PI Signaling Role in Ephitelial/Mesenchymal Transition

描述（由申请人提供）：细胞粘附至细胞外基质、形成E-钙粘蛋白细胞-细胞接触以及胞吞介导的质膜受体调节均为正常细胞功能所需。 这些过程的失调与上皮/间充质转化（EMT）相关，EMT是癌症发生和发展的关键事件。 磷脂酰肌醇4，5二磷酸（PI 4，5 P2）是这些过程的关键调节剂。 在离散的亚细胞位点产生PI 4，5 P2是由磷脂酰肌醇磷酸激酶的独特靶向介导的。 I型γ PIP激酶（PIPKIgamma）定位为介导粘着斑组装、内吞作用和细胞-细胞接触的维持，这是由于其特异性靶向这些亚细胞位置以及其与关键组分的相互作用和通过关键信号传导途径的调节。 我们建议阐明PIPKI在这些过程中的作用，从而为EMT和癌症的发生和转移提供见解。 本论文的主要目的是：（1）确定PIPKI γ通过与E-cadherin相互作用靶向细胞间接触的机制，以及这种靶向作用如何影响EMT;（2）研究PIPKI γ在EMT中的作用（通过其与衔接蛋白（AP）复合物的μ-亚基的相互作用的内吞作用，以及该功能如何与细胞-细胞接触的维持相关;（3）研究导致PIPKI γ Src磷酸化的信号，作为调节E-钙粘蛋白和AP 2功能的机制。 对PIPKIgamma在这些过程中的作用的集体理解将提供对EMT和随后的癌症转移机制的深入了解。 PIPKIgamma在E-钙粘蛋白细胞-细胞连接组装、钙粘蛋白内化和调节EMT的信号传导机制中的作用对癌症具有许多意义。 上皮细胞来源的癌症占所有癌症的约80%，其中E-钙粘蛋白表面表达的丧失是患者预后不良的决定因素。 对E-钙粘蛋白内在化的潜在机制的理解有可能影响我们对上皮起源的癌症的理解。

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.