MECHANISMS OF FGF RECEPTOR REGULATION AND SIGNALING
Moosa Mohammadi
New York University School Of Medicine, New York, Ny 10016
Grant 5R01DE013686-10 from National Institute Of Dental & Craniofacial Research
Abstract: Fibroblast growth factors (FGFs) execute their ubiquitous roles in the developing embryo, as well as in the adult, by binding and activating FGF receptor tyrosine kinases (FGFRs). FGFRs are single pass transmembrane receptors composed of an extracellular ligand binding region and a cytoplasmic region harboring the conserved tyrosine kinase domain. FGF-FGFR binding specificity is essential for the regulation of FGF signaling and is determined by primary sequence differences among FGFs and FGFRs. Similarly, specific recognition and tyrosine phosphorylation of intracellular targets by the activated FGFR is a fundamental step in FGF signaling and determines which specific downstream pathways are activated and, hence, what cellular response ensues. Aberrant FGF signaling is responsible for a wide spectrum of human pathological conditions including skeletal syndromes, olfactory syndromes, phosphate wasting disorders and cancer. The diversity of these diseases reflects the versatile and vital functions that FGFs play in human biology and provides a strong impetus for a thorough understanding of FGF signaling at the molecular level. The specific aims of this proposal are I. Establish the pattern of, and determine the structural basis for, FGF-FGFR binding specificity/promiscuity. II. Elucidate the structural basis for autoinhibition in the extracellular region of FGFR. III. Elucidate the structural basis by which FGFR interacts with intracellular signaling molecules. IV. Elucidate the structural basis by which FGFR kinase domain mutations result in constitutive activation of FGFRs in human skeletal syndromes and cancer. The primary means to accomplish these aims will be X-ray crystallography, coupled with surface plasmon resonance and steady-state kinetic analysis. The fundamental structural and biochemical information obtained from these studies will enhance our knowledge of FGF signaling and will allow us to understand the effects of pathogenic FGF and FGFR mutations. In broader terms, these studies will facilitate the rational design of novel antagonists of FGF signaling for use in treatment of a variety of pathological conditions and will also enhance our understanding of signaling of the entire receptor tyrosine kinase superfamily
Keywords: 21+ years old; ATP[{..}]protein-tyrosine O-phosphotransferase; Acids; Adult; Affinity; Alternate Splicing; Alternative Splicing; BEK; BFR-1; Binding; Binding (Molecular Function); Binding Sites; Biochemical; Boxing; Cancers; Cell Communication and Signaling; Cell Signaling; Cell surface; Charge; Classification; Combining Site; Complex; Comprehension; Coupled; Craniosynostosis; Crystallography, X-Ray; Crystallography, X-Ray Diffraction; Crystallography, X-Ray/Neutron; Crystallography, Xray; Cytoplasmic Domain; Cytoplasmic Tail; DNA Synthesis Factor; Data; Development; Disease; Disorder; EC 2.7; ECGF; EPH- and ELK-Related Tyrosine Kinase; EPH-and ELK-Related Kinase; EPHA8; Embryo; Embryonic; Endothelial Cell Growth Factor; EphA8 Protein; Ephrin Type-A Receptor 8; Ephrin Type-A Receptor 8 Precursor; Epithelial; FGF; FGF-1 receptor tyrosine kinase; FGF-R; FGFR; FGFR-1; FGFR1; FGFR1 protein; FGFR1 tyrosine kinase; FGFR2; FGFR2 gene; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 1; Fibroblast Growth Factor Receptor 2 Gene; Fibroblast Growth Factor Receptor Family; Fibroblast Growth Factor Receptors; Fibroblast Growth Regulatory Factor; GFAC; Genetic Alteration; Genetic Change; Genetic defect; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; HBGF; HEK3; Heparin; Heparin Binding; Heparinic Acid; Human; Human Biology; Human, Adult; Human, General; Immune Globulins; Immunoglobulins; Immunoglobulins / Antibodies; Intracellular Communication and Signaling; Investigators; KGFR Gene; KSAM-1; Keratinocyte Growth Factor Receptor Gene; Kinases; Kinetic; Kinetics; Knowledge; Lead; Lecithinases; Life Cycle; Life Cycle Stages; Ligand Binding; Literature; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Maps; Mediator; Mediator of Activation; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Molecular Configuration; Molecular Conformation; Molecular Interaction; Molecular Stereochemistry; Mutation; PTB Domain; PTK; PTK Receptors; Pathway interactions; Pattern; Pb element; Phosphates; Phospholipase; Phosphotransferases; Phosphotyrosine Binding Domain; Play; Position; Positioning Attribute; Property; Property, LOINC Axis 2; Protein Tyrosine Kinase; Protein Tyrosine Kinase EEK; Publishing; RNA Splicing, Alternative; RTK; Reactive Site; Receptor Activation; Receptor Protein; Receptor Protein-Tyrosine Kinases; Receptor Tyrosine Kinase Gene; Receptors, FGF; Regulation; Research Personnel; Researchers; Rest; Role; SH2 Domains; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; Single Crystal Diffraction; Specificity; Stretching; Structure; Surface Plasmon Resonance; Syndrome; Systematics; TK14; Testing; Therapeutic; Transmembrane Receptor Protein Tyrosine Kinase; Transphosphorylases; Tyrosine Kinase; Tyrosine Kinase Domain; Tyrosine Kinase Growth Factor Receptor; Tyrosine Kinase Linked Receptors; Tyrosine Kinase Receptors; Tyrosine Phosphorylation; Tyrosine-Protein Kinase Receptor EEK; Tyrosine-Specific Protein Kinase; Tyrosylprotein Kinase; X Ray Crystallographies; X-Ray Crystallography; adult human (21+); base; biological signal transduction; conformation; conformational state; design; designing; disease/disorder; extracellular; flexibility; gain of function mutation; genome mutation; heavy metal Pb; heavy metal lead; hydroxyaryl protein kinase; inhibitor; inhibitor/antagonist; inorganic phosphate; life course; malignancy; man; man`s; member; neoplasm/cancer; novel; olfactory syndrome; pathway; polypeptide; receptor; response; skeletal; small molecule; social role; src Homology Region 2 Domain; structural biology; synostosis (cranial); tyrosyl protein kinase; wasting
Project start date: 2000-07-01
Project end date: 2010-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2010
5R01DE013686-10 (2009): $621465
Sponsored Links Excellgen http://Excellgen.com
Mechanisms Of FGF Receptor Regulation And Signaling
Moosa Mohammadi, Associate Professor
Pharmacologynew York University School Of Medicine
550 1st Ave
new York, Ny 10016
Grant 5R01DE013686-09 from National Institute Of Dental & Craniofacial Research IRG: BBCA
Abstract: Fibroblast growth factors (FGFs) execute their ubiquitous roles in the developing embryo, as well as in the adult, by binding and activating FGF receptor tyrosine kinases (FGFRs). FGFRs are single pass transmembrane receptors composed of an extracellular ligand binding region and a cytoplasmic region harboring the conserved tyrosine kinase domain. FGF-FGFR binding specificity is essential for the regulation of FGF signaling and is determined by primary sequence differences among FGFs and FGFRs. Similarly, specific recognition and tyrosine phosphorylation of intracellular targets by the activated FGFR is a fundamental step in FGF signaling and determines which specific downstream pathways are activated and, hence, what cellular response ensues. Aberrant FGF signaling is responsible for a wide spectrum of human pathological conditions including skeletal syndromes, olfactory syndromes, phosphate wasting disorders and cancer. The diversity of these diseases reflects the versatile and vital functions that FGFs play in human biology and provides a strong impetus for a thorough understanding of FGF signaling at the molecular level. The specific aims of this proposal are I. Establish the pattern of, and determine the structural basis for, FGF-FGFR binding specificity/promiscuity. II. Elucidate the structural basis for autoinhibition in the extracellular region of FGFR. III. Elucidate the structural basis by which FGFR interacts with intracellular signaling molecules. IV. Elucidate the structural basis by which FGFR kinase domain mutations result in constitutive activation of FGFRs in human skeletal syndromes and cancer. The primary means to accomplish these aims will be X-ray crystallography, coupled with surface plasmon resonance and steady-state kinetic analysis. The fundamental structural and biochemical information obtained from these studies will enhance our knowledge of FGF signaling and will allow us to understand the effects of pathogenic FGF and FGFR mutations. In broader terms, these studies will facilitate the rational design of novel antagonists of FGF signaling for use in treatment of a variety of pathological conditions and will also enhance our understanding of signaling of the entire receptor tyrosine kinase superfamily
Keywords: biological signal transduction, fibroblast growth factor, growth factor receptor, protein structure function, protein tyrosine kinase, receptor binding, receptor expression binding site, carcinogenesis, intermolecular interaction, phosphorylation, posttranslational modification, skeletal disorder X ray crystallography, surface plasmon resonance, tissue /cell culture
Project start date: 2000-07-01
Project end date: 2010-06-30
5R01DE013686-09 (2008): $603362
5R01DE013686-08 (2007): $592303
5R01DE013686-07 (2006): $592227
5R01DE013686-05 (2004): $368684
5R01DE013686-04 (2003): $357944
5R01DE013686-02 (2001): $337399
Grants awarded to Moosa Mohammadi
2010 FIBROBLAST GROWTH FACTORS IN DEVELOPMENT AND DISEASES GORDON RESEARCH CONFER
Moosa Mohammadi
Gordon Research Conferences, West Kingston, Ri 02892
Grant 1R13HD063210-01A1 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: This application requests funding to partially support the 2010 Gordon Research Conference on Fibroblast Growth Factors in Development and Disease, to be held on March 14 - 19, 2010, at the Four Points by Sheraton in Ventura, California. The overarching goal of this conference is to enhance our understanding of the ubiquitous roles of FGF signaling in human biology. Among the topics to be covered in this meeting are 1) the mechanisms by which FGF signaling governs organogenesis and tissue patterning during embryonic development; 2) the role of FGF signaling in adult tissue homeostasis, repair, regeneration, and angiogenesis; 3) the emerging roles of the endocrine FGFs in the regulation of glucose/lipid/bile acid metabolism, and energy homeostasis, as well as in phosphate/vitamin D homeostasis; 4) crosstalk between FGF signaling and other morphogenetic pathways, including Wnt, Hedgehog, and BMP signaling pathways; 5) aberrant FGF signaling in developmental/hereditary diseases, including skeletal syndromes, hearing loss, and hypogonadism; and 6) roles of FGF signaling in various cancers. The five-day conference will be convened in a relatively isolated setting, with 36 invited speakers as well as approximately 15 speakers selected from s that represent current areas of FGF research, and a total of approximately 135 participants. At least one third of the speakers will be women, and female scientists as well as individuals from minority groups will be particularly encouraged to participate. The program will kick off with three featured talks The first presentation will give a historical update on the discovery of FGFs, the second will summarize the current knowledge on the FGF family, and the third talk will introduce the recently discovered endocrine FGFs. Eight sessions will follow that broadly address structural and biochemical aspects of FGF signaling, as well as the roles of FGFs in organogenesis and tissue patterning, in development and disease of the nervous and sensory systems, in glucose/lipid metabolism and phosphate/vitamin D homeostasis, in the pathogenesis of hereditary/developmental diseases, in tissue repair and regeneration (including stem cell biology), and in tumorigenesis. Reflecting the pleiotropic functions of FGF signaling in human biology, FGF researchers encompass a wide range of scientific disciplines, including structural biologists, biochemists, cell biologists, endocrinologists, developmental biologists, geneticists, pharmacologists, and clinicians. Consequently, the majority of FGF investigators do not attend other common meetings. Thus, the significance of this application is that this Gordon Research Conference on FGFs in Development and Disease will provide an interdisciplinary forum for new as well as established basic researchers, clinicians, and scientists from industry to discuss the latest results, exchange ideas, foster interdisciplinary collaborations, and shape future avenues of research. The health relatedness of this application is to provide a forum to define and tackle questions pertaining to the human development, metabolism, tissue repair, and human diseases of the nervous and sensory systems, metabolic disorders, skeletal and reproductive diseases, as well as cancer. Moreover, an emphasis will be placed on how to apply the latest discoveries in the field to develop new therapies for a variety of human diseases
Keywords: 21+ years old; Acids, Bile; Address; Adult; Area; Autoregulation; Bile Acids; Biochemical; Body Tissues; California; Cancers; Cell Communication and Signaling; Cell Signaling; Cells; D-Glucose; DNA Synthesis Factor; Development; Dextrose; Discipline; Disease; Disorder; ECGF; Embryo Development; Embryogenesis; Embryonic Development; Endocrine; Endocrinologist; Endothelial Cell Growth Factor; Energy Expenditure; Energy Metabolism; Erinaceidae; Ethnic and Racial Minorities; FGF; Family; Female; Fibroblast Growth Factor; Fibroblast Growth Regulatory Factor; Fostering; Funding; Future; Genetic Condition; Genetic Diseases; Glucose; Goals; HBGF; Health; Hearing Loss; Hedgehogs; Hereditary; Hereditary Disease; Homeostasis; Human Biology; Human Development; Human, Adult; Hypoacuses; Hypoacusis; Hypogonadism; Individual; Industry; Inherited; Intermediary Metabolism; Intracellular Communication and Signaling; Investigators; Knowledge; Lipids; METBL; Malignant Neoplasms; Malignant Tumor; Metabolic Diseases; Metabolic Disorder; Metabolic Processes; Metabolism; Metabolism, Lipids/Lipoproteins/Membrane Constituents; Minority Groups; Molecular Disease; NIH RFA; Natural regeneration; Oncogenesis; Organogenesis; Participant; Pathogenesis; Pathway interactions; Pattern; Phosphates; Physiological Homeostasis; Programs (PT); Programs [Publication Type]; R01 Mechanism; R01 Program; RPG; Regeneration; Request for Applications; Research; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; Role; Scientist; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Structural Biologist; Syndrome; Thesaurismosis; Tissues; Update; VIT D; Vitamin D; Woman; Wound Healing; Wound Repair; ing; adult human (21+); angiogenesis; biological signal transduction; blood glucose regulation; conference; disease/disorder; fat metabolism; genetic disorder; glucose control; glucose homeostasis; glucose regulation; hearing impairment; hereditary disorder; human disease; inorganic phosphate; interdisciplinary collaboration; lipid metabolism; malignancy; meetings; metabolism disorder; neoplasm/cancer; pathway; programs; regenerate; repair; repaired; reproductive; sensory system; skeletal; social role; stem cell biology; symposium; tissue repair; tumorigenesis
Relevance: The health relatedness of this application is to provide a forum to define and tackle questions pertaining to the human development, metabolism, tissue repair, and human diseases of the nervous and sensory systems, metabolic disorders, skeletal and reproductive diseases, as well as cancer. Moreover, an emphasis will be placed on how to apply the latest discoveries in the field to develop new therapies for a variety of human diseases
Project start date: 2010-03-05
Project end date: 2011-02-28
Budget start date: 5-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-08-149
1R13HD063210-01A1 (2010): $6000
MECHANISMS OF FGF RECEPTOR REGULATION AND SIGNALING
Moosa Mohammadi
New York University School Of Medicine, New York, Ny 10016
Grant 3R01DE013686-10S2 from National Institute Of Dental & Craniofacial Research
Abstract: Fibroblast growth factors (FGFs) execute their ubiquitous roles in the developing embryo, as well as in the adult, by binding and activating FGF receptor tyrosine kinases (FGFRs). FGFRs are single pass transmembrane receptors composed of an extracellular ligand binding region and a cytoplasmic region harboring the conserved tyrosine kinase domain. FGF-FGFR binding specificity is essential for the regulation of FGF signaling and is determined by primary sequence differences among FGFs and FGFRs. Similarly, specific recognition and tyrosine phosphorylation of intracellular targets by the activated FGFR is a fundamental step in FGF signaling and determines which specific downstream pathways are activated and, hence, what cellular response ensues. Aberrant FGF signaling is responsible for a wide spectrum of human pathological conditions including skeletal syndromes, olfactory syndromes, phosphate wasting disorders and cancer. The diversity of these diseases reflects the versatile and vital functions that FGFs play in human biology and provides a strong impetus for a thorough understanding of FGF signaling at the molecular level. The specific aims of this proposal are I. Establish the pattern of, and determine the structural basis for, FGF-FGFR binding specificity/promiscuity. II. Elucidate the structural basis for autoinhibition in the extracellular region of FGFR. III. Elucidate the structural basis by which FGFR interacts with intracellular signaling molecules. IV. Elucidate the structural basis by which FGFR kinase domain mutations result in constitutive activation of FGFRs in human skeletal syndromes and cancer. The primary means to accomplish these aims will be X-ray crystallography, coupled with surface plasmon resonance and steady-state kinetic analysis. The fundamental structural and biochemical information obtained from these studies will enhance our knowledge of FGF signaling and will allow us to understand the effects of pathogenic FGF and FGFR mutations. In broader terms, these studies will facilitate the rational design of novel antagonists of FGF signaling for use in treatment of a variety of pathological conditions and will also enhance our understanding of signaling of the entire receptor tyrosine kinase superfamily
Keywords: 21+ years old; ATP[{..}]protein-tyrosine O-phosphotransferase; Acids; Adult; Affinity; Alternate Splicing; Alternative Splicing; BEK; BFR-1; Binding; Binding (Molecular Function); Binding Sites; Biochemical; Boxing; Cancers; Cell Communication and Signaling; Cell Signaling; Cell surface; Charge; Classification; Combining Site; Complex; Comprehension; Coupled; Craniosynostosis; Crystallography, X-Ray; Crystallography, X-Ray Diffraction; Crystallography, X-Ray/Neutron; Crystallography, Xray; Cytoplasmic Domain; Cytoplasmic Tail; DNA Synthesis Factor; Data; Development; Disease; Disorder; EC 2.7; ECGF; EPH- and ELK-Related Tyrosine Kinase; EPH-and ELK-Related Kinase; EPHA8; Embryo; Embryonic; Endothelial Cell Growth Factor; EphA8 Protein; Ephrin Type-A Receptor 8; Ephrin Type-A Receptor 8 Precursor; Epithelial; FGF; FGF-1 receptor tyrosine kinase; FGF-R; FGFR; FGFR-1; FGFR1; FGFR1 protein; FGFR1 tyrosine kinase; FGFR2; FGFR2 gene; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 1; Fibroblast Growth Factor Receptor 2 Gene; Fibroblast Growth Factor Receptor Family; Fibroblast Growth Factor Receptors; Fibroblast Growth Regulatory Factor; GFAC; Genetic Alteration; Genetic Change; Genetic defect; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; HBGF; HEK3; Heparin; Heparin Binding; Heparinic Acid; Human; Human Biology; Human, Adult; Human, General; Immune Globulins; Immunoglobulins; Immunoglobulins / Antibodies; Intracellular Communication and Signaling; Investigators; KGFR Gene; KSAM-1; Keratinocyte Growth Factor Receptor Gene; Kinases; Kinetic; Kinetics; Knowledge; Lead; Lecithinases; Life Cycle; Life Cycle Stages; Ligand Binding; Literature; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Maps; Mediator; Mediator of Activation; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Molecular Configuration; Molecular Conformation; Molecular Interaction; Molecular Stereochemistry; Mutation; PTB Domain; PTK; PTK Receptors; Pathway interactions; Pattern; Pb element; Phosphates; Phospholipase; Phosphotransferases; Phosphotyrosine Binding Domain; Play; Position; Positioning Attribute; Property; Property, LOINC Axis 2; Protein Tyrosine Kinase; Protein Tyrosine Kinase EEK; Publishing; RNA Splicing, Alternative; RTK; Reactive Site; Receptor Activation; Receptor Protein; Receptor Protein-Tyrosine Kinases; Receptor Tyrosine Kinase Gene; Receptors, FGF; Regulation; Research Personnel; Researchers; Rest; Role; SH2 Domains; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; Single Crystal Diffraction; Specificity; Stretching; Structure; Surface Plasmon Resonance; Syndrome; Systematics; TK14; Testing; Therapeutic; Transmembrane Receptor Protein Tyrosine Kinase; Transphosphorylases; Tyrosine Kinase; Tyrosine Kinase Domain; Tyrosine Kinase Growth Factor Receptor; Tyrosine Kinase Linked Receptors; Tyrosine Kinase Receptors; Tyrosine Phosphorylation; Tyrosine-Protein Kinase Receptor EEK; Tyrosine-Specific Protein Kinase; Tyrosylprotein Kinase; X Ray Crystallographies; X-Ray Crystallography; adult human (21+); base; biological signal transduction; conformation; conformational state; design; designing; disease/disorder; extracellular; flexibility; gain of function mutation; genome mutation; heavy metal Pb; heavy metal lead; hydroxyaryl protein kinase; inhibitor; inhibitor/antagonist; inorganic phosphate; life course; malignancy; man; man`s; member; neoplasm/cancer; novel; olfactory syndrome; pathway; polypeptide; receptor; response; skeletal; small molecule; social role; src Homology Region 2 Domain; structural biology; synostosis (cranial); tyrosyl protein kinase; wasting
Project start date: 2000-07-01
Project end date: 2010-08-31
Budget start date: 22-SEP-2009
Budget end date: 31-AUG-2010
3R01DE013686-10S2 (2009): $99000
2R01DE013686-06 (2005): $588815
2R01DE013686-11 (2010): $678213
3R01DE013686-10S1 (2009): $206036
1R01DE013686-01 (2000): $348821