MECHANISMS OF FGF RECEPTOR REGULATION AND SIGNALING

Summary

Principal Investigator: Moosa Mohammadi
Abstract: DESCRIPTION (provided by applicant): Fibroblast growth factor (FGF) signaling plays pleiotropic roles in mammalian development and metabolism, and disease. The paracrine FGF1, FGF4, FGF7, FGF8, and FGF9 subfamilies play essential roles in spermatogenesis, mesoderm induction, somitogenesis, organogenesis, and pattern formation, whereas the FGF19 subfamily acts in an endocrine fashion to regulate major metabolic processes including glucose, lipid, cholesterol, and bile acid metabolism, and phosphate/vitamin D homeostasis. The diverse activities of FGFs are transmitted by the FGF receptor (FGFR) subfamily of receptor tyrosine kinases (RTKs). Perturbed FGF signaling leads to numerous human diseases, including skeletal, reproductive syndromes, hearing loss, renal phosphate wasting, neurodegenerative disorders, and cancer. Several paracrine FGFs and all the endocrine FGFs are being pursued for drug development. The four specific aims of this competing renewal are: I. Characterize the structural basis by which epithelially-expressed FGF4 and FGF9 subfamilies attain their specificity towards mesenchymally-expressed FGFRc isoforms. II. Elucidate the structural basis by which a/bKlotho co-receptors promote signaling by the endocrine FGFs. III. Dissect the role of A-loop tyrosine phosphorylation in the hyperactivation of FGFR tyrosine kinase by pathogenic gain-of-function mutations. IV. Elucidate the structural basis by which FGFR recruits and phosphorylates FRS2a. Recombinant protein expression and engineering, x-ray crystallography, Surface Plasmon Resonance (SPR) spectroscopy, isothermal titration calorimetry (ITC), steady-state kinetics analysis, and time-resolved mass spectrometry will be used to accomplish the Specific Aims of this proposal. The structural and biophysical/biochemical results obtained will also be validated using cell- and animal-based assays. The data obtained under Aim I should provide molecular insights into the roles of paracrine FGFs in embryonic development and also facilitate the discovery of drugs for tissue repair and bioengineering, promotion of self- renewal and differentiation of human embryonic stem cells for cell-replacement therapy. The data generated under Aim II should enhance our understanding of the role of endocrine FGFs in human metabolism and provide blueprints for drug discovery for major human diseases including diabetes, obesity, hypercholesterolemia, colon cancer, and chronic kidney disease, most of which represent a huge burden on public health. The results of Aim III will enhance our understanding of the mechanism of action of pathogenic mutations in FGFRs and other RTKs as well as the regulation of tyrosine kinase activity of the entire RTK superfamily. Since substrate recruitment and phosphorylation by RTKs is a general event in RTK signaling, the mechanistic insights gained under Aim IV will also be directly applicable to the entire RTK superfamily.
Funding Period: 2013-08-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc FGF23 promotes renal calcium reabsorption through the TRPV5 channel
    Olena Andrukhova
    University of Veterinary Medicine Vienna, Vienna, Austria
    EMBO J 33:229-46. 2014
  2. pmc Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia
    Taneli Raivio
    Children s Hospital, Helsinki University Central Hospital, Institute of Biomedicine Physiology, University of Helsinki 00290 Helsinki, Finland
    J Clin Endocrinol Metab 97:E694-9. 2012
  3. pmc Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 109:3143-8. 2012
  4. pmc Urothelial tumor initiation requires deregulation of multiple signaling pathways: implications in target-based therapies
    Haiping Zhou
    Department of Urology, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA
    Carcinogenesis 33:770-80. 2012
  5. pmc The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition
    Juliya Kalinina
    Department of Pharmacology, New York University School of Medicine, 550, First Avenue, New York, NY 10016, USA
    Structure 20:77-88. 2012
  6. pmc Plasticity in interactions of fibroblast growth factor 1 (FGF1) N terminus with FGF receptors underlies promiscuity of FGF1
    Andrew Beenken
    Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA
    J Biol Chem 287:3067-78. 2012
  7. pmc Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice
    Hongwei Wang
    Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York 10461, USA
    J Clin Invest 121:3220-32. 2011
  8. pmc Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4
    Jyothsna Gattineni
    Dept of Pediatrics, U T Southwestern Medical Center, Dallas, TX 75390 9063, USA
    Am J Physiol Renal Physiol 301:F371-7. 2011
  9. pmc Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse
    Klementina Fon Tacer
    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Mol Endocrinol 24:2050-64. 2010
  10. pmc Influence of heparin mimetics on assembly of the FGF.FGFR4 signaling complex
    Krishna Saxena
    Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany
    J Biol Chem 285:26628-40. 2010

Detail Information

Publications54

  1. pmc FGF23 promotes renal calcium reabsorption through the TRPV5 channel
    Olena Andrukhova
    University of Veterinary Medicine Vienna, Vienna, Austria
    EMBO J 33:229-46. 2014
    ..Our data thereby identify FGF23, not αKlotho, as a calcium-conserving hormone in the kidney. ..
  2. pmc Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia
    Taneli Raivio
    Children s Hospital, Helsinki University Central Hospital, Institute of Biomedicine Physiology, University of Helsinki 00290 Helsinki, Finland
    J Clin Endocrinol Metab 97:E694-9. 2012
    ..Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain...
  3. pmc Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 109:3143-8. 2012
    ..Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration...
  4. pmc Urothelial tumor initiation requires deregulation of multiple signaling pathways: implications in target-based therapies
    Haiping Zhou
    Department of Urology, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA
    Carcinogenesis 33:770-80. 2012
    ....
  5. pmc The alternatively spliced acid box region plays a key role in FGF receptor autoinhibition
    Juliya Kalinina
    Department of Pharmacology, New York University School of Medicine, 550, First Avenue, New York, NY 10016, USA
    Structure 20:77-88. 2012
    ..These data, together with the strong amino acid sequence conservation of the AB subregion among FGFR orthologs, highlight the universal role of the AB subregion in FGFR autoinhibition...
  6. pmc Plasticity in interactions of fibroblast growth factor 1 (FGF1) N terminus with FGF receptors underlies promiscuity of FGF1
    Andrew Beenken
    Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA
    J Biol Chem 287:3067-78. 2012
    ....
  7. pmc Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice
    Hongwei Wang
    Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York 10461, USA
    J Clin Invest 121:3220-32. 2011
    ..Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas...
  8. pmc Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4
    Jyothsna Gattineni
    Dept of Pediatrics, U T Southwestern Medical Center, Dallas, TX 75390 9063, USA
    Am J Physiol Renal Physiol 301:F371-7. 2011
    ..In addition, when 1,25(OH)(2)Vitamin D(3) levels are not affected by FGF23, as in FGFR3(-/-)FGFR4(-/-) mice, a reduction in PTH can override the effects of FGF23 on renal phosphate transport...
  9. pmc Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse
    Klementina Fon Tacer
    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Mol Endocrinol 24:2050-64. 2010
    ..This FGF atlas provides an important resource for guiding future studies to elucidate the physiological functions of FGFs in adult animals...
  10. pmc Influence of heparin mimetics on assembly of the FGF.FGFR4 signaling complex
    Krishna Saxena
    Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe University Frankfurt, Frankfurt, Germany
    J Biol Chem 285:26628-40. 2010
    ..Notably FGF2.HM(8) exhibits pronounced positive binding cooperativity. Based on our findings we propose a refined symmetric FGF.FGFR dimerization model, which incorporates the differential ability of HM to dimerize FGFs...
  11. pmc Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency
    Ericka B Trarbach
    Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42 da Disciplina de Endocrinologia do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, 05403 900, Sao Paulo, Brasil
    J Clin Endocrinol Metab 95:3491-6. 2010
    ..Recently, missense mutations in FGF8, a key ligand for fibroblast growth factor receptor (FGFR) 1 in the ontogenesis of GnRH, were identified in IHH patients, thus establishing FGF8 as a novel locus for human GnRH deficiency...
  12. pmc Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation
    Regina Goetz
    Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA
    Proc Natl Acad Sci U S A 107:407-12. 2010
    ..We propose that peptides derived from the C-terminal tail of FGF23 or peptidomimetics and small-molecule organomimetics of the C-terminal tail can be used as therapeutics to treat renal phosphate wasting...
  13. pmc The structural biology of the FGF19 subfamily
    Andrew Beenken
    Department of Pharmacology, New York University School of Medicine, New York, NY, USA
    Adv Exp Med Biol 728:1-24. 2012
    ..The isolated FGF23 C-terminus can be used to effectively inhibit the formation of the FGF23-FGFR1c-αklotho complex and alleviate hypophosphatemia in renal phosphate disorders due to elevated levels of FGF23...
  14. pmc Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands
    Regina Goetz
    Department of Pharmacology, New York University School of Medicine, New York, New York, USA
    Mol Cell Biol 32:1944-54. 2012
    ..Based on this binding site overlap, we conclude that while Klotho coreceptors enhance binding affinity of FGFR for endocrine FGFs, they actively suppress binding of FGF8 subfamily ligands to FGFR...
  15. pmc FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway
    Olena Andrukhova
    University of Veterinary Medicine Vienna, Vienna, Austria
    Bone 51:621-8. 2012
    ....
  16. pmc Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion
    Hannes Olauson
    Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
    PLoS Genet 9:e1003975. 2013
    ..The presence of Klotho-independent FGF23 effects in a Klotho-expressing target organ represents a paradigm shift in the conceptualization of FGF23 endocrine action...
  17. pmc Structural mimicry of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation
    Zhifeng Huang
    School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA
    Structure 21:1889-96. 2013
    ..We propose that the targeted inhibition of this pathogenic FGFR3 kinase may be achievable by small molecule kinase inhibitors that selectively bind the active-state conformation of FGFR3 kinase...
  18. pmc The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib, and ponatinib ATP-competitive inhibitors
    Sara A Byron
    Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA
    Neoplasia 15:975-88. 2013
    ..We propose that tumors harboring mutationally activated FGFRs should be treated with FGFR inhibitors that specifically bind the active kinase...
  19. pmc Cracking the molecular origin of intrinsic tyrosine kinase activity through analysis of pathogenic gain-of-function mutations
    Huaibin Chen
    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA
    Cell Rep 4:376-84. 2013
    ..Our data demonstrate that the fractional population of RTKs in the active state determines intrinsic kinase activity and underscore how a slight increase in the active population of kinases can have grave consequences for human health. ..
  20. pmc FGF23-induced hypophosphatemia persists in Hyp mice deficient in the WNT coreceptor Lrp6
    Kazuyoshi Uchihashi
    Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA
    Contrib Nephrol 180:124-37. 2013
    ..Our in vivo studies provide genetic and pharmacological evidence for a WNT-independent function of FGF23 in the regulation of phosphate homeostasis...
  21. pmc Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism
    Hichem Miraoui
    Faculty of Biology and Medicine, University of Lausanne in collaboration with Service of Endocrinology, Diabetology, and Metabolism, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 7, Lausanne CH 1005, Switzerland
    Am J Hum Genet 92:725-43. 2013
    ..Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH...
  22. pmc Arterial klotho expression and FGF23 effects on vascular calcification and function
    Karolina Lindberg
    Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
    PLoS ONE 8:e60658. 2013
    ..Thus, our data do not support Klotho-mediated FGF23 effects in the vasculature although confirmative studies in humans are warranted...
  23. pmc Exploring mechanisms of FGF signalling through the lens of structural biology
    Regina Goetz
    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
    Nat Rev Mol Cell Biol 14:166-80. 2013
    ....
  24. pmc Grb2, a double-edged sword of receptor tyrosine kinase signaling
    Artur A Belov
    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA
    Sci Signal 5:pe49. 2012
    ..Grb2 is conventionally known for playing positive roles in RTK signaling. The discovery of a negative regulatory role for Grb2 reveals that this adaptor acts as a double-edged sword in the regulation of RTK signaling...
  25. pmc Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor
    Regina Goetz
    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA
    J Biol Chem 287:29134-46. 2012
    ....
  26. pmc Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism
    Taneli Raivio
    Reproductive Endocrine Unit, Department of Medicine, The Harvard Center for Reproductive Endocrine Sciences, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    J Clin Endocrinol Metab 94:4380-90. 2009
    ..FGFR1 mutations have been identified in about 10% of patients with Kallmann syndrome. Recently cases of idiopathic hypogonadotropic hypogonadism (IHH) with a normal sense of smell (nIHH) have been reported...
  27. pmc Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis
    Helen P Makarenkova
    The Neurobiology Department, The Scripps Research Institute, La Jolla, CA 92037, USA
    Sci Signal 2:ra55. 2009
    ..Our data may provide a general model for understanding how binding to HS regulates other morphogenetic gradients...
  28. pmc A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis
    Shoji Ichikawa
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202 5121, USA
    J Clin Invest 117:2684-91. 2007
    ....
  29. pmc Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21
    Hiroshi Kurosu
    Departments of Pathology and Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA
    J Biol Chem 282:26687-95. 2007
    ..We conclude that the expression of betaKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21...
  30. ncbi Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21
    Takeshi Inagaki
    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Cell Metab 5:415-25. 2007
    ..These findings demonstrate an unexpected role for the PPARalpha-FGF21 endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation...
  31. pmc BetaKlotho is required for metabolic activity of fibroblast growth factor 21
    Yasushi Ogawa
    Department of Pathology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 104:7432-7. 2007
    ..Importantly, administration of FGF21 into mice induces MAP kinase phosphorylation in white adipose tissue and not in tissues without betaKlotho expression. Thus, betaKlotho functions as a cofactor essential for FGF21 activity...
  32. pmc Impaired FGF signaling contributes to cleft lip and palate
    Bridget M Riley
    Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
    Proc Natl Acad Sci U S A 104:4512-7. 2007
    ..The data suggest that the FGF signaling pathway may contribute to as much as 3-5% of NS CLP and will be a consideration in the clinical management of CLP...
  33. pmc Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members
    Regina Goetz
    Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA
    Mol Cell Biol 27:3417-28. 2007
    ..Klotho/betaKlotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of FGF19, -21, and -23 to their cognate receptors...
  34. pmc Selective enrichment and fractionation of phosphopeptides from peptide mixtures by isoelectric focusing after methyl esterification
    Chong Feng Xu
    Department of Pharmacology and Skirball Institute of Biomolecular Medicine, and Department of Biochemistry, NYU School of Medicine, New York, New York 10016, USA
    Anal Chem 79:2007-14. 2007
    ..We also showed that 2,6-dihydroxy-acetophenone is superior to 2,5-dihydroxybenzoic acid as a matrix for MALDI Q-TOF MS of methylated phosphopeptides in both positive and negative ion modes...
  35. pmc Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism
    Nelly Pitteloud
    Reproductive Endocrine Unit of the Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    J Clin Invest 117:457-63. 2007
    ..Therefore, 2 different gene defects can synergize to produce a more severe phenotype in IHH families than either alone. This genetic model could account for some phenotypic heterogeneity seen in GnRH deficiency...
  36. ncbi Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes
    Nelly Pitteloud
    Reproductive Endocrine Unit of the Department of Medicine and National Center for Infertility Research, Bartlett Hall Extension 5, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, United States
    Mol Cell Endocrinol 254:60-9. 2006
    ....
  37. pmc Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism
    Nelly Pitteloud
    Reproductive Endocrine Unit of the Department of Medicine and Harvard Reproductive Endocrine Science Centers, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
    Proc Natl Acad Sci U S A 103:6281-6. 2006
    ..These mutations also account for some of the mixed pedigrees, thus challenging the current idea that KS and nIHH are distinct entities...
  38. pmc Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family
    Xiuqin Zhang
    Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Biol Chem 281:15694-700. 2006
    ..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...
  39. pmc A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases
    Huaibin Chen
    Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA
    Mol Cell 27:717-30. 2007
    ..Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly...
  40. pmc The parathyroid is a target organ for FGF23 in rats
    Iddo Z Ben-Dov
    Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel
    J Clin Invest 117:4003-8. 2007
    ..These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis...
  41. ncbi Somatic FGF9 mutations in colorectal and endometrial carcinomas associated with membranous beta-catenin
    Wael M Abdel-Rahman
    Department of Medical Genetics, University of Helsinki, Helsinki, Finland
    Hum Mutat 29:390-7. 2008
    ..These data suggest that FGF9 plays a role in colorectal and endometrial carcinogenesis...
  42. pmc Compositional analysis of heparin/heparan sulfate interacting with fibroblast growth factor.fibroblast growth factor receptor complexes
    Fuming Zhang
    Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, USA
    Biochemistry 48:8379-86. 2009
    ..FGFR complexes tested...
  43. pmc Homodimerization controls the fibroblast growth factor 9 subfamily's receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix
    Juliya Kalinina
    Department of Pharmacology of New York University School of Medicine, New York, New York 10016, USA
    Mol Cell Biol 29:4663-78. 2009
    ....
  44. pmc FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response
    Matthew J Potthoff
    Department of Pharmacology, Howard Hughes Medical Institute, Advanced Imaging Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 106:10853-8. 2009
    ..These results reveal an unexpected relationship between FGF21 and PGC-1alpha and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation...
  45. pmc FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1
    Jyothsna Gattineni
    Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 9063, USA
    Am J Physiol Renal Physiol 297:F282-91. 2009
    ..6 +/- 0.3 vs. 5.2 +/- 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role...
  46. pmc Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels
    Regina Goetz
    Department of Pharmacology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA
    J Biol Chem 284:17883-96. 2009
    ..The mutations also disabled FHF modulation of voltage-dependent fast inactivation of sodium channels in neuronal cells. Based on our data, we propose that FHFs constitute auxiliary subunits for Navs...
  47. pmc The FGF family: biology, pathophysiology and therapy
    Andrew Beenken
    Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA
    Nat Rev Drug Discov 8:235-53. 2009
    ....
  48. pmc Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma
    Michael G Gartside
    Division of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
    Mol Cancer Res 7:41-54. 2009
    ..Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer...
  49. pmc A crystallographic snapshot of tyrosine trans-phosphorylation in action
    Huaibin Chen
    Department of Pharmacology and Kimmel Center for Biology and Medicine at Skirball Institute, New York University School of Medicine, New York, NY 10016, USA
    Proc Natl Acad Sci U S A 105:19660-5. 2008
    ..We propose that the salient mechanistic features of Y769 trans-phosphorylation are applicable to trans-phosphorylation of the equivalent major phosphorylation sites in many other RTKs...
  50. pmc In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis
    Teruyo Nakatani
    Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave, Boston, MA 02115, USA
    FASEB J 23:433-41. 2009
    ..Together, these results provide compelling evidence that Fgf23 does not have a klotho-independent role in the regulation of systemic phosphate and vitamin D homeostasis...
  51. pmc Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice
    John Falardeau
    Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital MGH, Boston, Massachusetts 02114, USA
    J Clin Invest 118:2822-31. 2008
    ..In conclusion, we identified FGF8 as a gene implicated in GnRH deficiency in both humans and mice and demonstrated an exquisite sensitivity of GnRH neuron development to reductions in FGF8 signaling...
  52. pmc Inhibition of growth hormone signaling by the fasting-induced hormone FGF21
    Takeshi Inagaki
    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Cell Metab 8:77-83. 2008
    ..Chronic exposure to FGF21 markedly inhibits growth in mice. These data suggest a central role for FGF21 in inhibiting growth as part of its broader role in inducing the adaptive response to starvation...
  53. pmc Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain
    Shaun K Olsen
    Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA
    Genes Dev 20:185-98. 2006
    ..Consistent with the indispensable role of FGF8 in embryonic development, we show that the FGF8 mode of receptor binding appeared as early as in nematodes and has been preserved throughout evolution...

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Experimental Therapeutics of Leukemia
    John C Byrd; Fiscal Year: 2013
    ..We believe that this SPORE group, as a multidisciplinary, highly interactive and accomplished team, will have a substantial impact on improving the clinical outcome of leukemia patients. ..
  3. Interdisciplinary center of excellence for the study of pain and sensory function
    Ian D Meng; Fiscal Year: 2013
    ..Completion of these Aims will develop the research careers of a multidisciplinary group of junior investigators, and establish the core facilities and equipment necessary to constitute a competitive research center. ..
  4. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  5. STUDIES OF ORGAN TRANSPLANTATION IN ANIMALS AND MAN
    Arthur J Matas; Fiscal Year: 2013
    ..2. To maximize rehabilitation. The focus here is on minimizing complications and maximizing quality of life. ..
  6. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
    ..This multidisciplinary approach is absolutely necessary to develop translational strategies for prevention and treatment of skeletal joint diseases. ..
  7. BARRIER FUNCTION OF THE GI TRACT IN HEALTH AND DISEASE
    W Allan Walker; Fiscal Year: 2013
    ..abstract_text> ..
  8. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  9. Biochemical and structural studies of HER2/ErbB2-containing heterodimers
    Lily L Raines; Fiscal Year: 2013
    ..As HER2 is a target of many successful cancer treatments, an improved understanding of this receptor may inform and direct current treatment strategies. ..
  10. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  11. CANCER CENTER SUPPORT GRANT
    Nancy E Davidson; Fiscal Year: 2013
    ..abstract_text> ..
  12. B-cell Biology of Mucosal Immune Protection from SIV Challenge
    Eric Hunter; Fiscal Year: 2013
    ....
  13. PRESYNAPTIC MECHANISMS OF NEURAL PLASTICITY
    Robert H Edwards; Fiscal Year: 2013
    ..and action of dopamine in the reward pathway: 1) The mechanism of dendritic dopamine release (Projects 1 and 3);2) The mechanism and physiological role of glutamate co-release by dopamine neurons (Project 3);3) Trafficking and regulation ..
  14. ApoE Receptor Biology and Neurodegeneration
    Mary Jo Ladu; Fiscal Year: 2013
    ..This Program will thus provide new and valuable information about how apoE and apoE receptors affect the pathogenesis of Alzheimer's disease. ..
  15. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  16. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  17. Structure/Function of Protein Tyrosine Phosphatases
    Zhong Yin Zhang; Fiscal Year: 2013
    ..Successful completion of this project will create a solid framework for understanding how individual SHP2 mutations cause diseases and provide insight into novel points of therapeutic intervention for these diseases. ..
  18. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  19. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  20. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  21. Spatial and Temporal Regulation of Angiogenesis
    HAROLD FISHER DVORAK; Fiscal Year: 2013
    ..abstract_text> ..
  22. Protein Dynamics in Enzymatic Catalysis
    Robert Callender; Fiscal Year: 2013
    ..The Equipment Core (Core A) supports the specialized comprehensive suite of instrumentation for the Program. The Administrative Core (Core B) administers the Program Project. ..
  23. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  24. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....