Threonine 348 regulates the subcellular localization of PTEN

The tumor suppressor PTEN (phosphatase and tensin homolog) dephosphorylates PIP ₃ (phosphatidylinositol (3,4,5)‐trisphosphate) at the plasma membrane and protects genomic integrity in the nucleus; thus, regulation of PTEN subcellular localization is crucial. Previous studies have shown that the PTEN ₃₅₀ fragment is markedly enriched in the nucleus, a feature not explained by the N‐terminal nuclear localization signal. In this study, we generated PTEN fragments of various lengths and identified PTEN ₃₄₈ (residues 1–348), which showed prominent nuclear localization. Furthermore, the replacement of threonine 348 (Thr348) with other amino acids reduced the nuclear localization of the PTEN ₃₄₈ and PTEN ₃₅₀ fragments. Moreover, we found that PTEN _A4 and PTEN _K13R,A4 localized predominantly to the nucleus and plasma membrane, respectively, and that substitution of Thr348 with aspartic acid resulted in cytoplasmic localization in both mutants. Collectively, these results indicate that Thr348 is a key contributor to the regulation of PTEN subcellular localization.