PI Signaling Role in Epithelial/Mesenchymal Transition

PI 信号在上皮/间质转化中的作用

• 批准号: 8250252
• 负责人: Richard A. Anderson
• 金额: $ 28.84万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-02 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250252
• 关键词: Actins; Adherens Junction; Binding; Biochemical; Biological; Biological Process; Breast Cancer Cell; Cadherins; Cell Nucleus; Cell membrane; Cell physiology; Cell-Cell Adhesion; Cells; Data; E-Cadherin; EGF gene; Endocytosis; Ensure; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Epithelium; Event; Focal Adhesions; Generations; Genes; Genetic Transcription; Growth; Growth Factor; Growth Factor Receptors; Human; In Vitro; Life; Lipids; Lymph; Lysosomes; Malignant Neoplasms; Maps; Mesenchymal; Modification; Morphogenesis; N-Cadherin; Neoplasm Metastasis; Nuclear Translocation; Organ; Pathway interactions; Patients; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Protein Isoforms; RNA Splicing; Receptor Signaling; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Specificity; Transcriptional Activation; Tumor Cell Biology; Variant; adhesion receptor; base; cell motility; epithelial to mesenchymal transition; in vivo Model; malignant breast neoplasm; migration; nexin; outcome forecast; protein protein interaction; public health relevance; receptor; second messenger; src-Family Kinases; trafficking; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): A hallmark of epithelial cancer progression is the epithelia to mesenchymal transition (EMT). In EMT the cell-cell adhesion receptor E-cadherin is lost from the plasma membrane and degraded in the lysosome and its expression is down regulated. This event results in the targeting of ?-catenin to the nucleus where it activates the transcription of genes that stimulate proliferation. The resulting mesenchymal cells are migratory and have the potential to migrate into the vasculature and lymph, initiating metastasis. We have discovered a phosphoinositide signaling pathway that regulates E-cadherin trafficking, degradation and assembly into adherens junctions in epithelial cells. The same pathway stimulates the activity of ?-catenin transcription. Phosphoinositide signaling pathways generate second messengers that target a plethora of effectors. We study the spatial and temporal generation of PI4,5P2 that controls most biological function. PI4,5P2 is synthesized by the phosphatidylinositol phosphate kinases (PIPK). Our evidence supports a key role for the PIPKI? in regulation of epithelial cell-cell contacts by an ordered set of interactions between PIPKI?, E- cadherin, ?-catenin, and trafficking components. Growth factor signaling and the tyrosine kinase Src regulate these interactions. Hypothesis and significance: PIPKI? controls the formation, stabilization and dissolution of cadherin based adherens junctions. In addition, PIPKI? associates with and stimulates ?-catenin's translocation to the nucleus and transcriptional activity. All of these events are regulated by the generation of PI4,5P2 and its regulation of effectors. These functions place PIPKI? at the center of EMT associated with cancer progression. These functions are regulated by a set of posttranslational events that drive either normal epithelial morphogenesis, or EMT, that results in increased migration and invasion. The following focused aims will assess this hypothesis (1) We will investigate the role of PIPKI? in the endocytosis of cadherins. The focus will be on the basal and growth factor stimulated E-cadherin endocytosis regulated by PIPKI?. The role of posttranslation modifications of E-cadherin and PIPKI? will be defined. (2) Delineate the role of PIPKI? isoforms in the lysosomal destruction of EGFR and E-cadherin. A newly discovered PIPKI? splice isoform sorts E-cadherin for degradation in the lysosome. The mechanism and factors involved will be defined with an emphasis on signaling pathways that control EMT. (3) PIPKI? regulation of ?-catenin transcriptional activity will be revealed. The activation of ?-catenin by PIPKI? will be integrated into pathways that are known to activate ?-catenin upon EMT. PUBLIC HEALTH RELEVANCE: Cancers of epithelial origin represent at least 80% of all human cancers and are often the most difficult to cure. The life threatening aspect of epithelial cancer is metastasis and this process is dependent upon the loss of epithelial cell organization a process that is controlled by the E-cadherin receptor. E-cadherin holds epithelial cells together and suppresses growth and metastasis. When E-cadherin is lost epithelial cancers are free to metastasize or migrate to different organs. We have discovered a signaling pathway that regulates both E-cadherin's ability to hold cells together and also the loss of E-cadherin from epithelial cancers.

描述(申请人提供)：上皮癌进展的一个标志是上皮向间充质转化(EMT)。在EMT中，细胞-细胞黏附受体E-钙粘附素从细胞膜上丢失，在溶酶体中降解，其表达下调。这一事件导致β-连环蛋白被定位到细胞核，在那里它激活了刺激增殖的基因的转录。由此产生的间充质细胞是可迁移的，并有可能迁移到血管和淋巴系统，启动转移。我们已经发现了一条磷脂酰肌醇信号通路，调节E-钙粘附素在上皮细胞中的运输、降解和组装成黏附连接。同样的途径也能刺激β-连环蛋白的转录活性。 磷脂酰肌醇信号通路产生针对过多效应器的第二信使。我们研究了控制大多数生物学功能的PI4，5P2的时空生成。PI4，5P2是由磷脂酰肌醇磷酸酶(PIPK)合成的。我们的证据支持PIPKI的关键作用？通过PIPKI？、E-钙粘蛋白、β-连环蛋白和运输成分之间的一系列有序的相互作用来调节上皮细胞-细胞接触。生长因子信号和酪氨酸激酶Src调节这些相互作用。 假设和意义：PIPKI？控制基于钙粘附素的粘附性连接的形成、稳定和溶解。此外，PIPKI？与连环蛋白转位到细胞核并刺激其转录活性有关。所有这些事件都受PI4，5P2的产生及其对效应器的调节。这些功能放置了PIPKI？处于与癌症进展相关的EMT的中心。这些功能受一系列翻译后事件的调控，这些事件驱动正常的上皮形态发生或EMT，从而导致更多的迁移和侵袭。以下重点目标将评估这一假设 (1)我们将调查PIPKI的角色？在钙粘蛋白的内吞作用中。重点将放在PIPKI？调节的基础和生长因子刺激的E-钙粘素内吞作用上。E-钙粘蛋白和PIPKI翻译后修饰的作用？将会被定义。 (2)界定PIPKI的角色？EGFR和E-钙粘蛋白在溶酶体破坏中的异构体新发现的PIPKI？剪接异构体对E-钙粘附素进行分类，以便在溶酶体中降解。所涉及的机制和因素将被定义，重点是控制EMT的信号通路。 (3)PIPKI？？-连环蛋白转录活性的调节将被揭示。PIPKI？激活β-连环蛋白？将被整合到已知激活的途径中？-连环蛋白在EMT上。 公共卫生相关性：上皮性癌症至少占所有人类癌症的80%，而且往往是最难治愈的。上皮癌威胁生命的方面是转移，这一过程依赖于上皮细胞组织的丧失，这一过程由E-钙粘素受体控制。E-钙粘附素将上皮细胞结合在一起，抑制生长和转移。当E-钙粘附素丢失时，上皮性癌症就可以自由转移或迁移到不同的器官。我们已经发现了一条信号通路，它既调节E-钙粘蛋白将细胞聚集在一起的能力，也调节上皮性癌症中E-钙粘蛋白的丢失。