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.
| Thapa, N; Tan, X; Choi, S et al. (2017) PIPKI? and talin couple phosphoinositide and adhesion signaling to control the epithelial to mesenchymal transition. Oncogene 36:899-911 |
| Thapa, Narendra; Tan, Xiaojun; Choi, Suyong et al. (2016) The Hidden Conundrum of Phosphoinositide Signaling in Cancer. Trends Cancer 2:378-390 |
| Choi, Suyong; Anderson, Richard A (2016) IQGAP1 is a phosphoinositide effector and kinase scaffold. Adv Biol Regul 60:29-35 |
| Choi, Suyong; Hedman, Andrew C; Sayedyahossein, Samar et al. (2016) Agonist-stimulated phosphatidylinositol-3,4,5-trisphosphate generation by scaffolded phosphoinositide kinases. Nat Cell Biol 18:1324-1335 |
| Tan, Xiaojun; Thapa, Narendra; Liao, Yihan et al. (2016) PtdIns(4,5)P2 signaling regulates ATG14 and autophagy. Proc Natl Acad Sci U S A 113:10896-901 |
| Tan, Xiaojun; Lambert, Paul F; Rapraeger, Alan C et al. (2016) Stress-Induced EGFR Trafficking: Mechanisms, Functions, and Therapeutic Implications. Trends Cell Biol 26:352-366 |
| Tan, Xiaojun; Thapa, Narendra; Choi, Suyong et al. (2015) Emerging roles of PtdIns(4,5)P2--beyond the plasma membrane. J Cell Sci 128:4047-56 |
| Thapa, Narendra; Choi, Suyong; Tan, Xiaojun et al. (2015) Phosphatidylinositol Phosphate 5-Kinase I? and Phosphoinositide 3-Kinase/Akt Signaling Couple to Promote Oncogenic Growth. J Biol Chem 290:18843-54 |
| Choi, Suyong; Thapa, Narendra; Tan, Xiaojun et al. (2015) PIP kinases define PI4,5P?signaling specificity by association with effectors. Biochim Biophys Acta 1851:711-23 |
| Tan, Xiaojun; Thapa, Narendra; Sun, Yue et al. (2015) A kinase-independent role for EGF receptor in autophagy initiation. Cell 160:145-60 |
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