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[Cancer Research 65, 4108-4116, May 15, 2005]
© 2005 American Association for Cancer Research

Molecular Biology, Pathobiology, and Genetics

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

Ji-Hyun Chung1,2, Margaret E. Ginn-Pease1,2 and Charis Eng1,2,3,4

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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