Wnt signaling

Wnt信号传导

基本信息

批准号：
8212562
负责人：
Dianqing Wu
金额：
$ 37.52万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212562
关键词：
Adenomatous Polyposis Coli Adenosine B-Lymphocytes Binding Biochemical Bioinformatics Biological Bone Development Caenorhabditis elegans Cell Communication Cell Line Cell Nucleus Cell Surface Receptors Cell membrane Cell physiology Cells Collaborations Complex Cyclic GMP Cytoskeletal Modeling Defect Developmental Process Disease Drosophila genus EGF gene Embryo Embryonic Development Event Exhibits Expeditions Family Felis catus Fishes Funding G Protein-Coupled Receptor Genes G-substrate GTP Binding GTP-Binding Proteins Generations Genes Genetic Genetic Epistasis Genetic Transcription Genome Glycogen Synthase Kinases Glycoproteins Grant Growth Factor Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Hela Cells Heterotrimeric GTP-Binding Proteins Homologous Gene Human Inositol Integral Membrane Protein Integrins Ion Channel LDL-Receptor Related Proteins Laboratories Lead Libraries Ligands Link Low Density Lipoprotein Receptor Low-Density Lipoproteins Lymphoid MAPK8 gene Mammalian Cell Mammals Mammary Neoplasms Mediating Membrane Membrane Protein Traffic Metabolic syndrome Metabolism Minor Molecular Monomeric GTP-Binding Proteins Mus Mutation Organism PTEN gene Pathway interactions Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipids Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Point Mutation Positioning Attribute Process Production Proline Protein Binding Protein Isoforms Protein S Protein Tyrosine Kinase Proteins RNA Splicing Recruitment Activity Regulation Reporter Genes Reporting Research Proposals Role Scaffolding Protein Screening procedure Sequence Homology Serine Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Small Interfering RNA Solid Source Stimulus Stream Structural Biologist Structure System T cell transcription factor 1 Threonine Transcriptional Activation Transducers Transmembrane Domain United States National Institutes of Health Variant Wnt proteins Work Xenopus base bone mass cell type enhancing factor extracellular high risk human FZD6 protein member migration multicatalytic endopeptidase complex novel osteogenic protein function receptor research study response tumor tumorigenesis wortmannin

项目摘要

DESCRIPTION (provided by applicant): Wnt signaling is known for its roles in regulation of embryonic development and in tumorigenesis. The first Wnt gene was identified by virtue of its ability to induce mammary tumors in mice. Studies have now implicated Wnt signaling in many different types of tumors. The best characterized Wnt signaling pathway, the canonical Wnt signaling pathway, is initiated by the binding of canonical Wnts to their receptor complexes consisting of the LDL receptor-related protein (LRP) 5/6 and frizzled (Fz) proteins, which eventually leads to the stabilization of -catenin and activation of gene transcription. Despite remarkable advances in our understanding of Wnt signaling mechanisms, significant gaps still remain. These include the mechanism by which Wnt regulates LRP phosphorylation, an early intracellular event and the biochemical basis for the involvement of Wnt co-receptor Fz and downstream signaling molecule Dishevelled (Dvl) in the Wnt/2-catenin signaling pathway. By screening a siRNA library for human kinases, we identified a group of phosphatidylinositide (PtdIns) kinase siRNAs that could inhibit canonical Wnt signaling. We went on demonstrating that Wnt3a could induce the accumulation of PtdIns (4,5) P2 in mammalian cells, which depends on both Fz and Dvl. We also showed that PtdIns (4,5) P2 is required for Wnt3a-induced canonical signaling events. Moreover, we found that there is possible involvement of heterotrimeric G proteins in Wnt-regulated PtdIns (4,5) P2 formation. Furthermore, we have preliminary results to support the two possible mechanisms by which PtdIns (4,5)P2 may regulate LRP phosphorylation. Putting all of these together, we hypothesize that Wnt3a may, via Fz, Dvl and G, activate PtdIns kinases to stimulate the formation of PtdIns (4,5)P2, which in turn stimulates the phosphorylation of LRP5/6, an early Wnt signaling event. Specially, in this application we will: 1) Investigate the mechanisms by which Wnt3a induces the formation of PtdIns (4,5)P2. 2) Investigate the mechanisms by which PtdIns (4,5)P2 regulates LRP phosphorylation. PUBLIC HEALTH RELEVANCE: Cell-cell communication is essential for normal functions of multi-cellular organisms including human. Problems in this process would lead to various pathological conditions including tumorigenesis. This research proposal is to understand how the Wnt protein, one of the key molecules in cell-cell communication, regulate cellular functions and how the defects in this mechanism would cause diseases.

描述（由申请人提供）：Wnt信号传导在调节胚胎发育和肿瘤发生中的作用而闻名。第一个Wnt基因是通过其在小鼠中诱导乳腺肿瘤的能力来鉴定的。现在，研究暗示了许多不同类型的肿瘤中的Wnt信号传导。最佳特征的Wnt信号通路是规范WNT信号通路，是由规范WNT与由LDL受体相关蛋白（LRP）5/6和毛躁（FZ）蛋白组成的受体配合物的结合来启动的，最终导致-catenin and -catenin and activeration of Gene and Costriptation of Gene and of Costription of Gene and Costrication of Gene and Costription of Cositivation。尽管我们对Wnt信号传导机制的理解取得了显着进步，但仍然存在明显的差距。其中包括Wnt调节LRP磷酸化的机制，早期的细胞内事件以及Wnt共受体FZ参与的生化基础和Wnt/2-catenin信号通路中的Wnt CoE受体FZ和下游信号分子调味（DVL）。通过筛选人类激酶的siRNA库，我们确定了一组磷脂酰肌醇（PTDINS）激酶siRNA，可以抑制规范的Wnt信号传导。我们继续证明，Wnt3a可以诱导PTDINS（4,5）P2在哺乳动物细胞中的积累，这取决于FZ和DVL。我们还表明，WNT3A诱导的规范信号事件需要PTDINS（4,5）P2。此外，我们发现异三聚体G蛋白可能参与WNT调节的PTDIN（4,5）P2形成。此外，我们有初步的结果来支持PTDINS（4,5）P2可能调节LRP磷酸化的两种可能机制。将所有这些放在一起，我们假设Wnt3a可以通过FZ，DVL和G激活PTDINS激酶，以刺激PTDINS（4,5）P2的形成，这反过来刺激了LRP5/6的磷酸化，这是一个早期的Wnt信号事件。特别是，在此应用中，我们将：1）研究WNT3A诱导PTDINS（4,5）P2形成的机制。 2）研究PTDINS（4,5）P2调节LRP磷酸化的机制。公共卫生相关性：细胞 - 细胞通信对于包括人在内的多细胞生物的正常功能至关重要。在此过程中的问题将导致各种病理状况，包括肿瘤发生。该研究建议是了解Wnt蛋白（细胞 - 细胞通信中的关键分子之一）如何调节细胞功能以及该机制中的缺陷如何引起疾病。