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黏附，E-钙粘素细胞-细胞接触的形成，以及细胞内吞作用介导的质膜受体的调节都是细胞正常功能所必需的。这些过程的失调与上皮/间充质转化(EMT)有关，EMT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在离散的亚细胞位置的产生是由磷脂酰肌醇磷酸激酶的独特靶向介导的。IGamma型PIP Kinase(PIPKIGamma)定位于介导焦点黏附组装、内吞作用和维持细胞-细胞接触，因为它针对这些亚细胞位置，并与关键成分相互作用，并受关键信号通路的调节。我们建议阐明PIPKI(PIPKI)在这些过程中的作用，从而为深入了解EMT和癌症的启动和转移提供依据。拟议的工作将严格评估这一假说，具体目标如下：(1)确定PIPKIGamma通过与E-钙粘蛋白相互作用靶向细胞间接触的机制，以及这种靶向如何影响EMT；(2)研究PIPKI(通过其与适配器蛋白(AP)复合体的Mu亚基相互作用在细胞吞噬中的作用以及这一功能与维持细胞-细胞接触的关系；(3)研究导致PIPKIGamma Src磷酸化的信号，作为调节E-钙粘素和AP2功能的机制。集体了解PIPKIGamma在每个过程中的作用将有助于深入了解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、钙粘附素的内化以及调节EMT的信号机制中的作用对癌症有许多意义。上皮细胞起源的癌症约占所有癌症的80%，其中E-钙粘附素表面表达的缺失是患者预后不良的预后指标。对E-钙粘附素内化的潜在机制的理解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.