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Protein Tyrosine Dephosphorylation & signal Transduction

蛋白质酪氨酸去磷酸化

基本信息

批准号：
7246633
负责人：
NICHOLAS K TONKS
金额：
$ 66.56万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-08-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7246633
关键词：
1-Phosphatidylinositol 3-Kinase 5&apos -AMP-activated protein kinase AICA ribonucleotide Ablation Academia Academy Accession Number Achievement Acids Active Sites Acute Adopted Adverse effects Affect Affinity Agonist Alberta province Alternative Splicing American American Association of Cancer Research Amides Amino Acid Sequence Animals Antibodies Antibody Specificity Antigens Antineoplastic Agents Antisense Oligonucleotides Arabidopsis Architecture Attention Australia Austria Automobile Driving Back Bacteria Bacteriophages Base Sequence Basic Amino Acids Be++ element Belgium Beryllium Binding Binding Proteins Binding Sites Biochemical Biochemistry Bioinformatics Biological Biological Assay Biology Biotechnology Blast Cell Blood Glucose Bone Marrow Boxing Brain Buffers C-terminal C2H2 Zinc Finger Caenorhabditis elegans Canada Cancer cell line Cataloging Catalogs Catalysis Catalytic Domain Categories Cations Cell Adhesion Cell Cycle Cell Line Cell Nucleus Cell Proliferation Cells Cellular Stress Cellular biology Charge Chemistry Chickens China Chinese People Chronic Myeloid Leukemia Cities Class Classification Cleaved cell Collaborations Communities Complement Complementary DNA Complex Complex Mixtures Computer Analysis Condition Congresses Consensus Coupled Coupling Crystallization Cyclin-Dependent Kinases Cytokine Signaling Cytoplasm Cytosol DNA Sequence DNA binding protein B Data Data Analyses Databases Depth Development Developmental Biology Diabetes Mellitus Diet Diffusion Disease Disruption District of Columbia Dose Down-Regulation Drosophila genus Drosophila melanogaster Drug Industry EGF gene Eels Elements Embryo Endoplasmic Reticulum Enhancers Environment Enzymes Epidermal Growth Factor Epidermal Growth Factor Receptor Epitopes Equilibrium Erythropoietin Receptor Etiology Evolution Excision Exons Experimental Pathology Extended Family Face Facility Construction Funding Category Faculty Family Fatty acid glycerol esters Fiber Fibroblasts Foundations France Fred Hutchinson Cancer Research Center Funding Funding Agency Future Genbank Gene Expression Gene Family Gene Structure General Hospitals Generations Genes Genetic Genetic Transcription Genome Genomics Genus Capra German population Germany Gleevec Global Change Goals Goat Grant Group Structure Growth Growth Factor Hepatotoxicity Hereditary Disease Histocompatibility Testing Homologous Gene Hormones Human Hungary Hydrogen Peroxide Image Imagery Immune Immunoglobulin Fragments In Vitro Incubated Individual Industry Inflammation Inositol Institutes Institution Insulin Insulin Receptor Insulin Resistance Integral Membrane Protein Interferons International Internet Iron binding capacity measurement Isoenzymes JAK2 gene Japan Japanese Population Joints Kinetics Knock-out Knockout Mice Laboratories Lead Length Leptin Libraries Ligands Light Link Lipids Localized Location London Luciferases Lysophospholipids MAP Kinase Gene Malignant Neoplasms Maps Mass Spectrum Analysis Mediating Mediator of activation protein Membrane Membrane Proteins Messenger RNA Metabolic stress Metabolism Methods Mexican Mexico Mind Mitogen-Activated Protein Kinases Mitosis Modeling Modification Molecular Molecular Biology Molecular Conformation Molecular Profiling Mono-S Mus Mutate NADPH Oxidase Nature New York Nitrogen Non obese Nuclear Nuclear Export Nuclear Import Numbers Obesity Object Attachment Oncogene Proteins Organism Oryctolagus cuniculus Oxidants Oxidases Oxidation-Reduction Oxidative Stress Oxygen PTEN gene PTEN protein PTPN1 gene PTPN11 gene Pan Genus Paper Peptide Sequence Determination Peptide Transport Peptides Phage Display Pharmaceutical Preparations Pharmacology Phenotype Philadelphia Phosphatidylinositols Phospho-Specific Antibodies Phosphoproteins Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Phylogenetic Analysis Physiologic pulse Physiological Physiological Processes Placenta Play Point Mutation Polymerase Chain Reaction Positioning Attribute Postdoctoral Fellow Preclinical Drug Evaluation Predisposition Principal Investigator Prize Process Production Program Development Property Protein Binding Protein Databases Protein Dephosphorylation Protein Family Protein Kinase Protein Overexpression Protein Tyrosine Kinase Protein Tyrosine Phosphatase Protein Tyrosine Phosphatase Gene Protein phosphatase Proteins Proteolytic Processing Proteomics Pseudogenes Publications Publishing Pulse taking Quebec RNA RNA Interference RNA Splicing Radiation Rat-1 Reaction Reactive Oxygen Species Reading Frames Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Recombinant Antibody Recording of previous events Reducing Agents Regulation Regulatory Element Relative (related person)Reporter Reporting Repression Research Research Institute Research Personnel Resistance Resort Resources Response Elements Rodent Role Sampling San Francisco Science Scientist Screening procedure Second Messenger Systems Sequence Alignment Sequence Analysis Series Serum Shock Side Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Site Skeletal Muscle Societies Solutions Solvents Son of Sevenless Proteins Source Spain Specificity Stimulus Stress Structure Subcellular Fractions Substrate Specificity Sulfenic Acids Sulfhydryl Compounds Sulfonic Acids Sulfur Surface SwissProt Switzerland System T-cell protein tyrosine phosphatase TP53 gene TYK2 Taiwan Technology Tertiary Protein Structure Testing Therapeutic Therapeutic Intervention Therapeutic Radiology specialty Thinking Time Torafugu Transactivation Transcript Transcription Initiation Site Transcriptional Activation Translating Trees Tumor Suppressor Proteins Tyrosine Tyrosine Kinase Domain Tyrosine Phosphorylation Universities Up-Regulation Update Upper arm Vaccinia virus Vanadates Virulence Factors Washington Weight Gain Work X-Ray Crystallography Yang Yarrow abstracting angiogenesis anticancer research base biological adaptation to stress cancer cell carboxylate caspase-3 cell growth regulation cell motility cell type chemical property chemotherapy college combinatorial concept covalent bond cytokine diabetic rat drug development drug discovery ds-DNA enzyme activity genome database genome sequencing handbook human PTPRT protein human disease in vivo inhibitor/antagonist inorganic phosphate inositol-1,4,5-trisphosphate 5-phosphatase insight insulin signaling lectures lymph nodes lysophosphatidic acid markov model medical schools member migration molecular pathology mouse genome mutant myo-inositol-1 (or 4)-monophosphatase myotubularin non-diabetic novel novel strategies novel therapeutics nuclear protein import factor p97 oncology oxidation phosphatase inhibitor polyclonal antibody preference progesterone 11-hemisuccinate-(2-iodohistamine)programs promoter protein function protein tyrosine phosphatase 1B receptor reconstitution research and development research study response restoration scale up second messenger small molecule stoichiometry symposium synthetic peptide therapeutic target tool transcription factor tumor upstream kinase uptake vector web-accessible

项目摘要

The broad, long-term objectives of the project are to characterize the structure, regulation and function of the protein tyrosine phosphatase (FTP) family of enzymes. It is now apparent that the coordinated and competing actions of both protein tyrosine kinases {PTKs) and PTPs are integrated in vivo to control such fundamental processes as growth and proliferation, differentiation, survival, motility andmetabolism. Furthermore, disruption of the delicate balance between the action of PTPs and PTKs has been implicatedin the etiology of human diseases. Therefore, characterization of the PTPs is a prerequisite to gaininga complete understanding of the physiological consequences of tyrosine phosphorylaticn under normal diseased conditions. This research program is focused primarily on two nontransmembrane PTPs, PTP1B and TCPTP, which have been shown to be critical regulators of growth factor and hormone-induced signal transduction pathways in vivo, with links to major human diseases including cancer and diabetes.The four Specific Aims are;1) To conduct a structure:function analysis of PTP1B that will define mechanismsof substrate recognition and regulation of enzymatic activity, 2} To characterize the PTP 1Bpromoter and elucidate mechanims by which expression of the PTP is alteredin human diseases, 3) To characterize the regulation and function of TCPTP and 4) To develop proteomics-based strategies for profiling theexpression of members of the PTP family. Both PTP1B and TCPTP are regulated by reversible oxidation in vivo, which induces inhibitory conformational changes of the PTP active site. Strategies have been developedto test whether trapping the oxidized, inactive conformation can be pursued to exploit the PTPs astherapeutic targets. Furthermore, proteomics-based strategies are being developed for PTP identification in biological samples, to define novel therapeutic targets for human disease.

该项目的广泛和长期目标是确定蛋白酪氨酸磷酸酶（FTP）家族的酶。现在很明显，协调和蛋白酪氨酸激酶（PTK）和PTP两者的竞争作用在体内被整合以控制这种竞争。生长和增殖、分化、存活、运动和代谢等基本过程。此外，PTPs和PTKs作用之间的微妙平衡被破坏，人类疾病的病因学因此，PTP的表征是获得完全理解正常条件下酪氨酸磷酸化的生理后果疾病的条件。该研究计划主要集中在两个非跨膜PTP，PTP 1B 和TCPTP，它们已被证明是生长因子和细胞诱导信号的关键调节剂在体内的转导途径，与包括癌症和糖尿病在内的主要人类疾病的联系。具体目的是：1）进行PTP 1B的结构：功能分析，以确定底物识别和酶活性的调节，2}为了表征PTP 1B启动子和阐明PTP表达在人类疾病中改变的机制，3）为了表征PTP的表达， TCPTP的调控和功能; 4）发展基于蛋白质组学的表达谱分析策略 PTP家族的成员。PTP 1B和TCPTP在体内都受到可逆氧化的调节，诱导PTP活性位点的抑制性构象变化。已经制定了策略来测试是否可以通过捕获氧化的非活性构象来开发PTP作为治疗药物目标的此外，基于蛋白质组学的策略正在开发用于生物学中的PTP鉴定。样品，以确定人类疾病的新的治疗靶点。