Threonine 348 regulates the subcellular localization of PTEN.

The tumor suppressor PTEN (phosphatase and tensin homolog) dephosphorylates PIP3 (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 PTEN350 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 PTEN348 (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 PTEN348 and PTEN350 fragments. Moreover, we found that PTENA4 and PTENK13R,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.