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.
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