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Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Has Nuclear Localization Signal–Like Sequences for Nuclear Import Mediated by Major Vault Protein

¹ Clinical Cancer Genetics Program, Human Cancer Genetics Program, Comprehensive Cancer Center, ² Department of Molecular Virology, Immunology and Medical Genetics, and ³ Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio and ⁴ Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, United Kingdom

Requests for reprints: Charis Eng, Human Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, 420 West 12th Avenue, Suite 690 TMRF, Columbus, OH 43210. Phone: 614-292-2347; Fax: 614-688-3582; E-mail: eng-1{at}medctr.osu.edu.

Although phosphatase and tensin homologue deleted on chromosome 10 (PTEN) localization in the nucleus and cytoplasm is established, the mechanism is unknown. PTEN is a tumor suppressor phosphatase that causes cell cycle arrest and/or apoptosis. Nuclear-cytoplasmic compartmentalization may be a novel mechanism in regulating these events. PTEN does not contain a traditional nuclear localization sequence (NLS); however, we identified putative NLS-like sequences, which we analyzed by site-directed mutagenesis and localization studies in MCF-7 cells. Two double site mutations exhibited nuclear localization defects. Furthermore, unlike wild-type PTEN, double NLS mutant PTEN did not interact with major vault protein (MVP), a previously hypothesized nuclear-cytoplasmic transport protein. We conclude that these two NLS-like sequences are required for PTEN nuclear import that is mediated by MVP. Further, we show that this MVP-mediated nuclear import is independent of PTEN phosphorylation and of the lipid and protein phosphatase activities of PTEN.

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