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Structure and regulation of non-receptor tyrosine kinases

非受体酪氨酸激酶的结构和调控

基本信息

批准号：
9037683
负责人：
MICHAEL J ECK
金额：
$ 41.52万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-10 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9037683
关键词：
Active Sites Architecture Asthma Autoimmune Process Binding Binding Sites Biochemistry Biosensor Cell Differentiation process Cell Line Cell Proliferation Cells Cellular biology Chemistry Complex Crystallization Cysteine Cytokine Receptors Cytoplasmic Tail Disease Drug Targeting Electron Microscopy Elements Erythrocytes Erythropoietin Erythropoietin Receptor Family Family member Fluorescence Resonance Energy Transfer Focal Adhesion Kinase 1 Goals Gray unit of radiation dose Growth Factor Receptors Health Hematopoietic Neoplasms Human In Vitro Individual Induced Mutation Inflammatory Integrins Interferons Interleukins Invaded Length Leukocytes Malignant Neoplasms Molecular Conformation Mutagenesis Mutation Myeloproliferative disease Neoplasm Metastasis Normal tissue morphology Phospholipids Phosphotransferases Play Production Property Protein Family Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Regulation Reporting Rheumatoid Arthritis Role SH3 Domains Signal Transduction Site Somatotropin Specificity Staging Stimulus Structure Surface T-Lymphocyte TEC Protein Tyrosine Kinase Testing Tyrosine Kinase Domain Work X-Ray Crystallography base cell motility cytokine design drug development improved inhibitor/antagonist insight intercellular communication migration mutant novel novel therapeutics receptor response src Homology Region 2 Domain structural biology tool

项目摘要

Non-receptor tyrosine kinases (NRTKs) function as tightly regulated, integrating switches in cellular signal transduction. Here we focus on representatives of three NRTK families, which have distinct multi-domain architectures: Jak-family kinases, Focal Adhesion Kinase (FAK), and the Tec-family member ITK (Il-2 inducible tyrosine kinase). Our longterm goals are to elucidate autoregulatory mechanisms of NRTKs at a structural level, to understand how these regulatory mechanisms are disrupted in cancer, and to use structural insights to facilitate discovery of novel inhibitors. With our collaborators, we are combining the tools of structural biology, biochemistry, cell biology, and chemistry in a unified way to advance these goals. We propose three Specific Aims. First, we will discover how Jak kinases recognize their cognate cytokine receptors and how they are regulated by interactions among their constituent domains. We have crystallized an Nterminal fragment of Jak2, and have also prepared a complex of this portion of Jak2 with the cytoplasmic tail of the erythropoietin receptor for structural analysis. Our studies of Jak regulation build on our recently determined structure of a linker/pseudokinase regulatory module, and through elucidation of the structure of essentially full-length Jak2, we will explain how the this module controls the activity of the adjacent kinase domain, and how this control is disrupted by the V617F mutation in myeloproliferative neoplasms. Second, we will determine structurally how focal adhesion kinase (FAK) is activated by PI(4,5)P2. This aim builds on our determination of the structure of FAK in its autoinhibited state, and our discovery that it binds and is activated by the PI(4,5)P2. Third, we will elucidate the structure an SH3-SH2-kinase fragment of Itk in order to understand its regulation and to facilitate inhibitor discovery. Based on our structural insights, we are developing irreversible inhibitors specific for Jak3 that may be useful in treatment of autoimmune and inflammatory disorders.

非受体酪氨酸激酶（NRTKs）的功能受到严格调控，整合了细胞信号中的开关