Wnt signaling

Wnt信号传导

• 批准号: 8019088
• 负责人: Dianqing Wu
• 金额: $ 37.72万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/8019088
• 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

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信号传导以其在胚胎发育调节和肿瘤发生中的作用而闻名。第一个 Wnt 基因因其在小鼠体内诱导乳腺肿瘤的能力而被鉴定。现在的研究表明 Wnt 信号传导与许多不同类型的肿瘤有关。最典型的 Wnt 信号通路，即经典 Wnt 信号通路，是通过经典 Wnt 与其受体复合物（由 LDL 受体相关蛋白 (LRP) 5/6 和卷曲 (Fz) 蛋白组成）结合而启动的，最终导致β-连环蛋白的稳定和基因转录的激活。尽管我们对 Wnt 信号传导机制的理解取得了显着进展，但仍然存在重大差距。其中包括 Wnt 调节 LRP 磷酸化的机制、早期细胞内事件以及 Wnt 共受体 Fz 和下游信号分子 Disheveled (Dvl) 参与 Wnt/2-catenin 信号通路的生化基础。通过筛选人类激酶的 siRNA 文库，我们鉴定了一组可以抑制经典 Wnt 信号传导的磷脂酰肌醇 (PtdIns) 激酶 siRNA。我们继续证明Wnt3a可以诱导哺乳动物细胞中PtdIns(4,5)P2的积累，这取决于Fz和Dvl。我们还表明 PtdIns (4,5) P2 是 Wnt3a 诱导的典型信号事件所必需的。此外，我们发现异源三聚体 G 蛋白可能参与 Wnt 调节的 PtdIns (4,5) P2 形成。此外，我们的初步结果支持 PtdIns (4,5)P2 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 可能通过 Fz、Dvl 和 G 激活 PtdIns 激酶，刺激 PtdIns (4,5)P2 的形成，进而刺激 LRP5/6（一种早期 Wnt 信号传导）的磷酸化事件。特别地，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：细胞间通讯对于包括人类在内的多细胞生物的正常功能至关重要。这个过程中的问题会导致包括肿瘤发生在内的各种病理状况。这项研究计划旨在了解细胞间通讯的关键分子之一Wnt蛋白如何调节细胞功能以及该机制的缺陷如何导致疾病。