In the fifteen years since the tumor suppressor phosphatase PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) was initially discovered in the search for the enzyme that dephosphorylates Akt at the hydrophobic motif (Ser473), a number of new substrates of PHLPP1 have been identified, suggesting a broad and varied role for this newly classified serine/threonine phosphatase. Not surprisingly, deregulation of PHLPP1 signaling has been implicated in a diverse set of disease states, ranging from cancer to diabetes to inflammation. However, there was still progress to be made to better understand how PHLPP1 itself is regulated. This thesis expands on the knowledge of how PHLPP1 localization, expression, protein interactions, and function are all dynamically regulated in the cell. First, mechanistic studies reveal that the previously unstudied PHLPP1 N-terminal extension, which accounts for the first roughly 30% of the protein sequence, is dynamically regulated by phosphorylation during mitosis and is required for a mitotic “switch” in the PHLPP1 interactome. Second, biochemical analysis of this N-terminal extension revealed that it houses a nuclear localization signal, allowing it to control PHLPP1 localization and function in the context of inflammatory signaling pathways. Finally, these studies exposed that PHLPP1 expression levels are dramatically reduced in the absence of extracellular glutamine, suggesting that PHLPP1 expression is sensitive to environmental nutrient levels. Taken together, these studies not only provide novel insight into how PHLPP1 functions in a normal physiological context but also how its regulation can go awry in various disease states.