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Dynamic events of protein and lipid phosphorylation and dephosphorylation are involved virtually in all cellular signaling networks and transduction pathways. Kinases are the enzymes that catalyze phosphorylation reactions, while phosphatases are responsible for phosphate hydrolysis from the substrates. Defective or inappropriate activity of phosphatases contributes to the development of many human diseases, including cancer. PRL-3 is a plasma membrane-associated dual specificity phosphatase that exhibits a highly restricted and tightly regulated expression pattern. Additionally, PRL-3 is an emerging prognostic marker for cancer progression and a promising therapeutic target. Although in the last decade numerous clinical studies have extensively validated the causative role of PRL-3 in cancer metastasis, to date its substrate(s) and the direct downstream transduction pathways affected by PRL-3 overexpression are still elusive.The first part of this work concerns the in vitro characterization of PRL-3 phosphatase activity towards phosphopeptides and phosphoinositides. We show that PRL-3 does not present any activity against the library of phosphopeptides tested, while it robustly dephosphorylates the phosphoinositide PtdIns(4,5)P2. Moreover, our experimental results and molecular docking studies suggest that PRL-3 is a phosphatidylinositol 5-phosphatase. Finally, structure-activity relationship studies correlate the PRL-3 phosphatase activity toward PI(4,5)P2 with its ability to promote cell migration.The second part of this work concerns the characterization of PRL-3 oncogenic activity with respect to epithelial cell polarity. Using an organotypic 3D-culture system, in which epithelial cells form highly organized spherical cysts, we show that overexpression of PRL-3 significantly affects epithelial morphogenesis leading to the development of cysts with ectopic lumens. Moreover, we prove that a remnant organelle from the cytokinesis process, the post-mitotic midbody, is the first polarization signal during cyst development. Finally, we show that PRL-3 over- expression generates major defects in epithelial cell polarization by interfering with the fate of post-mitotic midbodies.In conclusion, we show that PRL-3 could be a new phosphoinositide phosphatase and that its overexpression affects epithelial cell polarization by altering post-mitotic midbody fate, suggesting a novel mechanism for epithelial tumorigenesis.