PIPKIgammai5 in the Control of HNSCC Progression

PIPKIgammai5 在控制 HNSCC 进展中的作用

• 批准号: 10614482
• 负责人: Yue Sun
• 金额: $ 36.87万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614482
• 关键词: 1-Phosphatidylinositol 4-Kinase; Attention; Biological; Biological Assay; Biological Process; Cell Differentiation process; Cell Line; Cell Nucleus; Cell Proliferation; Cell membrane; Cells; Data; Development; Down-Regulation; Early Endosome; Endosomes; Enzymes; Epidermal Growth Factor Receptor; Event; Exhibits; Genetic Transcription; Growth; Head and Neck Squamous Cell Carcinoma; In Vitro; Invaded; Knockout Mice; LATS2 gene; Laboratories; Link; Lipids; Lysosomes; Malignant Neoplasms; Mammalian Cell; Mediating; Modeling; Molecular; Monomeric GTP-Binding Proteins; Neoplasm Metastasis; Neurons; Oncogenes; PTEN gene; Pathologic; Pathway interactions; Patients; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphotransferases; Play; Proteins; Publishing; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Sorting; System; Testing; Transcription Coactivator; Transportation; Ubiquitination; Work; Xenograft procedure; cancer stem cell; cancer type; cell growth; design; in vivo; inorganic phosphate; migration; mouse model; novel; novel strategies; phosphatidylinositol phosphate 4-kinase; precursor cell; prevent; public health relevance; recruit; stem cell biomarkers; stem cell self renewal; trafficking; tumor; tumor progression; tumorigenesis; ubiquitin-protein ligase

Project Summary Phosphatidylinositol 4,5-bisphosphate (PIP2) is a key lipid-signaling molecule that regulates a vast array of biological activities. However, the function of PIP2-regulated signaling in mammalian cell-fate decision and tumorigenesis has received less attention. Research from our laboratory indicates that an endosome-localized PIP2 producing enzyme, type I gamma phosphatidylinositol phosphate kinase i5 (PIPKIγi5), is crucial for the regulation of Epidermal Growth Factor Receptor (EGFR) and Hippo signaling, two essential signaling pathways in the control of cell proliferation and Cancer Stem Cell (CSC) regeneration. The dysregulation of EGFR or Hippo signaling has been found in many types of cancers including head and neck squamous cell carcinoma (HNSCC). Here is the current hypothesis: By interacting with the small GTPase Rab7a, PIPKIγi5 modulates EGFR endosomal trafficking and degradation; By interacting with the E3 ubiquitin ligase Neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4), PIPKIγi5 controls the stability of Hippo pathway core components WW45 and LATS2; Via modulating the EGFR and Hippo signaling, PIPKIγi5 controls HNSCC CSC regeneration, tumorigenesis, and metastasis. Aim 1 will characterize the PIPKIγi5-Rab7a interaction and determine whether this interaction controls EGFR signaling by modulating endosome maturation. Aim 1 will also demonstrate whether PIPKIγi5 controls the Hippo core components WW45/LATS2 ubiquitination and degradation by associating with NEDD4. In Aim 2, both in vitro cell line models and in vivo xenograft mouse models will be used to determine the effects of PIPKIγi5 on HNSCC CSC self-renewal and metastasis. Furthermore, Aim 2 will further validate the function of PIPKIγi5 in HNSCC tumorigenesis by using PIPKIγi5-knockout mouse models. The successful completion of this application will reveal a novel PIP2- regulated pathway that controls HNSCC progression by modulating EGFR and Hippo signaling.

项目摘要 磷脂酰肌醇4，5-二磷酸（PIP 2）是一种关键的脂质信号分子，调节大量的脂质代谢， 生物活动。然而，PIP 2调节的信号在哺乳动物细胞命运决定中的功能， 肿瘤发生受到的关注较少。我们实验室的研究表明， 产生PIP 2的酶，I型γ磷脂酰肌醇磷酸激酶i5（PIPKIγi5），对于细胞的生长至关重要。 调节表皮生长因子受体（EGFR）和Hippo信号传导，两种重要的信号传导途径 在控制细胞增殖和癌症干细胞（CSC）再生方面。EGFR的失调或 Hippo信号已经在包括头颈部鳞状细胞癌在内的许多类型的癌症中发现 （HNSCC）。以下是目前的假设：通过与小的GTdR Rab 7a相互作用，PIPKIγi5调节 EGFR内体运输和降解;通过与E3泛素连接酶相互作用 细胞表达的发育下调蛋白4（NEDD 4），PIPKIγi5控制Hippo通路的稳定性 核心组分WW 45和LATS 2;通过调节EGFR和Hippo信号传导，PIPKIγ 15控制 HNSCC CSC再生、肿瘤发生和转移。目的1将表征PIPKIγi5-Rab 7a 相互作用，并确定这种相互作用是否通过调节内体来控制EGFR信号传导 成熟目标1还将证明PIPKIγi5是否控制Hippo核心组件WW 45/LATS 2 泛素化和降解与NEDD 4。在目标2中，体外细胞系模型和体内 异种移植小鼠模型将用于确定PIPKIγ 15对HNSCC CSC自我更新的影响， 转移此外，目的2将通过使用PIPKIγ 15在HNSCC肿瘤发生中的作用来进一步验证PIPKIγ 15在HNSCC肿瘤发生中的功能。 PIPKIγi5基因敲除小鼠模型。该应用程序的成功完成将揭示一种新的PIP 2- 通过调节EGFR和Hippo信号传导控制HNSCC进展的受调节的通路。