Phosphatidylinositol (PI) Signaling Role in Ephitelial / Mesenchymal Transition

描述（由申请人提供）：细胞与细胞外基质的粘附，e -钙粘蛋白细胞-细胞接触的形成，以及胞吞介导的质膜受体调节都是正常细胞功能所必需的。这些过程的失调与上皮/间充质转化（EMT）有关，这是癌症发生和发展的关键事件。磷脂酰肌醇4,5二磷酸（pi4,5p2）是这些过程的关键调节因子。pi4,5p2在离散亚细胞位点的产生是由磷脂酰肌醇磷酸激酶的独特靶向介导的。PIPKIgamma型PIP激酶（PIPKIgamma）通过其特异性靶向这些亚细胞位置以及与关键成分的相互作用和关键信号通路的调节，定位于介导局灶粘附组装，内吞作用和细胞-细胞接触的维持。我们建议阐明PIPKI在这些过程中的作用，从而深入了解EMT和癌症的发生和转移。提出的工作将以以下具体目标批判性地评估这一假设：(1)确定PIPKIgamma通过其与E-cadherin的相互作用靶向细胞-细胞接触的机制，以及这种靶向如何影响EMT；(2)研究PIPKI通过与接头蛋白（AP）复合体的mu亚基相互作用在内吞作用中的作用，以及这种功能如何与维持细胞-细胞接触相关；(3)研究导致Src磷酸化PIPKIgamma的信号作为调节E-cadherin和AP2功能的机制。对PIPKIgamma在这些过程中的作用的集体理解将有助于深入了解EMT和随后的癌症转移的机制。PIPKIgamma在e -钙粘蛋白细胞-细胞连接的组装、钙粘蛋白的内化以及调节EMT的信号机制中的作用对癌症有许多影响。上皮细胞起源的癌症约占所有癌症的80%，其中e -钙粘蛋白表面表达的缺失是患者预后不良的一个预后指标。了解e -钙粘蛋白内化的潜在机制有可能影响我们对上皮源性癌症的理解。

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.