Mechanisms of Regulating Planar Cell Polarity by Deubiquitinating Enzyme USP7 in Cancer Cells
DescriptionPlanar cell polarity (PCP) controls the asymmetric organization of cellular structures and activities across the epithelial plane and is of critical importance to tissue development and health. Comparing to the advances in our knowledge about the PCP organization in epithelial tissues, our understanding of the function and regulation of PCP in cancer remains rudimentary. Growing evidence indicates that PCP signaling plays an essential role in cell migration and invasion, which are fundamental to cancer progression and metastasis. For example, our previous work discovered that the interplay between PCP components Pk1 and Smurf2 E3 ubiquitin ligase regulates migration and metastasis of breast cancer cells by controlling cytoskeleton networks and morphological dynamics. However, many questions remain outstanding with regards to the molecular mechanisms that regulate PCP signaling in cancer.The ubiquitin-proteasome system (UPS) represents a principal pathway that controls protein levels and activities in all eukaryotic cells. A number of PCP proteins, such as Dvl and Pk, are subjected to UPS-mediated ubiquitination and degradation. Interestingly, our preliminary studies revealed that Pk1 interacts with USP7, a deubiquitinating enzyme (DUB) in UPS. Functionally, silencing of USP7 leads to low level of Pk1 and inhibition of cell migration. Furthermore, USP7 antagonizes Smurf2-mediated ubiquitination and degradation of Pk1, suggesting a role of USP7 in PCP signaling through modulating Pk1.The central hypothesis of this proposal is that USP7-mediated regulation of PCP is critical for cell migration and cancer progression.We aim to delineate the molecular mechanisms of how USP7 regulates Pk1 and integrates with PCP signaling in cancer cells. To achieve this, we will employ multidisciplinary approaches that integrate biochemistry and molecular biology with microscopy imaging to address three specific aims. We will first define the molecular basis of USP7-Pk1 interaction and its implication in cancer cell migration. In addition, we will investigate the integration of USP7-Pk1 with other PCP proteins including Vangl, Fzd and Dvl. Finally, we will investigate the functional significance of USP7-Pk1 in three-dimensional models of breast cancer. Our studies will define novel molecular and functional mechanisms of the integration between UPS and PCP pathways and will provide novel mechanistic insights into the role of PCP signaling in cancer. Moreover, outcomes for these studies will form the key underpinnings for development of novel therapeutics that target PCP-regulated cell migration and cancer metastasis.?
|Effective start/end date||1/01/18 → …|