PIPKIgammai5 in the Control of HNSCC Progression

PIPKIgammai5 在控制 HNSCC 进展中的作用

• 批准号: 10383714
• 负责人: Yue Sun
• 金额: $ 36.5万
• 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/10383714
• 关键词: 1-Phosphatidylinositol 4-Kinase; Attention; Biological; Biological Assay; Biological Process; Cell Line; Cell Nucleus; Cell Proliferation; Cell membrane; Cells; Data; Development; Differentiation and Growth; Down-Regulation; Early Endosome; Endosomes; Enzymes; Epidermal Growth Factor Receptor; Event; Exhibits; Genetic Transcription; Growth; Head and Neck Squamous Cell Carcinoma; In Vitro; 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 - Cell Movement; System; Testing; Transcription Coactivator; Transportation; Ubiquitination; Work; Xenograft procedure; base; cancer stem cell; cancer type; cell growth; design; in vivo; migration; mouse model; novel; novel strategies; 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.

项目概要 磷脂酰肌醇 4,5-二磷酸 (PIP2) 是一种关键的脂质信号分子，可调节多种 生物活性。然而，PIP2 调节的信号传导在哺乳动物细胞命运决定和 肿瘤发生受到的关注较少。我们实验室的研究表明，内体定位 PIP2 产生酶，I 型 γ 磷脂酰肌醇磷酸激酶 i5 (PIPKIγi5)，对于 表皮生长因子受体 (EGFR) 和 Hippo 信号传导（两种重要信号传导途径）的调节 控制细胞增殖和癌症干细胞（CSC）再生。 EGFR 失调或 Hippo 信号传导已在多种癌症中发现，包括头颈鳞状细胞癌 （HNSCC）。目前的假设如下：通过与小型 GTPase Rab7a 相互作用，PIPKIγi5 进行调节 EGFR 内体运输和降解；通过与 E3 泛素连接酶神经元前体相互作用 细胞表达的发育下调4（NEDD4），PIPKIγi5控制Hippo通路的稳定性 核心部件WW45和LATS2； PIPKIγi5 通过调节 EGFR 和 Hippo 信号传导进行控制 HNSCC CSC 再生、肿瘤发生和转移。目标 1 将表征 PIPKIγi5-Rab7a 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还将演示PIPKIγi5是否控制Hippo核心组件WW45/LATS2 通过与 NEDD4 结合进行泛素化和降解。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 PIPKIγi5 对 HNSCC CSC 自我更新和 转移。此外，目标2将进一步验证PIPKIγi5在HNSCC肿瘤发生中的功能 PIPKIγi5 敲除小鼠模型。该应用程序的成功完成将揭示一种新颖的 PIP2- 通过调节 EGFR 和 Hippo 信号传导来控制 HNSCC 进展的调节途径。