PTEN, a tumor suppressor gene, is involved in regulating cell survival and proliferation. In this study, the authors investigate the role of PTEN in negative regulation of the PI3K/Akt signaling pathway. They found that *mPTEN*-deficient mouse embryos exhibit increased proliferation, while immortalized mouse embryonic fibroblasts from *mPTEN*-deficient cells show decreased sensitivity to apoptosis. Expression of exogenous PTEN in *mPTEN*-deficient cells restores their sensitivity to apoptosis and normal PKB/Akt phosphorylation. PTEN negatively regulates intracellular levels of phosphatidylinositol (3,4,5) triphosphate (PIP3) and dephosphorylates it in vitro. The results suggest that PTEN exerts its tumor suppressor function by negatively regulating the PI3K/Akt signaling pathway, which is crucial for cell survival and proliferation.PTEN, a tumor suppressor gene, is involved in regulating cell survival and proliferation. In this study, the authors investigate the role of PTEN in negative regulation of the PI3K/Akt signaling pathway. They found that *mPTEN*-deficient mouse embryos exhibit increased proliferation, while immortalized mouse embryonic fibroblasts from *mPTEN*-deficient cells show decreased sensitivity to apoptosis. Expression of exogenous PTEN in *mPTEN*-deficient cells restores their sensitivity to apoptosis and normal PKB/Akt phosphorylation. PTEN negatively regulates intracellular levels of phosphatidylinositol (3,4,5) triphosphate (PIP3) and dephosphorylates it in vitro. The results suggest that PTEN exerts its tumor suppressor function by negatively regulating the PI3K/Akt signaling pathway, which is crucial for cell survival and proliferation.