BPS2026 - Characterization of the human voltage sensing phosphatase specificity and regulation of the AKT/mTOR pathway

Metastatic melanoma is a highly aggressive form of skin cancer, and 30% of tumors show increased metastasis due to a loss of PTEN function. PTEN is a well-established tumor suppressor; however, a homolog of PTEN, the voltage sensing phosphatase (VSP), is not well understood. VSPs use a transmembrane voltage sensing domain (VSD) that changes conformation in response to membrane depolarization, activating a cytosolic phosphatase. Much like PTEN, VSPs dephosphorylate phosphatidylinositol phosphates (PIPs) but in a voltage dependent manner, indicating that VSPs directly modulate the AKT/mTOR pathway. The two human isoforms of VSP, Hs-VSP1, and Hs-VSP2, have not been thoroughly studied in part because they do not express well on the plasma membrane in heterologous systems. My preliminary data show that I have overcome this limitation, opening the study of Hs-VSPs in cancers like melanomas. Specifically, I hypothesize that Hs-VSPs uniquely impact melanoma progression as a result of the electrical signaling of the cell. Beyond just the homology to PTEN, Hs-VSPs are found in many cancer databases, identified as a potential driver of melanomas and other cancers. Other studies show that overexpression of Hs-VSP1 (gene TPTE2), the active isoform, rescues the cancer-like phenotype of PTEN knockout cells while the gene for HsVSP2 (TPTE), the inactive isoform, was identified in multiple cancers as a potential biomarker and immunogenic tumor associated antigen (TAA). Taken together, these studies suggest that the two Hs-VSP isoforms have distinct functional roles, and that Hs-VSP1 is able to regulate the AKT/mTOR pathway similar to PTEN. Results from this proposal will lead to the first full characterization of Hs-VSPs and is an essential first step to understanding how Hs-VSPs impact the AKT/mTOR signaling pathway, potentially identifying novel therapeutic targets for cancer treatment.