The lipid phosphatase activity of PTEN dampens FRA1 expression via AKT/mTOR signaling to suppress melanoma

PTEN, a phosphatase frequently inactivated in melanoma, opposes PI3K/AKT/mTOR pathway activation. However, AKT- and mTOR-targeted therapies have so far yielded insufficient results in preclinical models and clinical trials of melanoma. We therefore examined whether PTEN suppresses melanoma through lipid phosphatase-independent functions or by opposing lipid phosphatase-dependent, AKT-independent pathways. Restoring different PTEN functions in PTEN-deficient cells or mouse models revealed that PTEN lipid phosphatase activity predominantly suppresses melanoma with minimal contribution from its protein phosphatase and scaffold functions. A drug screen highlighted the dependence of PTEN-deficient melanoma cells on the AKT/mTOR pathway. Moreover, activation of AKT was sufficient to overcome several aspects of PTEN-mediated melanoma suppression. Phosphoproteomics analysis of the PTEN lipid phosphatase activity identified the AP-1 transcription factor FRA1 as a downstream effector. PTEN regulates FRA1 translation via AKT/mTOR and FRA1 overexpression overcomes PTEN-mediated melanoma suppression. Our study affirms AKT as the key mediator of PTEN inactivation in melanoma and identifies an AKT/mTOR/FRA1 axis as a driver of melanomagenesis. ### Competing Interest Statement The authors have declared no competing interest.