGCCTCGAGAGACGAGACCAAGACTGGCAG-3′) (32Umemori H. Linhoff M.W. Ornitz D.M. Sanes J.R. Cell. 2004; 118: 257-270Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). The PCR product (∼500 bp) was inserted into the NheI-XhoI sites of the APtag5 vector (GenHunter Inc.), replacing both the signal sequence and the alkaline phosphatase sequence. APtag5-mFGF22 or the APtag5 empty vector was transfected into baby hamster kidney (BHK) cells (cultured in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, 2 mm l-glutamine, and penicillin/streptomycin). The cells were replated at 80–90% confluence into 90-mm dishes the day before transfection and then were transfected with 24 μg of plasmid and 60 μl of Lipofectamine 2000 in 1.5 ml of Opti-MEM (Invitrogen) medium according to the manufacturer's directions. After 48 h, the cells were split 1:20 into Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, 2 mm l-glutamine, penicillin/streptomycin, and 500 μg/ml Zeocin (Invitrogen). Isolated colonies were picked after 10–14 days and propagated in the same medium. Reverse transcription-PCR (forward primer, 5′-GCTTCTATGTGGCCATGAATCGCA-3′; reverse primer, 5′-AGACCAAGACTGGCAGGAAGTGT-3′) was used to identify stable clonal cell lines expressing high levels of Aptag5-FGF22 (see Fig. 1A). Subconfluent stably transfected cell lines, grown in selection medium, were washed twice with phosphate-buffered saline and allowed to grow in BaF3 assay medium containing 2 μg/ml heparin for 48–72 h. Conditioned medium from control APtag-5 cells and Aptag5-FGF22 cells was collected, centrifuged to remove debris, and used for subsequent BaF3 assays. Data Analysis—FGF1 was used as a positive control to normalize the mitogenic activity of the other FGFs. To reduce sampling error in the comparison of the relative mitogenic activity, the mitogenic activity for each ligand was averaged at two different concentrations (312 and 1250 pm) (see Table 1) and normalized to the activity of FGF1 at these concentrations, or in the case of FGF19, -21, -23 to 5 nm FGF1.TABLE 1Relative mitogenic activity of FGF subfamiliesFGF receptorRelative mitogenic activity ± S.D.FGF-1FGF7 subfamilyFGF8 subfamilyFGF9 subfamilyFGF19 subfamily (×103)FGF7FGF10FGF22FGF8FGF17FGF18FGF9FGF16FGF20FGF19FGF21FGF231c100 ± 514.2 ± 4.112.5 ± 2.510.2 ± 1.757.5 ± 3.222.7 ± 0.34.7 ± 0.412.5 ± 1.44.3 ± 0.328.1 ± 4.0123 ± 5.734 ± 3.023 ± 2.72c100 ± 310.4 ± 4.06.1 ± 1.77.1 ± 1.191.6 ± 8.927.1 ± 9.528.9 ± 4.757.2 ± 5.432.5 ± 3.568.4 ± 2.8238 ± 11.586 ± 4.789 ± 10.53c100 ± 63.3 ± 1.40.8 ± 0.91.0 ± 0.5209 ± 6111 ± 577.7 ± 3.490.4 ± 6.032.4 ± 6.889.5 ± 7.3140 ± 11.123 ± 02.343 ± 5.51b100 ± 48.0 ± 1.539.4 ± 1.340.3 ± 1.65.3 ± 0.46.0 ± 2.26.3 ± 1.17.3 ± 1.06.5 ± 1.17.3 ± 0.912 ± 0.519 ± 3.411 ± 2.42b100 ± 5168 ± 6217 ± 1232 ± 35.9 ± 1.46.3 ± 0.67.8 ± 1.82.9 ± 0.41.8 ± 0.512.3 ± 0.761 ± 6.983 ± 5.466 ± 2.73b100 ± 46.7 ± 1.86.0 ± 0.55.3 ± 0.718.6 ± 6.310.7 ± 2.712.5 ± 2.042.7 ± 2.913 ± 2.644.3 ± 1.520 ± 1.726 ± 1.521 ± 0.84Δ100 ± 417.8 ± 0.511.5 ± 0.512.5 ± 0.9102 ± 0.485.5 ± 1.152.8 ± 1.710.1 ± 0.19.9 ± 0.326.6 ± 0.9410 ± 27.7128 ± 9.6222 ± 11.9 Open table in a new tab Receptor Binding Specificity of FGF Subfamilies—The murine pro-B cell line, BaF3, is an interleukin-3-dependent cell line that is commonly used for the analyses of receptor tyrosine kinase activity. Wild-type BaF3 cells do not express FGFRs, and BaF3 cells transfected with FGFRs proliferate in the absence of interleukin-3 when stimulated with FGF and heparin (19Ornitz D.M. Yayon A. Flanagan J.G. Svahn C.M. Levi E. Leder P. Mol. Cell. Biol. 1992; 12: 240-247Crossref PubMed Google Scholar). Receptor binding specificity for FGFs 1–9 has been previously described (12Ornitz D.M. Xu J. Colvin J.S. McEwen D.G. MacArthur C.A. Coulier F. Gao G. Goldfarb M. J. Biol. Chem. 1996; 271: 15292-15297Abstract Full Text Full Text PDF PubMed Scopus (1355) Google Scholar). To directly compare the activity of FGF subfamilies containing newly described members, all seven FGFR-expressing BaF3 cell lines were assayed with each FGF at concentrations ranging from 20 to 5000 pm (FGFs 1, 7–10, 16–18, and 20) and from 3 to 800 nm (FGFs 19, 21, and 23). FGFs 7, 10, and 22 are more closely related to each other by sequence than to any other FGF and were predicted to have similar activity toward FGFRs. We and others have failed to produce active recombinant FGF22 protein. We therefore developed a cell line that secretes FGF22 into the culture medium (Fig. 1A). Dilutions of conditioned medium were assayed on FGFR2b-BaF3 cells. The concentration of the FGF22-conditioned medium was estimated to be equivalent to an FGF10 concentration of 300–600 pm. Control-conditioned medium showed no activity toward any of the BaF3 cell lines. FGFs 7, 10, and 22 all strongly activated FGFR2b. FGFs 10 and 22 showed weak activity toward FGFR1b, and all three of these FGFs failed to activate any of the other FGFR-expressing cell lines (Fig. 1, B and C; Fig. 5; and Table 1). The FGFs 8, 17, and 18 subfamily members showed similar activities to each other as those previously described (33Xu J.S. Liu Z.H. Ornitz D.M. Development (Camb.). 2000; 127: 1833-1843Crossref PubMed Google Scholar, 34Moon A.M. Guris D.L. Seo J.H. Li L. Hammond J. Talbot A. Imamoto A. Dev. Cell. 2006; 10: 71-80Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). These FGFs specifically activated FGFRs 1c, 2c, and 3c and the two Ig-like domain forms of FGFR4 (4Δ). FGF8 subfamily members showed higher relative activity on FGFR3c cells and less activity toward FGFR1c. No activity was observed on the FGFRb isoform-expressing cell lines (Figs. 2 and 5 and Table 1). The FGFs 9, 16, and 20 subfamily members showed a similar profile to that of FGF9 (12Ornitz D.M. Xu J. Colvin J.S. McEwen D.G. MacArthur C.A. Coulier F. Gao G. Goldfarb M. J. Biol. Chem. 1996; 271: 15292-15297Abstract Full Text Full Text PDF PubMed Scopus (1355) Google Scholar, 35Santos-Ocampo S. Colvin J.S. Chellaiah A.T. Ornitz D.M. J. Biol. Chem. 1996; 271: 1726-1731Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). These FGFs activated FGFRc isoforms and FGFR4 with high activity, and unlike other FGFs that preferentially activate c splice form receptors, these FGFs consistently showed activity toward FGFR3b-expressing cells. FGF20 showed slight activity on FGFR2b cells and no activity on FGFR1b cells. FGFs 9 and 16 showed no activity toward FGFR1b or -2b (Figs. 3 and 5 and Table 1). The FGF19 (mouse FGF15), FGF21, and FGF23 subfamily is unique in that these FGFs can behave as secreted hormones (36Inagaki T. Choi M. Moschetta A. Peng L. Cummins C.L. McDonald J.G. Luo G. Jones S.A. Goodwin B. Richardson J.A. Gerard R.D. Repa J.J. Mangelsdorf D.J. Kliewer S.A. Cell Metab. 2005; 2: 217-225Abstract Full Text Full Text PDF PubMed Scopus (1130) Google Scholar, 37Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. Gromada J. Brozinick J.T. Hawkins E.D. Wroblewski V.J. Li D.S. Mehrbod F. Jaskunas S.R. Shanafelt A.B. J. Clin. Investig. 2005; 115: 1627-1635Crossref PubMed Scopus (1406) Google Scholar, 38White K.E. Carn G. Lorenz-Depiereux B. Benet-Pages A. Strom T.M. Econs M.J. Kidney Int. 2001; 60: 2079-2086Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar, 39Riminucci M. Collins M.T. Fedarko N.S. Cherman N. Corsi A. White K.E. Waguespack S. Gupta A. Hannon T. Econs M.J. Bianco P. Gehron Robey P. J. Clin. Investig. 2003; 112: 683-692Crossref PubMed Scopus (0) Google Scholar, 40Yu X. White K.E. Cytokine Growth Factor Rev. 2005; 16: 221-232Crossref PubMed Scopus (93) Google Scholar, 41Ezzat S. Asa S.L. Horm. Metab. Res. 2005; 37: 355-360Crossref PubMed Scopus (18) Google Scholar). To obtain significant activity of these FGFs on FGFR-expressing BaF3 cells required a protein concentration ranging from 3 to 800 nm and a heparin concentration >10 μg/ml (Fig. 4A). These parameters indicated low relative activity compared with other classic members of the FGF family. However, at these concentrations, FGFs 19, 21, and 23 showed consistent activity toward FGFR1c, 2c, 3c, and FGFR4 but no activity toward FGFR1b, 2b, or 3b (Fig. 4, C and D; Fig. 5; and Table 1). The FGF11 family has no known activity toward any FGFR (30Olsen S.K. Garbi M. Zampieri N. Eliseenkova A.V. Ornitz D.M. Goldfarb M. Mohammadi M. J. Biol. Chem. 2003; 278: 34226-34236Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 42Goldfarb M. Cytokine Growth Factor Rev. 2005; 16: 215-220Crossref PubMed Scopus (139) Google Scholar, 43Schoorlemmer J. Goldfarb M. Curr. Biol. 2001; 11: 793-797Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Recombinant FGF12 and FGF14 protein showed no activity on any of the FGFR-expressing BaF3 cell lines, consistent with previous observations (30Olsen S.K. Garbi M. Zampieri N. Eliseenkova A.V. Ornitz D.M. Goldfarb M. Mohammadi M. J. Biol. Chem. 2003; 278: 34226-34236Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar) (data not shown). The FGF family is one of the largest growth factor families, consisting of 22 members sharing 13–71% sequence similarity in mammals (2Ornitz D.M. Itoh N. Genome Biol. 2001; 2 (Reviews 3005)Crossref PubMed Google Scholar). FGFs possess a large range of activities in embryonic development and physiological functions in the adult. In the embryo, FGFs often signal across mesenchymal-epithelial boundaries, where they regulate organogenesis and pattern formation (44Boilly B. Vercoutter-Edouart A.S. Hondermarck H. Nurcombe V. Le Bourhis X. Cytokine Growth Factor Rev. 2000; 11: 295-302Crossref PubMed Scopus (214) Google Scholar, 45Ornitz D.M. Cytokine Growth Factor Rev. 2005; 16: 205-213Crossref PubMed Scopus (282) Google Scholar, 46Huang P. Stern M.J. Cytokine Growth Factor Rev. 2005; 16: 151-158Crossref PubMed Scopus (51) Google Scholar, 47Thisse B. Thisse C. Dev. Biol. 2005; 287: 390-402Crossref PubMed Scopus (365) Google Scholar). In the adult, FGFs play important roles in regulating homeostasis, wound healing, and tissue repair (48Finch P.W. Rubin J.S. Adv. Cancer Res. 2004; 91: 69-136Crossref PubMed Scopus (181) Google Scholar). Unregulated expression of FGFs can cause cancer (41Ezzat S. Asa S.L. Horm. Metab. Res. 2005; 37: 355-360Crossref PubMed Scopus (18) Google Scholar, 49Grose R. Dickson C. Cytokine Growth Factor Rev. 2005; 16: 179-186Crossref PubMed Scopus (311) Google Scholar, 50Dailey L. Ambrosetti D. Mansukhani A. Basilico C. Cytokine Growth Factor Rev. 2005; 16: 233-247Crossref PubMed Scopus (498) Google Scholar). The expression patterns of FGF receptors 1, 2, and 3 are distinct but overlap in some tissues. Analysis of the alternative splicing pattern of these receptors demonstrates that the utilization of either the b or c exon is dependent upon cell lineage. The b isoform is preferentially expressed in epithelial tissues, whereas the c isoform is expressed in mesenchymal tissues (17Orr-Urtreger A. Bedford M.T. Burakova T. Arman E. Zimmer Y. Yayon A. Givol D. Lonai P. Dev. Biol. 1993; 158: 475-486Crossref PubMed Scopus (460) Google Scholar, 51Goldstrohm A.C. Greenleaf A.L. Garcia-Blanco M.A. Gene (Amst.). 2001; 277: 31-47Crossref PubMed Scopus (137) Google Scholar, 52Beer H.D. Vindevoghel L. Gait M.J. Revest J.M. Duan D.R. Mason I. Dickson C. Werner S. J. Biol. Chem. 2000; 275: 16091-16097Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 53Wuechner C. Nordqvist A.C. Winterpacht A. Zabel B. Schalling M. Int. J. Dev. Biol. 1996; 40: 1185-1188PubMed Google Scholar). The activity of several of the FGFs can be divided along these lines. For example, the FGF7 subfamily is expressed in mesenchyme and shows the greatest activity toward FGFR2b. The FGF8 subfamily is expressed in epithelial tissues and activates c splice forms of FGFRs. Binding specificity between FGF and FGFRs is thus critical for the spatial regulation of FGF signaling. The specificity of the FGF7 subfamily, demonstrated in vitro in the BaF3 cell assay (Fig. 5), closely reflects the in vivo function of FGF10, a molecule expressed in mesenchymal tissue that signals to epithelial FGFR2b. Disruption of FGF10 signaling is catastrophic to embryonic development, resulting in severe defects in limb development and in organs requiring branching morphogenesis, such as the pancreas, salivary glands, and lungs (54Miralles F. Czernichow P. Ozaki K. Itoh N. Scharfmann R. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6267-6272Crossref PubMed Scopus (145) Google Scholar, 55Ye F. Duvillie B. Scharfmann R. Diabetologia. 2005; 48: 277-281Crossref PubMed Scopus (64) Google Scholar, 56Steinberg Z. Myers C. Heim V.M. Lathrop C.A. Rebustini I.T. Stewart J.S. Larsen M. Hoffman M.P. Development (Camb.). 2005; 132: 1223-1234Crossref PubMed Scopus (177) Google Scholar, 57Arman E. Haffner-Krausz R. Gorivodsky M. Lonai P. Proc. Natl. Acad. Sci., U. S. A. 1999; 96: 11895-11899Crossref PubMed Scopus (157) Google Scholar, 58Sekine K. Ohuchi H. Fujiwara M. Yamasaki M. Yoshizawa T. Sato T. Yagishita N. Matsui D. Koga Y. Itoh N. Kato S. Nat. Genet. 1999; 21: 138-141Crossref PubMed Scopus (935) Google Scholar, 59Park W.Y. Miranda B. Lebeche D. Hashimoto G. Cardoso W.V. Dev. Biol. 1998; 201: 125-134Crossref PubMed Scopus (252) Google Scholar, 60Bellusci S. Grindley J. Emoto H. Itoh N. Hogan B.L. Development (Camb.). 1997; 124: 4867-4878Crossref PubMed Google Scholar). The interaction between FGF10 and FGFR2b is also required for embryonic palate and cecum development (61Burns R.C. Fairbanks T.J. Sala F. De Langhe S. Mailleux A. Thiery J.P. Dickson C. Itoh N. Warburton D. Anderson K.D. Bellusci S. Dev. Biol. 2004; 265: 61-74Crossref PubMed Scopus (59) Google Scholar, 62Rice R. Spencer-Dene B. Connor E.C. Gritli-Linde A. McMahon A.P. Dickson C. Thesleff I. Rice D.P. J. Clin. Investig. 2004; 113: 1692-1700Crossref PubMed Scopus (0) Google Scholar). Mutations in FGFR2 that alter ligand binding specificity also result in developmental disease. Apert syndrome is a debilitating disease involving craniosynostosis, syndactyly, and mental retardation (63Cohen M.M.J. Cohen M.M.J. MacLean R.E. Craniosynostosis, Diagnosis, Evaluation, and Management. 2nd Ed. Oxford University Press, New York2000Google Scholar, 64Cohen Jr., M.M. Kreiborg S. Am. J. Med. Genet. 1990; 35: 36-45Crossref PubMed Scopus (142) Google Scholar, 65Cohen Jr., M.M. Kreiborg S. Am. J. Med. Genet. 1995; 57: 82-96Crossref PubMed Scopus (64) Google Scholar). The molecular etiology of Apert syndrome stems from inappropriate activation of mesenchymal FGFR2c by FGF7 family members (31Ibrahimi O.A. Zhang F. Eliseenkova A.V. Itoh N. Linhardt R.J. Mohammadi M. Hum. Mol. Genet. 2004; 13: 2313-2324Crossref PubMed Scopus (117) Google Scholar, 66Yu K. Ornitz D.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3641-3643Crossref PubMed Scopus (42) Google Scholar, 67Yu K. Herr A.B. Waksman G. Ornitz D.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 14536-14541Crossref PubMed Scopus (206) Google Scholar, 68Ibrahimi O.A. Chiu E.S. McCarthy J.G. Mohammadi M. Plast. Reconstr. Surg. 2005; 115: 264-270PubMed Google Scholar, 69Ibrahimi O.A. Eliseenkova A.V. Plotnikov A.N. Yu K. Ornitz D.M. Mohammadi M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 7182-7187Crossref PubMed Scopus (155) Google Scholar). The crystal structure of FGF10 in complex with FGFR2b has revealed that specific contacts between residues from the alternatively spliced βC′–βE loop region of FGFR2b and residues in the β4 strand and N terminus of FGF10 account for the FGF10-FGFR2b binding specificity (14Yeh B.K. Igarashi M. Eliseenkova A.V. Plotnikov A.N. Sher I. Ron D. Aaronson S.A. Mohammadi M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 2266-2271Crossref PubMed Scopus (132) Google Scholar). In particular, two highly specific hydrogen bonds involving Asp-76 in the N terminus of FGF10 and Ser-315 in the βC′–βE loop of FGFR2b are essential for FGF10-FGFR2b specificity. The involvement of these hydrogen bonds in conferring specificity between the FGF7 subfamily and FGFR2b is further supported by the fact that Asp-76 is unique to the FGF7 subfamily and Ser-315 is located in the b splice isoform-specific βC′–βE loop (14Yeh B.K. Igarashi M. Eliseenkova A.V. Plotnikov A.N. Sher I. Ron D. Aaronson S.A. Mohammadi M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 2266-2271Crossref PubMed Scopus (132) Google Scholar). FGF8 subfamily members exclusively bind FGFRc splice forms and FGFR4 (Fig. 5). The recent crystal structure of FGF8b in complex with FGFR2c has provided the molecular basis by which FGF8 subfamily members attain their specificity/promiscuity toward c splice isoforms of FGFRs 1–3 and FGFR4 (70Olsen S.K. Li J.Y. Bromleigh C. Eliseenkova A.V. Ibrahimi O.A. Lao Z. Zhang F. Linhardt R.J. Joyner A.L. Mohammadi M. Genes Dev. 2006; 20: 185-198Crossref PubMed Scopus (146) Google Scholar). Importantly, in the case of the FGF8 subfamily, the alternatively spliced βF and βG strands, and not the βC′–βE loop, harbor the primary receptor determinants of FGF8 subfamily binding specificity. This is because the spatial positioning of the N terminus of FGF8 subfamily members, relative to the β-trefoil core, is opposite to that of other FGFs (70Olsen S.K. Li J.Y. Bromleigh C. Eliseenkova A.V. Ibrahimi O.A. Lao Z. Zhang F. Linhardt R.J. Joyner A.L. Mohammadi M. Genes Dev. 2006; 20: 185-198Crossref PubMed Scopus (146) Google Scholar). FGFs 8, 17, and 18 have distinct and overlapping expression patterns in several tissues, such as the developing mid-hindbrain junction (71Maruoka Y. Ohbayashi N. Hoshikawa M. Itoh N. Hogan B.M. Furuta Y. Mech. Dev. 1998; 74: 175-177Crossref PubMed Scopus (161) Google Scholar, 72Xu J. Lawshe A. MacArthur C.A. Ornitz D.M. Mech. Dev. 1999; 83: 165-178Crossref PubMed Scopus (91) Google Scholar, 73Ohbayashi N. Hoshikawa M. Kimura S. Yamasaki M. Fukui S. Itoh N. J. Biol. Chem. 1998; 273: 18161-18164Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). Several of these FGFs are required for central nervous system morphogenesis (33Xu J.S. Liu Z.H. Ornitz D.M. Development (Camb.). 2000; 127: 1833-1843Cross

View PDF Chat

Cellular signaling by fibroblast growth factor receptors

2005-02-02

Veraragavan P. Eswarakumar , Irit Lax , Joseph Schlessinger

Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth

1996-03-01

Chu‐Xia Deng , Anthony Wynshaw‐Boris , Fen Zhou +2 more

View PDF Chat

Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

2003-03-10

Catherine Dodé , Jacqueline Levilliers , Jean‐Michel Dupont +7 more

View PDF Chat

The Effects of LY2405319, an FGF21 Analog, in Obese Human Subjects with Type 2 Diabetes

2013-09-01

Gregory Gaich , Jenny Y. Chien , Haoda Fu +7 more

Receptor Specificity of the Fibroblast Growth Factor Family

1996-06-01

David M. Ornitz , Jian Xu , Jennifer S. Colvin +5 more

Fibroblast growth factors (FGFs) are essential molecules for mammalian development. The nine known FGF ligands and the four signaling FGF receptors (and their alternatively spliced variants) are expressed in specific … Fibroblast growth factors (FGFs) are essential molecules for mammalian development. The nine known FGF ligands and the four signaling FGF receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual FGF receptors. To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. We have assayed the mitogenic activity of the nine known FGF ligands on these cell lines. These studies demonstrate that FGF 1 is the only FGF that can activate all FGF receptor splice variants. Using FGF 1 as an internal standard we have determined the relative activity of all the other members of the FGF family. These data should serve as a biochemical foundation for determining developmental, physiological, and pathophysiological processes that involve FGF signaling pathways.

View PDF Chat

Purification and characterization of a newly identified growth factor specific for epithelial cells.

1989-02-01

Jeffrey S. Rubin , Hiroyuki Osada , Paul W. Finch +3 more

A growth factor specific for epithelial cells was identified in conditioned medium of a human embryonic lung fibroblast cell line. The factor, provisionally termed keratinocyte growth factor (KGF) because of … A growth factor specific for epithelial cells was identified in conditioned medium of a human embryonic lung fibroblast cell line. The factor, provisionally termed keratinocyte growth factor (KGF) because of its predominant activity on this cell type, was purified to homogeneity by a combination of ultrafiltration, heparin-Sepharose affinity chromatography, and hydrophobic chromatography on a C4 reversed-phase HPLC column. KGF was both acid and heat labile and consisted of a single polypeptide chain of approximately 28 kDa. Purified KGF was a potent mitogen for epithelial cells, capable of stimulating DNA synthesis in quiescent BALB/MK epidermal keratinocytes by greater than 500-fold with activity detectable at 0.1 nM and maximal at 1.0 nM. Lack of mitogenic activity on either fibroblasts or endothelial cells indicated that KGF possessed a target cell specificity distinct from any previously characterized growth factor. Microsequencing revealed an amino-terminal sequence containing no significant homology to any known protein. The release of this growth factor by human embryonic fibroblasts raises the possibility that KGF may play a role in mesenchymal stimulation of normal epithelial cell proliferation.

View PDF Chat

Capillary endothelial cells express basic fibroblast growth factor, a mitogen that promotes their own growth

1987-01-01

Lothar Schweigerer , Gera Neufeld , Jeff Friedman +3 more

Biological Roles of Fibroblast Growth Factor-2*

1997-02-01

Andréas Bikfalvi , Sharon Klein , Giuseppe Pintucci +1 more

I. Introduction II. Structure of FGF-2 III. Mechanisms of Action of FGF-2: Extra- and Intracellular Signaling A. Exogenous 18-kDa FGF-2 B. Endogenous 18-kDa FGF-2 and HMW FGF-2 IV. Release of … I. Introduction II. Structure of FGF-2 III. Mechanisms of Action of FGF-2: Extra- and Intracellular Signaling A. Exogenous 18-kDa FGF-2 B. Endogenous 18-kDa FGF-2 and HMW FGF-2 IV. Release of FGF-2 V. Roles of FGF-2 in Development and Differentiation in Various Organ Systems A. Mesoderm induction B. Angiogenesis C. Vessel wall D. Lung E. Hematopoiesis F. Nervous system G. Reproductive system H. Skin I. Eye J. Muscle and skeleton K. Digestive system VI. Conclusions

View PDF Chat

Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene.

1992-01-01

Toyokazu Miki , Donald P. Bottaro , Timothy P. Fleming +4 more

Expression cDNA cloning and structural analysis of the human keratinocyte growth factor receptor (KGFR) revealed identity with one of the fibroblast growth factor (FGF) receptors encoded by the bek gene … Expression cDNA cloning and structural analysis of the human keratinocyte growth factor receptor (KGFR) revealed identity with one of the fibroblast growth factor (FGF) receptors encoded by the bek gene (FGFR-2), except for a divergent stretch of 49 amino acids in their extracellular domains. Binding assays demonstrated that the KGFR was a high-affinity receptor for both KGF and acidic FGF, while FGFR-2 showed high affinity for basic and acidic FGF but no detectable binding by KGF. Genomic analysis of the bek gene revealed two alternative exons responsible for the region of divergence between the two receptors. The KGFR transcript was specific to epithelial cells, and it appeared to be differentially regulated with respect to the alternative FGFR-2 transcript. Thus, two growth factor receptors with different ligand-binding specificities and expression patterns are encoded by alternative transcripts of the same gene.

View PDF Chat

Klotho converts canonical FGF receptor into a specific receptor for FGF23

2006-10-29

Itaru Urakawa , Yuji Yamazaki , Takashi Shimada +6 more

sprouty Encodes a Novel Antagonist of FGF Signaling that Patterns Apical Branching of the Drosophila Airways

1998-01-01

Nir Hacohen , Susanne Krämer , David E.R. Sutherland +2 more

Antagonists of several growth factor signaling pathways play important roles in developmental patterning by limiting the range of the cognate inducer. Here, we describe an antagonist of FGF signaling that … Antagonists of several growth factor signaling pathways play important roles in developmental patterning by limiting the range of the cognate inducer. Here, we describe an antagonist of FGF signaling that patterns apical branching of the Drosophila airways. In wild-type embryos, the Branchless FGF induces secondary branching by activating the Breathless FGF receptor near the tips of growing primary branches. In sprouty mutants, the FGF pathway is overactive and ectopic branches are induced on the stalks of primary branches. We show that FGF signaling induces sprouty expression in the nearby tip cells, and sprouty acts nonautonomously and in a competitive fashion to block signaling to the more distant stalk cells. sprouty encodes a novel cysteine-rich protein that defines a new family of putative signaling molecules that may similarly function as FGF antagonists in vertebrate development.

View PDF Chat

Growth inhibition by TGF-β linked to suppression of retinoblastoma protein phosphorylation

1990-07-01

Marikki Laiho , James A. DeCaprio , John W. Ludlow +2 more

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease

2002-06-15

David M. Ornitz , Pierre J. Marie

Over the last decade the identification of mutations in the receptors for fibroblast growth factors (FGFs) has defined essential roles for FGF signaling in both endochondral and intramembranous bone development.FGF … Over the last decade the identification of mutations in the receptors for fibroblast growth factors (FGFs) has defined essential roles for FGF signaling in both endochondral and intramembranous bone development.FGF signaling pathways are essential for the earliest stages of limb development and throughout skeletal development.In this review, we examine the role of FGF signaling in bone development and in human genetic diseases that affect bone development.We also explore what is presently known about how FGF signaling pathways interact with other major signaling pathways that regulate chondrogenesis and osteogenesis.

View PDF Chat

Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

2008-10-08

Jing Xu , David J. Lloyd , Clarence Hale +7 more

Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 … Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) model.DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques.FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity.FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes.

View PDF Chat

Fibroblast Growth Factor 21 Corrects Obesity in Mice

2008-08-07

Tamer Coşkun , Holly A. Bina , M. Schneider +5 more

Fibroblast growth factor 21 (FGF21) is a metabolic regulator that provides efficient and durable glycemic and lipid control in various animal models. However, its potential to treat obesity, a major … Fibroblast growth factor 21 (FGF21) is a metabolic regulator that provides efficient and durable glycemic and lipid control in various animal models. However, its potential to treat obesity, a major health concern affecting over 30% of the population, has not been fully explored. Here we report that systemic administration of FGF21 for 2 wk in diet-induced obese and ob/ob mice lowered their mean body weight by 20% predominantly via a reduction in adiposity. Although no decrease in total caloric intake or effect on physical activity was observed, FGF21-treated animals exhibited increased energy expenditure, fat utilization, and lipid excretion, reduced hepatosteatosis, and ameliorated glycemia. Transcriptional and blood cytokine profiling studies revealed effects consistent with the ability of FGF21 to ameliorate insulin and leptin resistance, enhance fat oxidation and suppress de novo lipogenesis in liver as well as to activate futile cycling in adipose. Overall, these data suggest that FGF21 exhibits the therapeutic characteristics necessary for an effective treatment of obesity and fatty liver disease and provides novel insights into the metabolic determinants of these activities.

Endocrine Regulation of the Fasting Response by PPARα-Mediated Induction of Fibroblast Growth Factor 21

2007-06-01

Takeshi Inagaki , Paul A. Dutchak , Guixiang Zhao +7 more

Fibroblast growth factors.

2001-01-01

David M. Ornitz , Nobuyuki Itoh

Fibroblast growth factors (FGFs) make up a large family of polypeptide growth factors that are found in organisms ranging from nematodes to humans. In vertebrates, the 22 members of the … Fibroblast growth factors (FGFs) make up a large family of polypeptide growth factors that are found in organisms ranging from nematodes to humans. In vertebrates, the 22 members of the FGF family range in molecular mass from 17 to 34 kDa and share 13-71% amino acid identity. Between vertebrate species, FGFs are highly conserved in both gene structure and amino-acid sequence. FGFs have a high affinity for heparan sulfate proteoglycans and require heparan sulfate to activate one of four cell-surface FGF receptors. During embryonic development, FGFs have diverse roles in regulating cell proliferation, migration and differentiation. In the adult organism, FGFs are homeostatic factors and function in tissue repair and response to injury. When inappropriately expressed, some FGFs can contribute to the pathogenesis of cancer. A subset of the FGF family, expressed in adult tissue, is important for neuronal signal transduction in the central and peripheral nervous systems.

View PDF Chat

Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in xenopus embryos

1991-07-01

Enrique Amaya , Thomas J. Musci , Marc W. Kirschner

Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARα and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States

2007-06-01

Michael K. Badman , Pavlos Pissios , Adam R. Kennedy +3 more

View PDF Chat

Understanding the Physiology of FGF21

2015-11-25

Ffolliott M. Fisher , Eleftheria Maratos–Flier

Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis. Excitement surrounding this relatively recently identified hormone is based on the … Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis. Excitement surrounding this relatively recently identified hormone is based on the documented metabolic beneficial effects of FGF21, which include weight loss and improved glycemia. The biology of FGF21 is intrinsically complicated owing to its diverse metabolic functions in multiple target organs and its ability to act as an autocrine, paracrine, and endocrine factor. In the liver, FGF21 plays an important role in the regulation of fatty acid oxidation both in the fasted state and in mice consuming a high-fat, low-carbohydrate ketogenic diet. FGF21 also regulates fatty acid metabolism in mice consuming a diet that promotes hepatic lipotoxicity. In white adipose tissue (WAT), FGF21 regulates aspects of glucose metabolism, and in susceptible WAT depots, it can cause browning. This peptide is highly expressed in the pancreas, where it appears to play an anti-inflammatory role in experimental pancreatitis. It also has an anti-inflammatory role in cardiac muscle. Although typically not expressed in skeletal muscle, FGF21 is induced in situations of muscle stress, particularly mitochondrial myopathies. FGF21 has been proposed as a novel therapeutic for metabolic complications such as diabetes and fatty liver disease. This review aims to interpret and delineate the ever-expanding complexity of FGF21 physiology.

View PDF Chat

Fibroblasts in fibrosis: novel roles and mediators

2014-05-27

Ryan T. Kendall , Carol A. Feghali-Bostwick

Fibroblasts are the most common cell type of the connective tissues found throughout the body and the principal source of the extensive extracellular matrix (ECM) characteristic of these tissues. They … Fibroblasts are the most common cell type of the connective tissues found throughout the body and the principal source of the extensive extracellular matrix (ECM) characteristic of these tissues. They are also the central mediators of the pathological fibrotic accumulation of ECM and the cellular proliferation and differentiation that occurs in response to prolonged tissue injury and chronic inflammation. The transformation of the fibroblast cell lineage involves classical developmental signaling programs and includes a surprisingly diverse range of precursor cell types—most notably, myofibroblasts that are the apex of the fibrotic phenotype. Myofibroblasts display exaggerated ECM production; constitutively secrete and are hypersensitive to chemical signals such as cytokines, chemokines, and growth factors; and are endowed with a contractile apparatus allowing them to manipulate the ECM fibers physically to close open wounds. In addition to ECM production, fibroblasts have multiple concomitant biological roles, such as in wound healing, inflammation, and angiogenesis, which are each interwoven with the process of fibrosis. We now recognize many common fibroblast-related features across various physiological and pathological protracted processes. Indeed, a new appreciation has emerged for the role of noncancerous fibroblast interactions with tumors in cancer progression. Although the predominant current clinical treatments of fibrosis involve nonspecific immunosuppressive and anti-proliferative drugs, a variety of potential therapies under investigation specifically target fibroblast biology.

View PDF Chat

Obesity Is a Fibroblast Growth Factor 21 (FGF21)-Resistant State

2010-08-03

Ffolliott M. Fisher , Patricia C. Chui , Patrick J. Antonellis +4 more

OBJECTIVE Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 improve glucose tolerance, lower serum free fatty acids, and … OBJECTIVE Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 improve glucose tolerance, lower serum free fatty acids, and lead to weight loss in obese mice. Surprisingly, however, FGF21 levels are elevated in obese ob/ob and db/db mice and correlate positively with BMI in humans. However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity. RESEARCH DESIGN AND METHODS To test the hypothesis that obesity is a state of FGF21 resistance, we evaluated the response of obese mice to exogenous FGF21 administration. In doing this, we assessed the impact of diet-induced obesity on FGF21 signaling and resultant transcriptional events in the liver and white adipose tissue. We also analyzed the physiologic impact of FGF21 resistance by assessing serum parameters that are acutely regulated by FGF21. RESULTS When obese mice are treated with FGF21, they display both a significantly attenuated signaling response as assessed by extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation as well as an impaired induction of FGF21 target genes, including cFos and EGR1. These effects were seen in both liver and fat. Similarly, changes in serum parameters such as the decline in glucose and free fatty acids are attenuated in FGF21-treated DIO mice. CONCLUSIONS These data demonstrate that DIO mice have increased endogenous levels of FGF21 and respond poorly to exogenous FGF21. We therefore propose that obesity is an FGF21-resistant state.

View PDF Chat

Growth factors in the extracellular matrix

1997-01-01

Jussi Taipale , Jorma Keski‐Oja

Much recent research has focused on the study of the expression of growth factor genes and on the identification of growth factor signaling mechanisms inside cells. However, growth factor signaling … Much recent research has focused on the study of the expression of growth factor genes and on the identification of growth factor signaling mechanisms inside cells. However, growth factor signaling can also be regulated outside of cells by extracellular matrix proteins and proteolytic en-zymes. The ability of extracellular proteins to pro-cess complex information in the absence of new protein synthesis is illustrated in blood clotting and complement pathways. An increasing number of growth factors, including IGFs, FGFs, TGF-β's, and HGF, have been found to associate with the extra-cellular matrix proteins or with heparan sulfate. Rapid and localized changes in the activity of these factors can be induced by release from matrix stor-age and/or by activation of latent forms. These growth factors, in turn, control cell proliferation, differentiation, and synthesis and remodeling of the extracellular matrix. It is therefore likely that much of the information processing necessary for construction of complex multicellular organisms occurs in the extracellular environment. This suggests that extracellular matrix plays a major role in the control of growth factor signaling.—Taipale, J., Keski- Oja, J. Growth factors in the extracellular matrix. FASEB J. 11, 51-59 (1997)

Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans

2008-02-06

Xinmei Zhang , Dennis C.Y. Yeung , Michal Karpíšek +7 more

OBJECTIVE— Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and insulin sensitivity in animal models. This study aimed to investigate the relationship … OBJECTIVE— Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and insulin sensitivity in animal models. This study aimed to investigate the relationship between its serum levels and various cardiometabolic parameters in humans. RESEARCH DESIGN AND METHODS— A newly developed immunoassay was used to measure serum FGF21 levels in 232 Chinese subjects recruited from our previous cross-sectional studies. The mRNA expression levels of FGF21 in the liver and adipose tissues were quantified by real-time PCR. RESULTS— Serum FGF21 levels in overweight/obese subjects were significantly higher than in lean individuals. Serum FGF21 correlated positively with adiposity, fasting insulin, and triglycerides but negatively with HDL cholesterol, after adjusting for age and BMI. Logistic regression analysis demonstrated an independent association between serum FGF21 and the metabolic syndrome. Furthermore, the increased risk of the metabolic syndrome associated with high serum FGF21 was over and above the effects of individual components of the metabolic syndrome. Our in vitro study detected a differentiation-dependent expression of FGF21 in 3T3-L1 adipocytes and human adipocytes. In db/db obese mice, FGF21 mRNA expression was markedly increased in both the liver and adipose tissue compared with that in their lean littermates. Furthermore, FGF21 expression in subcutaneous fat correlated well with its circulating concentrations in humans. CONCLUSIONS— FGF21 is a novel adipokine associated with obesity-related metabolic complications in humans. The paradoxical increase of serum FGF21 in obese individuals, which may be explained by a compensatory response or resistance to FGF21, warrants further investigation.

Frequent and Focal <i>FGFR1</i> Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer

2010-12-15

Jonathan M. Weiss , Martin L. Sos , Danila Seidel +7 more

FGFR1 amplification provides a therapeutic target for squamous cell lung cancer, which is resistant to other targeted lung cancer drugs. FGFR1 amplification provides a therapeutic target for squamous cell lung cancer, which is resistant to other targeted lung cancer drugs.

View PDF Chat

Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations.

1990-08-01

A P Sappino , Walter Schürch , Giulio Gabbiani

Rational Design and Identification of ISM7594 as a Tissue-Agnostic FGFR2/3 Inhibitor

2025-06-25

Yazhou Wang , Jinxin Liu , Yihong Zhang +7 more | Journal of Medicinal Chemistry

The selective inhibition of fibroblast growth factor receptors (FGFR) presents a significant challenge due to the high degree of sequence and the close structural similarity of the subtypes. Herein, we … The selective inhibition of fibroblast growth factor receptors (FGFR) presents a significant challenge due to the high degree of sequence and the close structural similarity of the subtypes. Herein, we designed selective dual FGFR2/3 inhibitors based on the in-depth understanding of protein-ligand interaction contributions. We efficiently identified ISM7594 (4) with distinctive flexible hinge binder and a unique central core that potently inhibited FGFR2/3 and selectively spared FGFR1/4. The "magic methyl" effect played a crucial role in enhancing the activity. ISM7594 maintained strong activity against multiple FGFR2/3 mutants known to drive resistance to current drugs and broad-spectrum antiproliferative potency in cancer cells harboring diverse FGFR2/3 alterations, including FGFR2/3 amplification, fusion, and mutation types. The compound demonstrated robust tumor growth suppression, favorable pharmacokinetic profile, and pharmacodynamic effects. This study supports the preclinical development of ISM7594 and demonstrates its potential in advancing tissue-agnostic therapy for advanced solid tumors with FGFR2/3 aberrations and mutation resistance.

Association of plasma placental growth factor with white matter hyperintensities in Alzheimer's disease

2025-06-25

Kazuya Igarashi , Tamao Tsukie , Kazuo Washiyama +7 more | medRxiv (Cold Spring Harbor Laboratory)

Background : The global prevalence of dementia, particularly Alzheimer's disease (AD), is increasing. With the introduction of anti-β-amyloid (Aβ) antibody drugs, the accurate in vivo diagnosis of AD has become … Background : The global prevalence of dementia, particularly Alzheimer's disease (AD), is increasing. With the introduction of anti-β-amyloid (Aβ) antibody drugs, the accurate in vivo diagnosis of AD has become crucial. Autopsy studies have shown that AD often coexists with cerebrovascular injury, which may affect cognitive outcomes and the effectiveness of anti-Aβ drugs. Although white matter hyperintensity (WMH) on magnetic resonance imaging (MRI) is an established marker of cerebrovascular injury, no fluid biomarker has been identified. Objective : This study investigated the association between WMH severity and fluid biomarkers, including cerebrospinal fluid (CSF) neurofilament light chain and plasma placental growth factor (PlGF) levels. Methods : The study included 242 patients from memory clinics, and MRI, CSF, and plasma samples were collected. Patients were classified as AD+ or non-AD based on the CSF Aβ42/Aβ40 ratio. In the discovery cohort (79 AD+ and 20 non-AD patients with 3D-T1 images), we analyzed the association between WMH volume and plasma PlGF. In the validation cohort (54 AD+ patients without 3D-T1 images), we analyzed the association between WMH grading and plasma PlGF. Results : Among AD+ patients in the discovery cohort, plasma PlGF levels remained significantly associated with WMH volume and grading after adjusting for age, sex, and global cognition. Among the AD+ patients in the validation cohort, the high-PlGF (above median) group had significantly greater WMH volumes and a higher number of patients with a high WMH grading than the low-PlGF (below median) group. Conclusions : Plasma PlGF is a promising marker of cerebrovascular injury in AD.

Role of FGF2 in Promoting Osteogenic Differentiation for Craniofacial Bone Regeneration

2025-06-25

Xianrui Yang , X. Peter | Regenerative Engineering and Translational Medicine

FGFR2, NOTCH1, PERP and AKT Expression in Progressive Cutaneous Carcinogenesis: Insights from an Experimental Mouse Model

2025-06-24

Mara C. Ebeling | International Journal of Oral and Maxillofacial Surgery

FH-2001 is a novel FGFR/VEGFR dual inhibitor with immune-modulating activity

2025-06-24

Aiguo Liu , Longfei Huang , Xin Gao +4 more | Anti-Cancer Drugs

Multiple cancers are driven by aberrant fibroblast growth factor receptor (FGFR) signaling and vascular endothelial growth factor receptor (VEGFR)-linked angiogenesis. Several therapeutic agents targeting FGFR and VEGFR have been developed … Multiple cancers are driven by aberrant fibroblast growth factor receptor (FGFR) signaling and vascular endothelial growth factor receptor (VEGFR)-linked angiogenesis. Several therapeutic agents targeting FGFR and VEGFR have been developed and approved for use in solid cancers; however, there is still a high unmet medical need for new agents that have a more powerful antitumor activity and a broader antitumor spectrum. Here, we report the discovery of FH-2001, a novel and potent FGFR/VEGFR dual inhibitor, with additional activity of modulating programmed cell death ligand 1 (PD-L1) gene expression. In biochemical assays, FH-2001 showed potent inhibition of FGFR1, 2, 3, and 4, with half-maximal inhibitory concentration (IC50) of 0.2, 0.2, 0.4, and 2.0 nM, respectively, and VEGFR1, 2, and 3, with IC50 values of 2.0, 0.3, and 0.5 nM, respectively. FH-2001 significantly suppressed the cell growth of FGFR- or VEGFR-driven cancer cell lines. In representative cell line- and patient-derived tumor xenografts with aberrant FGFR or VEGFR signaling, FH-2001 substantially inhibited tumor growth. Furthermore, FH-2001 demonstrated marked antitumor activities when treated alone or combined with PD-L1 or PD-1 antibody in syngeneic mouse models. Flow cytometric analysis revealed that FH-2001 alone or in combination with anti-PD-L1 increased T and natural killer cells and decreased myeloid cells in the tumor microenvironment. Mechanistically, FH-2001 treatment dramatically reduced c-Myc and PD-L1 mRNA and protein levels in a dose-dependent manner in vitro. Taken together, FH-2001 is a promising dual-target inhibitor of FGFR and VEGFR and also modulates cancer immunity, while its robust antitumor activity positions it as a potentially class-leading anticancer agent.

The C-terminal Kinase Domain-Binding and Suppression Motif Prevents Constitutive Activation of FGFR2

2025-06-24

Daniel Zingg , Chi-Chuan Lin , Julia Yemelyanenko +7 more | Cancer Research

Abstract Genetic alterations in receptor tyrosine kinase (RTK) genes can generate potent oncogenic drivers. Truncation of the fibroblast growth factor receptor 2 (FGFR2) gene by its last exon 18 (E18) … Abstract Genetic alterations in receptor tyrosine kinase (RTK) genes can generate potent oncogenic drivers. Truncation of the fibroblast growth factor receptor 2 (FGFR2) gene by its last exon 18 (E18) is caused by structural alterations, such as focal amplifications and gene fusions/rearrangements, as well as by mutations. All the E18-truncating FGFR2 variants (FGFR2ΔE18) act as strong driver alterations in cancer, and they commonly encode a receptor lacking the carboxy (C)-terminal tail. Here, we analyzed a compendium of Fgfr2-E18 variants to uncover the mechanism by which loss of the C-tail renders FGFR2 oncogenic. While permutation of previously annotated C-terminal FGFR motifs did not recapitulate the tumorigenicity of FGFR2ΔE18, the functional annotation efforts led to the discovery of a C-terminal phenylalanine–serine motif that mediates binding of the C-tail to the kinase domain and thereby suppresses FGFR2 kinase activity. Permutation of this kinase domain-binding and suppression (KDBS) motif in conjunction with other FGFR2-regulatory C-terminal sites fully phenocopied the oncogenic competence of FGFR2ΔE18. Together, these findings delineate how the C-terminal tail prevents FGFR2 from aberrant oncogenic activation.

Unpicking the effects of FGF21 on longevity

2025-06-24

Claire Greenhill | Nature Reviews Endocrinology

Paracrine signaling in cancer-associated fibroblasts: central regulators of the tumor immune microenvironment

2025-06-23

Ye Li , Longyun Wang , Wenzhe Ma +3 more | Journal of Translational Medicine

Despite groundbreaking advances in cancer immunotherapy, clinical efficacy remains constrained by the immunosuppressive tumor microenvironment (TME). As key stromal components within this TME, cancer-associated fibroblasts (CAFs) emerge as pivotal regulators … Despite groundbreaking advances in cancer immunotherapy, clinical efficacy remains constrained by the immunosuppressive tumor microenvironment (TME). As key stromal components within this TME, cancer-associated fibroblasts (CAFs) emerge as pivotal regulators of drug resistance and immune evasion. Beyond establishing physical barriers that exclude cytotoxic T cells from tumor nests, that is creating an immune "desert", CAFs dynamically reprogram the TME through multifaceted paracrine signaling, orchestrating crosstalk among tumor cells, stromal components, and immune cells. The complex paracrine signaling network jointly promotes the recruitment of immunosuppressive cells, alters the dynamics of immune cells, remodels the extracellular matrix, and ultimately establishes the immunosuppressive TME. Emerging strategies aimed at undermining the paracrine signaling Network of CAF-TME have shown potential in clinical studies to enhance the response to immunotherapy. Natural compounds such as curcumin and Baicalein and their derivatives have further expanded therapeutic approaches by regulating the paracrine phenotype of CAF due to their inherent multi-target intervention advantages. This review describes CAF and its paracrine effect as the central regulators of TME immunosuppression, emphasizing its key role in the immunotherapy response and providing new possibilities for clinical treatment strategies to restore CAFs paracrine-mediated immunosuppression and improve the efficacy of immunotherapy.

Role of FGF19 in regulating mitochondrial dynamics and macrophage polarization through FGFR4/AMPKα-p38/MAPK Axis in bleomycin-induced pulmonary fibrosis

2025-06-22

Yang Li , Hong Zhang , B. Li +2 more | Cytokine

Integrated Virtual Screening of NPACT-Derived Phytochemicals as Potential FGFR1 Inhibitors for Cholangiocarcinoma Therapy: Molecular Docking, ADMET, MM-GBSA, and Molecular Dynamics

2025-06-21

Atanda Opeyemi Emmanuel , Oyewale Malik Tomilola , Adeyeye Pius Oluwaseyi +2 more | Journal of Advances in Biology & Biotechnology

Bile duct cancer (cholangiocarcinoma) is a rare but aggressive malignancy with a poor prognosis and limited treatment options. Fibroblast growth factor receptor 1 (FGFR1), a key regulator of tumour growth … Bile duct cancer (cholangiocarcinoma) is a rare but aggressive malignancy with a poor prognosis and limited treatment options. Fibroblast growth factor receptor 1 (FGFR1), a key regulator of tumour growth and angiogenesis, has been identified as a plausible therapeutic target. Due to the limitations in the safety and selectivity of existing inhibitors, there is a growing interest in exploring natural compounds as alternative drug lead candidates. This study aimed to identify and evaluate plant-derived phytochemicals as potential FGFR1 inhibitors for the treatment of cholangiocarcinoma using an integrated computer-aided drug design approach. A structure-based virtual screening of 67 phytochemicals from the NPACT database was conducted. Molecular docking against FGFR1 (PDB ID: 7WCL) using iGEMDock and Molecular Operating Environment (MOE) identified 17 hit compounds with binding energies ranging from −12.3 to −9.8 kcal/mol (iGEMDock) and −9.7 to −8.0 kcal/mol (MOE), outperforming Pemigatinib (−9.7 and −7.5 kcal/mol). Lipinski’s Rule of Five narrowed them down to seven drug-like candidates. ADMET screening further identified four compounds as pharmacokinetically acceptable. MM-GBSA analysis revealed that 10-Hydroxytrilobacin (-47.63 kcal/mol) and Mosin B (-45.09 kcal/mol) had superior binding free energies than Pemigatinib (-31.01 kcal/mol). These two lead compounds were subjected to 100 ns molecular dynamics simulation to confirm their interaction behaviour and structural stability. Mosin B and 10-hydroxytrilobacin both surpassed pemigatinib across key structural metrics, establishing them as promising FGFR1 inhibitors with strong binding affinity, pharmacokinetic safety, and dynamic stability, and thus warranting further experimental validation for cholangiocarcinoma therapy.

Current Insights and Barriers in FGFR-Mediated Signaling in Lung Cancer

2025-06-21

Xiaohong Liu , Wuxuan Mei , Yikun Yao +1 more | European Journal of Medicinal Chemistry

Oxygen Sensing in Osteocytes: From Physiology to Age-related Osteoporosis

2025-06-21

Krzysztof Janeczko , Rafiou Agoro | Current Osteoporosis Reports

Future perspectives: targeting fibroblast growth factor receptor 1 to enhance the efficacy of immunotherapy

2025-06-20

Ilya Tsimafeyeu | Exploration of Targeted Anti-tumor Therapy

Fibroblast growth factor receptor 1 (FGFR1) plays a critical role in the progression of various cancers through its involvement in cell proliferation, survival, and differentiation. More recently, FGFR1 has been … Fibroblast growth factor receptor 1 (FGFR1) plays a critical role in the progression of various cancers through its involvement in cell proliferation, survival, and differentiation. More recently, FGFR1 has been implicated in the mechanisms of immune evasion, particularly its role in resistance to immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Targeting FGFR1 with monoclonal antibodies and tyrosine kinase inhibitors has emerged as a promising therapeutic strategy to enhance ICI efficacy by altering the tumor microenvironment and countering immune suppression. Preclinical studies demonstrate that combining FGFR1 inhibitors, such as the novel monoclonal antibody OM-RCA-01, with ICIs significantly improves antitumor activity, enhancing T cell responses and cytokine production. This article explores the role of FGFR1 in cancer biology, its contribution to immunotherapy resistance, and the therapeutic potential of targeting FGFR1 to enhance the efficacy of ICIs.

Analysis of Recurrence Risk After Radical Surgery for Differentiated Thyroid Carcinoma Based on Fibroblast Growth Factor Receptor 4 and Inflammatory Cytokines

2025-06-19

Yingying Sha , Yongjie Hu , Ping Huang | Journal of Medical Biochemistry

Objective: This study aimed to evaluate the synergistic role of fibroblast growth factor receptor 4 (FGFR4) and inflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α], and C-reactive protein [CRP]) in … Objective: This study aimed to evaluate the synergistic role of fibroblast growth factor receptor 4 (FGFR4) and inflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α], and C-reactive protein [CRP]) in predicting recurrence of differentiated thyroid carcinoma (DTC) after radical surgery, and to develop a combined predictive model for improved postoperative risk stratification. Methods: We enrolled 102 DTC patients treated between February 2022 and January 2024, along with 98 healthy controls. Serum levels of FGFR4, IL-6, TNF-α, and CRP were measured preoperatively and postoperatively using ELISA. Independent risk factors were identified through logistic regression, diagnostic performance was assessed using ROC analysis, and correlations of FGFR4 and inflammatory cytokines with postoperative recurrence were evaluated. Results: Preoperative levels of FGFR4, IL-6, TNF-α, and CRP were significantly elevated in DTC patients compared to healthy controls (P<0.05). A diagnostic model integrating these four markers demonstrated superior performance (AUC=0.931; sensitivity 94.12%, specificity 79.59%) over individual biomarkers (P<0.05). Among DTC patients, those with recurrence (n=26) exhibited significantly higher FGFR4 and inflammatory cytokine levels than the non-recurrent group (P<0.05). The combined model predicted 1-year recurrence with an AUC of 0.864 (sensitivity 73.08%, specificity 93.42%). Conclusion: The synergistic interaction between FGFR4 and inflammatory cytokines plays a critical role in DTC. Their combined detection enhances postoperative recurrence risk prediction, offering a valuable tool for clinical risk stratification.

Structure-based identification of potent fibroblast growth factor receptor 4 (FGFR4) inhibitors as potential therapeutics for hepatocellular carcinoma

2025-06-18

Lin Fan , Hui Xie , Weiyu Wang +3 more | PeerJ

Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth factor receptor family, plays a crucial role in cell growth, differentiation, and tissue repair. Increased FGFR4 expression has … Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth factor receptor family, plays a crucial role in cell growth, differentiation, and tissue repair. Increased FGFR4 expression has been detected in various cancers, including lung, liver, kidney and pancreatic cancer, making it a potential drug target. In this study, we conducted a structure-based virtual screening campaign to identify potential FGFR4 inhibitors. The retained compounds were further filtered based on pan assay interference compounds (PAINS) and absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties, leading to the identification of two promising candidates: MFCD00832235 and MFCD00204244. Quantum mechanical (QM) calculations revealed a large Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) (HUMO-LUMO) gaps for both compounds, indicating high dynamic stability and low chemical reactivity. Moreover, the stability of MFCD00832235 and MFCD00204244 at the adenosine triphosphate (ATP)-binding site of FGFR4 was confirmed through molecular dynamics (MD) simulations. The molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) approach predicted favorable binding free energy values for both compounds with the target protein. In vitro assay revealed that MFCD00832235 and MFCD00204244 inhibited the growth of HepG2 cells with IC50 values of 47.42 ± 12.93 µM and 77.83 ± 19.17 µM, respectively. Overall, this study suggested that MFCD00832235 and MFCD00204244 were potential FGFR4 inhibitors and may serve as start points for developing novel modulators of FGFR4 for cancer treatment, particularly hepatocellular carcinoma.

Obesity and cervical intraepithelial neoplasia: regulation of mitochondrial energy metabolism via the Kisspeptin/GPR54 signaling pathway

2025-06-18

Jiajia Pan , Yuanyuan Chen , Ye Yan +3 more | Cancer & Metabolism

FXR Stimulation by Obeticholic Acid Treatment Restores Gut Mucosa Functional and Structural Integrity in Individuals With Altered Glucose Tolerance

2025-06-17

Francesca De Vito , R. Marasco , Evelina Suraci +6 more | Diabetes

The farnesoid X receptor (FXR)–fibroblast growth factor 19 (FGF19) axis is involved in maintaining glucose homeostasis and gut tight-junction (TJ) integrity. We evaluated whether individuals with prediabetes or type 2 … The farnesoid X receptor (FXR)–fibroblast growth factor 19 (FGF19) axis is involved in maintaining glucose homeostasis and gut tight-junction (TJ) integrity. We evaluated whether individuals with prediabetes or type 2 diabetes (T2D) have altered intestinal FXR-FGF19 signaling and barrier function and whether high-glucose (HG) exposure may cause these aberrations. Moreover, we tested beneficial effects of the FXR agonist obeticholic acid (OCA) on intestinal FXR signaling in individuals with prediabetes or T2D. Included were 60 individuals with different glucose tolerance (normal glucose tolerance [NGT; n = 25], prediabetes [n = 19], or T2D [n = 16]) who underwent ileocolonoscopy with collection of ileal mucosa biopsy specimens, which were used for expression profiling analysis of the FXR/FGF19/TJ axis and tissue culture experiments. Individuals with prediabetes or T2D displayed lower ileal levels of FXR and its target genes FGF19 and TJ proteins zonula, occludens-1, occludin, and claudin-1, along with increased proinflammatory nuclear factor-κB (NF-κB) activity and cytokines expression compared with those with NGT. HG exposure on ileal explants collected from NGT individuals hampered the FXR/FGF19/TJ axis. OCA treatment on ileal fragments of individuals with prediabetes/T2D was able to restore FGF19 synthesis and secretion, TJ expression, and counteract NF-κB activity and cytokines expression. In conclusion, OCA treatment counteracts T2D-related intestinal abnormalities in the FXR/FGF19/TJ axis. Article Highlights The intestinal farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF19) axis is involved in maintaining glucose homeostasis and gut barrier function in animals. Do individuals with prediabetes and type 2 diabetes exhibit a compromised intestinal FXR/FGF19/barrier integrity axis? Can obeticholic acid (OCA) treatment counteract diabetes-related gut mucosa dysfunction? A downregulation of ileal FXR/FGF19/tight-junctions signaling occurs in individuals with hyperglycemia. OCA-mediated FXR activation reverts diabetes-related alterations. OCA-mediated intestinal FXR activation in individuals with hyperglycemia may represent a strategy for restoring FGF19 synthesis with positive effects on gut barrier.

Analytical and Clinical Validation of a Plasma Fibroblast Growth Factor 21 ELISA Kit Using an Automated Platform in Steatotic Liver Disease

2025-06-16

Makito Tanaka , Shingo Tanaka , Ryo Kobayashi +2 more | Biomolecules

Steatotic liver disease is a global health challenge that requires reliable and noninvasive diagnostic biomarkers. This research aimed to validate the analytical and clinical performance of a fibroblast growth factor … Steatotic liver disease is a global health challenge that requires reliable and noninvasive diagnostic biomarkers. This research aimed to validate the analytical and clinical performance of a fibroblast growth factor 21 (FGF21) enzyme-linked immunosorbent assay (ELISA) kit using an automated immunoassay analyzer. Plasma FGF21 levels were measured using a commercial ELISA kit on an automated immunoassay analyzer. Validation included intra- and inter-assay precision, dilution linearity, spike recovery, lower limit of quantification (LLOQ), interference testing, and sample stability analysis. Clinical evaluation involved 97 patients who underwent abdominal ultrasound-based attenuation imaging for the diagnosis of hepatic steatosis. The assay demonstrated high analytical precision, with intra- and inter-assay coefficients of variation <15% and an LLOQ of 3.260 pg/mL. Dilution linearity, spike recovery, and interference tests confirmed the reliability of the assay, whereas stability tests highlighted the minimal effect of freeze-thaw cycles and storage conditions. Clinically, FGF21 levels correlated with attenuation coefficient (r = 0.44). Diagnostic performance indicated 84% sensitivity and 81% specificity at defined FGF21 thresholds for the diagnosis of hepatic steatosis. This research confirmed the reliable analytical and clinical performance of the FGF21 ELISA kit, reinforcing its potential as a diagnostic biomarker of hepatic steatosis.

100-OR: Hypothalamic Fibroblast Growth Factor-1 Signaling Is Required for Normal Energy and Glucose Homeostasis

2025-06-13

Pique Choi , Bao Anh Phan , CAELEY BRYAN +4 more | Diabetes

Introduction and Objective: The brain is a primary target for the beneficial metabolic effects of members of the fibroblast growth factor (FGF) family. For example, our group and others have … Introduction and Objective: The brain is a primary target for the beneficial metabolic effects of members of the fibroblast growth factor (FGF) family. For example, our group and others have shown that a single intracerebroventricular (icv) injection of fibroblast growth factor-1 (FGF1) induces both transient anorexia and weight loss and sustained remission of diabetic hyperglycemia in rodent models of type 2 diabetes (T2D) via actions involving the mediobasal hypothalamus (MBH). While FGF1 is endogenously expressed in the MBH, its role in metabolic physiology is unknown. The goal of the current studies was to determine the role of endogenous FGF1 in the regulation of energy balance. Methods: To test whether MBH FGF1 plays a physiological role in energy and/or glucose homeostasis, we selectively deleted FGF1 from either MBH neurons or from tanycytes of adult male FGF1-floxed (FGF1fl/fl) chow-fed mice. The former was achieved by microinjecting either AAV1-hSyn-Cre-WPRE.hGH or control AAV1-CAG-GFP into the MBH bilaterally, whereas the latter involved microinjecting either TAT-Cre or heat-inactivated control TAT-Cre into the 3rd ventricle. Results: We report that FGF1 deletion specifically from MBH neurons caused an obesity phenotype associated with hyperphagia and glucose intolerance (*p&lt;0.05 for each). Interestingly, this phenotype was also characterized by pronounced disruption of circadian patterns of feeding, in which animals consumed a greater proportion of food intake during the light cycle, and it was complemented by decreased daily energy expenditure and decreased dark cycle locomotion. By comparison, selective FGF1 deletion from tanycytes resulted in greater percent change in body weight (*p&lt;0.05), but no other detectable metabolic abnormalities were observed in the animals. Conclusion: Based on these findings, we conclude that endogenous FGF1 expression by MBH neurons, but not tanycytes, is required for normal energy homeostasis and glucose metabolism. Disclosure P. Choi: None. B.N. Phan: None. C. Bryan: None. M.K. Hwang: None. G.J. Morton: Research Support; Novo Nordisk A/S. M.W. Schwartz: Consultant; NodThera, Olio Labs, PriveBio. J.M. Scarlett: None.

Abstract P3-02-03: HEPARANASE LIQUID BIOPSY AND BREAST CANCER

2025-06-13

Daniel Gimenes , Gislaine Patricia Andrade , Afonso Nazário +1 more | Clinical Cancer Research

Abstract Background: Breast cancer is a complex disease with high clinical and genetic heterogeneity and represents a public health problem worldwide, as it is among the four main causes of … Abstract Background: Breast cancer is a complex disease with high clinical and genetic heterogeneity and represents a public health problem worldwide, as it is among the four main causes of premature death in most countries. The molecular profile of solid tumors may be established using surgical or biopsy tissue samples. However, tissue-based tumor profiles are subject to sampling bias, provide only a snapshot of tumor heterogeneity, and cannot be obtained repeatedly. Therefore, analyses of circulating nucleic acids, blood samples, or other body fluids, commonly called liquid biopsies, can also contain tumor-derived genetic information. Liquid biopsy represents an innovative method that has gained prominence in recent years, a significant change in how we diagnose and monitor various diseases, especially cancer. Previous studies from our group showed that circulating lymphocytes obtained from patients with breast cancer have higher glycosidase heparanase (HPSE1) expression. Objective: We aimed to investigate the expression of HPSE1 in circulating T-lymphocytes collected from blood samples of patients with breast cancer compared to the control group (women not affected by neoplasms). Methods: To obtain the mononuclear cell fraction, T-lymphocytes were extracted using Ficoll-paque (Sigma-Aldrich) from the collected peripheral blood sample. Total RNA was extracted from T-lymphocytes with Trizol (Invitrogen), following the manufacturer's instructions. After obtaining the cDNA by reverse transcription, the expression of HPSE1 was evaluated by quantitative PCR. Results: A significant increase in the expression of HPSE1 was observed in T-lymphocytes obtained from breast cancer patients compared to unaffected individuals. The results also showed higher expression according to the different molecular subtypes of breast cancer (Luminal B, HER2 positive, and triple-negative). Conclusion: We conclude that expression analyses of HPSE1 using liquid biopsies allow a non-invasive and real-time assessment, favoring prospective studies where early diagnoses and personalized treatments can be developed. Citation Format: Daniel Gimenes, Gislaine Patricia Andrade, Afonso Celso Pinto Nazario, Maria Aparecida da Silva Pinhal. HEPARANASE LIQUID BIOPSY AND BREAST CANCER [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-02-03.

208-OR: PPP6C Directly Dephosphorylates TSC2, Improves Hepatic Lipid Metabolism, and Mediates FGF21 Action on Metabolic Dysfunction–Associated Steatohepatitis in Mice

2025-06-13

SHUANG WEI , Zhengshuai Liu , Yang Jiang +4 more | Diabetes

Introduction and Objective: Metabolic dysfunction-associated steatohepatitis (MASH) is a serious chronic liver disease and remains limited therapies. Although fibroblast growth factor 21 (FGF21) has shown promising therapeutic benefits for MASH, … Introduction and Objective: Metabolic dysfunction-associated steatohepatitis (MASH) is a serious chronic liver disease and remains limited therapies. Although fibroblast growth factor 21 (FGF21) has shown promising therapeutic benefits for MASH, how FGF21 signals are transduced into the cell and regulate MASH and whether the liver is a direct target of FGF21 remain obscure. Methods: Liver-specific PPP6C knockout mice, βKlotho knockout and their wild-type littermates were fed with AMLN diet for 16 weeks or CDA-HFD for 10-12 weeks, followed by daily subcutaneous injection of rFGF21 (0.5 mg/kg) or vehicle for 4 weeks. Mass spectrometry assay was used for identification of PPP6C as a βKlotho binding protein. The in vitro phosphatase assay was used to evaluate the effects of FGF21 on PPP6C activity. Results: We identified serine and threonine phosphatase PPP6C as the direct target of FGF21 in hepatocytes. PPP6C is uncovered as a coreceptor βklotho-binding protein, which is preferentially expressed in hepatocytes and significantly decreased in MASH livers of mice. PPP6C deficiency in hepatocytes exacerbates hepatic steatosis, inflammation, fibrosis and liver injury in mice fed with AMLN or CDA-HFD diets, which blocks beneficial effects of FGF21. Mechanistically, the phosphatase activity of PPP6C is activated by FGF21 via the FGFRs/βklotho complex, and subsequently PPP6C interacts with TSC2 to reduce the phosphorylation of TSC2, thereby inhibiting mTORC1 activity. Thus, TFE3 and Lipin1 are translocated to nucleus, where they inhibit the transcription of lipid synthesis genes but promote fatty acid oxidation genes. In livers of MASH subjects, expression levels of PPP6C are decreased whereas TSC2 phosphorylation is elevated. Conclusion: These results define a fundamental mechanism underlying FGF21 signals in hepatocytes and demonstrate that targeting PPP6C may have therapeutic potential for treating MASH. Disclosure S. Wei: None. Z. Liu: None. Y. Jiang: None. W. Su: None. F. Ma: None. A. Cui: None. Y. Li: None. Funding National Key R&D Program of China (2023YFA1801100); National Natural Science Foundation of China (81925008, 32130047); Project supported by Shanghai Municipal Science and Technology Major Project, Open Project Program of Metabolic Vascular Diseases Key Laboratory of Sichuan Province (2022MVDKL-K2)

Saponins from <i>Panax japonicus</i> Enhance Lipolysis via Acting on FGF21-β-Klotho/FGFR1 in Obese Mice

2025-06-13

Tongyao Wang , Yan Huang , Mingxin Hu +7 more | Journal of Agricultural and Food Chemistry

Saponins from Panax japonicus (SPJ) had a significant antiobesity action, and fibroblast growth factor 21 (FGF21) plays a central role in energy, lipid, and glucose homeostasis. We explored whether FGF21 … Saponins from Panax japonicus (SPJ) had a significant antiobesity action, and fibroblast growth factor 21 (FGF21) plays a central role in energy, lipid, and glucose homeostasis. We explored whether FGF21 is the target site of SPJ in lipolysis to improve lipid metabolism. We established an obese mouse model that was fed with a high-fat diet (HFD) for 16 weeks, and these obese mice were medicated with low-dose SPJ (15 mg/kg) or high-dose SPJ (45 mg/kg). The effects of SPJ on lipid metabolism, particularly on sympathetic activation and subsequent lipolysis in white adipose tissue (WAT), were evaluated. Furthermore, the impacts of SPJ on adipose FGF21 and its receptors β-Klotho (KLB) and FGFR1 within the central nervous system (CNS) were examined. Then, we observed the actions of FGF21 on WAT lipolysis as well as on KLB and FGFR1 within the CNS. Our results showed that SPJ treatment ameliorated lipid metabolism and protected against chronic HFD-induced obesity in a dose-independent manner. In WATs of HFD-induced obese mice, SPJ stimulated sympathetic innervation and enhanced lipolysis by increasing the expressions of FGF21 and its receptors (KLB and FGFR1). Moreover, SPJ had the capability to activate KLB- and FGFR1-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus and area postrema (AP)/nucleus tractus solitarius (NTS) of the HFD-induced obese mice. Interestingly, FGF21 analogue treatment partly recapitulated the action of SPJ on lipid metabolism by enhancing sympathetic activation and lipolysis in WATs of the HFD-induced obese mice. Like SPJ, FGF21 analogue treatment also activated KLB- and FGFR1-expressing neurons in PVN and AP/NTS. This study demonstrated that SPJ acted on adipose FGF21 and brain KLB/FGFR1 in obese mice to enhance sympathetic innervation and lipolysis, contributing to improved lipid metabolism.

1281-P: The Role of Depression in FGF21 Responsiveness after Glucose Loading and Sucrose Intake—The Bunkyo Health Study

2025-06-13

Shota Sakamoto , Saori Kakehi , Hideyoshi Kaga +6 more | Diabetes

Introduction and Objective: Fibroblast growth factor 21 (FGF21) is a hepatokine with potential therapeutic relevance in diabetes, as it modulates glucose and lipid metabolism and suppresses sugar preference. However, depression, … Introduction and Objective: Fibroblast growth factor 21 (FGF21) is a hepatokine with potential therapeutic relevance in diabetes, as it modulates glucose and lipid metabolism and suppresses sugar preference. However, depression, which is common in older adults, is associated with higher sucrose preference, especially in women, and its impact on FGF21’s metabolic effects remain unclear. We investigated whether depression modifies the relationship between FGF21 and sucrose intake in older adults. Methods: We analyzed 1,438 participants (845 women, aged 65-84) from the Bunkyo Health Study. Factors included body composition, dietary intake, and the Geriatric Depression Scale (GDS-15), with a GDS score of ≥5 indicating depressive tendencies. FGF21 responsiveness (iAUC-FGF21) was calculated from oral glucose tolerance test. Associations between FGF21 and sucrose intake were examined using sex-stratified multiple regression analyses. Participants were classified into four groups by depressive tendencies (no/present) and iAUC-FGF21 (high/low at median), and ANCOVA with Bonferroni post hoc test examined sucrose intake differences. Results: Women had higher sucrose intake (2.9% vs. 2.5%) and a higher prevalence of depressive tendencies (21.1% vs. 16.9%) than men. Only in women, sucrose intake positively correlated with GDS-15 levels (β=0.077, p=0.025) but negatively with iAUC-FGF21 (β=-0.119, p&lt;0.001). In the four-group analysis among women, only those without depressive tendencies and with higher iAUC-FGF21 showed significantly lower sucrose intake (3.0±0.1%) compared to those with lower iAUC-FGF21 (3.3±0.1%, p=0.030). Conclusion: In older women, depressive tendencies were associated with increased sucrose intakes and appeared to attenuate FGF21's suppressive effects on sucrose consumption, suggesting the need to consider mental health when evaluating FGF21’s potential in diabetes management. Disclosure S. Sakamoto: None. S. Kakehi: None. H. Kaga: None. H. Tabata: None. T. Tajima: None. H. Naito: None. T. Kogai: None. H. Watada: Speaker's Bureau; Novo Nordisk, Boehringer-Ingelheim, Sumitomo Pharma, Eli Lilly and Company, Roche Diabetes Care, Merck Sharp & Dohme Corp, Sanwa Kagaku, Daiichi Sankyo. Research Support; Sumitomo Pharma, SBI Pharma, Kowa Company, Ltd, Sanwa Kagaku, Boehringer-Ingelheim. Speaker's Bureau; Kyowa Kirin Co., Ltd, Bayer Pharmaceuticals, Inc, Abbott Japan Co., Ltd, Mitsubishi Tanabe Pharma Corporation. Y. Tamura: None.

Abstract P4-08-04: Selective activity of rogaratinib in PIK3CA- and ESR1-wild-type, FGFR1/2-amplified hormone receptor-positive breast cancer (HR+/HER2- BC): a co-clinical trial

2025-06-13

Silvana Mourón , María José Sánchez Bueno , Silvia Calabuig‐Fariñas +7 more | Clinical Cancer Research

Abstract Introduction: FGFR1/2 amplification is associated with poor outcomes and treatment resistance in HR+/HER2- BC. However, FGFR inhibitors have shown limited activity in this disease. Recently, we demonstrated that complete … Abstract Introduction: FGFR1/2 amplification is associated with poor outcomes and treatment resistance in HR+/HER2- BC. However, FGFR inhibitors have shown limited activity in this disease. Recently, we demonstrated that complete cell cycle arrest was only achieved if FGFR inhibitors were combined with CDK4/6i and endocrine treatment (ET) in FGFR-amplified breast cancer models (PMID33579347). Co-clinical trials (different study designs involving concurrent patient treatment and model testing) aim to expedite and enhance the translation of laboratory discoveries to clinical practice. Thus, we conducted a co-clinical trial with patient-derived tumor organoids (PDTOs) resistant to CDK4/6i and ET and a phase-I clinical trial of fulvestrant, palbociclib and the pan-FGFR inhibitor rogaratinib in women progressing to first-line CDK4/6i combined aromatase inhibitor (AI). Methods: PDTOs: 4 PDTOs, 3 FGFR1-amplified and 1 FGFR1-non-amplified. Among the amplified, one (H12-5) was PIK3CA mutant (H1047R); one (H12-31) was ESR1 mutant (Y537S); and one (H12-7) was wild-type for both genes; the FGFR1-non-amplified (H12-28) was double wild-type as well. PDTOs viability was explored in response to rogaratinib, fulvestrant, palbociclib, camizestrant, and alpelisib in monotherapy or in combinations. Trial: dose-escalation, multi-centric clinical trial. Women &gt;18 years old with metastatic HR+/HER2- BC progressing to a combination of CDK4/6i plus AI in the first-line, candidates for second-line therapy. Patients were pre-screened for FGFR1/2 amplification (FISH) or overexpression (RNAScope) in a recent tumor sample. Treatment consisted on 28-day cycles of fulvestrant 500 ug in day 1 (and day 15 on cycle 1), palbociclib 100 mg in days 1-21, and rogaratinib bid in days 1-28. Rogaratinib started at 400 mg/bid and was escalated in 200 mg intervals; palbociclib could be escalated to 125 on cycle 2. Results: PDTOs: the 4 PDTOs were refractory to fulvestrant, palbociclib, and the combination. Rogaratinib monotherapy only displayed modest activity in H12-31. The triple-combination of fulvestrant, palbociclib (1uM each) and increasing rogaratinib was highly effective in H12-7, but lacked activity in H12-5, H12-31 and H12-28 (an FGFR-amplified variant of the latter turned sensitive to the combination). PDTOs H12-5 and H12-31 were re-sensitized by replacing palbociclib for alpelisib and fulvestrant for camizestrant, respectively. Trial: 67 patients were screened; 29 (43%) were positive for FGFR1/2 amplification and/or overexpression. The RP2D was established at 500 ug fulvestrant, 100 mg palbociclib (days 1-21) and rogaratinib 600 mg/bid. Nine patients were treated. The most frequent grade 1/2 toxicity were hyperphosphatemia (77% of patients) and diarrhea (33%). Grade 3 neutropenia occurred in 66.7% of the patients; grade 3 asthenia, diarrhea and hyperphosphatemia were observed in 11.1% of the patients each. Median PFS was 3.5 months. Five patients displayed PIK3CA and/or ESR1 mutations in the tumor or plasma sample, and 4 were wild-type for both. All double wild-type patients remained PFS for longer than 6-months (185-330 days), and the PFS time comparison between double wild-type against PIK3CA/ESR1-mutant patients favored the former by an almost 5-fold advantage: 274 vs 58 days; P=0.005. Conclusion: A high percentage (43%) of second-line HR+/HER2- BC displays FGFR1/2 overexpression or amplification, of which approximately half are wild-type for ESR1 and PIK3CA. FGFR1/2 inhibition with rogaratinib in combination with palbociclib and fulvestrant is active in second-line, FGFR1/2-amplified/overexpressed HR+/HER2- BC, but the activity is restricted to wild-type PIK3CA/ESR1 patients. These results frame the population in which the development of this combination should be focused. Citation Format: Silvana Mouron, María J. Bueno, Silvia Calabuig, Laura Muinelo, Noelia Martínez-Jañez, Sonia Pernas, José Ángel García Saenz, Serafín Morales, Begoña Bermejo, Juan Antonio Guerra, Rodrigo Sánchez-Bayona, Pablo Tolosa, Manuel Alva, Eva Ciruelos, Miguel Quintela-Fandino. Selective activity of rogaratinib in PIK3CA- and ESR1-wild-type, FGFR1/2-amplified hormone receptor-positive breast cancer (HR+/HER2- BC): a co-clinical trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-08-04.

Clinical characterization of FGFR2b expression in patients with advanced gastric or gastroesophageal junction adenocarcinoma

2025-06-12

Seiya Sato , Shannon Rhodes , Yu Aoki +7 more | ESMO Open

Erdafitinib diminishes LPS-mediated neuroinflammatory responses through NLRP3 in wild-type mice

2025-06-05

Hyunju Lee , Se Ha Kim , Tae-Mi Jung +5 more | Frontiers in Pharmacology

Introduction Erdafitinib is an FDA-approved inhibitor of fibroblast growth factor receptor (FGFR) that is used clinically to treat metastatic urothelial cancer. FGFR activation is involved in proinflammatory responses, but the … Introduction Erdafitinib is an FDA-approved inhibitor of fibroblast growth factor receptor (FGFR) that is used clinically to treat metastatic urothelial cancer. FGFR activation is involved in proinflammatory responses, but the potential effects of FGFR inhibitors like erdafitinib on neuroinflammatory responses in the brain have not been fully established. Methods The effects of pretreatment with 1 μM or 5 μM erdafitinib on proinflammatory responses induced by 1 μg/mL or 200 ng/mL LPS in vitro were evaluated in BV2 microglial cells. For in vivo experiments, 3-month-old C57BL6/N mice were injected (i.p.) daily for 7 days with vehicle (5% DMSO +40% PEG +5% Tween80 + 50% saline) or 10 mg/kg erdafitinib. On the final day, the mice were injected (i.p.) with 10 mg/kg LPS or PBS after erdafitinib administration and sacrificed after 8 h. The mRNA and protein expression of neuroinflammatory-associated molecules were assessed in cells or mouse brain tissue by real-time PCR, immunofluorescence staining, and/or Western blotting. Results and Discussion In BV2 microglial cells, erdafitinib pretreatment significantly reduced the increases in proinflammatory cytokines, NLRP3 inflammasome activation and JNK/PLCγ signaling induced by LPS. In C57BL6/N mice, erdafitinib pretreatment significantly suppressed LPS-stimulated microglial/astroglial activation and proinflammatory cytokine expression. Importantly, erdafitinib pretreatment significantly downregulated LPS-induced NLRP3 inflammasome activation and astroglial neuroinflammation-associated molecules in C57BL6/N mice. Collectively, our experiments demonstrate that erdafitinib pretreatment diminishes LPS-induced neuroinflammation by suppressing NLRP3 inflammasome activation in vitro and in vivo and suggest that erdafitinib is a potential therapeutic agent for neuroinflammation-related diseases.

EGFRvIII-driven microenvironmental fibroblast activation and transformation accelerate oral cancer progression via lipocalin-2/STAT3 axis

2025-06-04

Hsuan‐Yu Peng , Kwang Yu Chang , Wei‐Min Chang +7 more | Neoplasia

An FGFR-p53 developmental signaling axis drives salivary cancer progression

2025-06-02

Adele M. Musicant , Julia Billington , Jeffrey S. Damrauer +7 more | Oncogene

Synergistic Pathways in Parkinson's Disease: The Promise of FGF21 and ACE2

2025-06-01

Tingting Liu , Jingwen Li , Haojie Wu +1 more | Ageing Research Reviews