PI Signaling Role in Epithelial/Mesenchymal Transition

PI 信号在上皮/间质转化中的作用

• 批准号: 6822309
• 负责人: Richard A. Anderson
• 金额: $ 29.83万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6822309
• 关键词: RNA interference; binding sites; biological signal transduction; cadherins; cell cell interaction; cell line; clathrin; embryo /fetus cell /tissue; endocytosis; epithelium; extracellular matrix; glycoproteins; histogenesis; immunofluorescence technique; intermolecular interaction; mesenchyme; neoplasm /cancer; nucleic acid sequence; phosphatidylinositols; phosphorylation; protein protein interaction; protein structure

DESCRIPTION (provided by applicant): Adhesion of cells to the extracellular matrix, formation of E-cadherin cell-cell contacts, and endocytosis-mediated regulation of plasma membrane receptors are all required for proper cell function. Dysregulation of these processes is associated with epithelial/mesenchymal transition (EMT), a key event in cancer initiation and progression. Phosphatidylinositol 4,5 bisphosphate (PI4,5P2) is a key regulator of these processes. Production of PI4,5P2 at discrete subcellular sites is mediated by the unique targeting of phosphatidylinositol phosphate kinases. Type Igamma PIP Kinase (PIPKIgamma) is positioned to mediate focal adhesion assembly, endocytosis, and maintenance of cell-cell contacts by virtue of its specific targeting to these subcellular locations and its interaction with key components and regulation by key signaling pathways. We propose to elucidate the role of PIPKI( in these processes, thus providing insight into EMT and cancer initiation and metastasis. The proposed work will critically assess this hypothesis with the following Specific Aims: (1) Determine the mechanism for PIPKIgamma targeting to cell-cell contacts via its interaction with E-cadherin and how this targeting influences EMT; (2) Investigate the role of PIPKI( in endocytosis via its interaction with the mu-subunits of the adaptor protein (AP) complexes and how this function relates to maintenance of cell-cell contacts; (3) Investigate signals that lead to Src phosphorylation of PIPKIgamma as a mechanism for regulation of E-cadherin and AP2 functions. Collective understanding of PIPKIgamma's role in each of these processes will provide insight into the mechanism of EMT and subsequent cancer metastasis. A role for PIPKIgamma in the assembly of E-cadherin cell-cell junctions, the internalization of cadherins, and signaling mechanisms that modulate EMT have many implications for cancer. Cancers of epithelial cell origin represent approximarely 80% of all cancers, and of these the loss of surface expression of E-cadherin is a prognosticator of poor patient outcome. An understanding of the underlying mechanism of E-cadherin internalization has the potential to impact our understanding of cancers of epithelial origin.

描述（由申请人提供）：细胞对细胞外基质的粘附，E-钙粘蛋白细胞 - 细胞接触的形成以及内吞作用介导的质膜受体的调节都是正确的细胞功能。 这些过程的失调与上皮/间质转变（EMT）有关，这是癌症起步和进展的关键事件。 磷脂酰肌醇4,5双磷酸（PI4,5P2）是这些过程的关键调节剂。 在离散亚细胞位点生产Pi4,5p2是由磷脂酰肌醇磷酸激酶的独特靶向介导的。 Igamma型激酶（PIPKIGAMMA）定位可介导局灶性粘附组件，内吞作用，并通过其特异性靶向这些亚细胞位置的特定靶向细胞 - 细胞接触，并通过关键信号通路与关键成分和调节。 我们建议阐明Pipki的作用（在这些过程中，从而提供了对EMT，癌症的起始和转移的见解。拟议的工作将以以下具体目的对这一假设进行批判性评估：（1）确定PIPKIGAMMA靶向与细胞细胞接触的机制，通过与细胞 - 核电蛋白的相互作用进行靶标（通过如何通过靶标有影响）（2）（2）（2）（2）（2）（2）（2）（2）（2）；与适配器蛋白（AP）复合物的MU-支出相互作用，以及该功能如何与细胞 - 细胞接触的维持有关；（3）调查导致PIPKIGAMMA的SRC磷酸化的信号，以此作为调节E-Cadherin和Ap2功能的调节的机制。 PIPKIGAMMA在E-Cadherin细胞 - 细胞连接的组装中的作用，钙粘着蛋白的内在化和调节EMT的信号传导机制对上皮细胞起源的癌症具有许多影响。内部化有可能影响我们对上皮癌症的理解。