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Nuclear Localization of PTEN Is Regulated by Ca²⁺ through a Tyrosil Phosphorylation–Independent Conformational Modification in Major Vault Protein

¹ Genomic Medicine Institute, ² Lerner Research Institute, and ³ Taussig Cancer Center, Cleveland Clinic Foundation; and ⁴ Department of Genetics and ⁵ CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

Requests for reprints: Charis Eng, Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Mailstop NE-50, Cleveland, OH 44195. Phone: 216-444-3440; Fax: 216-636-0655; E-mail: engc{at}ccf.org.

We have recently shown in MCF-7 cells that nuclear phosphatase and tensin homologue deleted on chromosome 10 (PTEN) down-regulates phosphorylation of p44/42 and cyclin D1 and induces G₁ cell cycle arrest, whereas cytoplasmic PTEN down-regulates phosphorylation of Akt, up-regulates p27, and induces apoptosis. In this manner, nucleocytoplasmic partitioning of PTEN seems to differentially regulate the cell cycle and apoptosis. We have also reported that PTEN has nuclear localization signal–like sequences required for major vault protein (MVP)–mediated nuclear translocation. To date, several other proteins are reported to interact with MVP, including extracellular signal-regulated kinases and steroid receptors, suggesting that MVP is likely to be involved in signal transduction through nucleocytoplasmic transport. However, the exact mechanism of MVP-mediated nucleocytoplasmic shuttling remains elusive. PTEN reportedly interacts in vitro with the EF hand–like motif of MVP in a Ca²⁺-dependent manner. The current study shows that small interfering RNA–mediated MVP silencing decreases the nuclear localization of PTEN and increases phosphorylation of nuclear p44/42. We show in situ that PTEN-MVP interaction is Ca²⁺ dependent and is abolished by Mg²⁺. Nuclear localization of PTEN is decreased by increasing Ca²⁺ levels in culture medium in a dose-dependent manner. Ca²⁺ ionophore A23187 increases nuclear localization of PTEN and decreases phosphorylation of nuclear p44/42. Finally, we show that Ca²⁺-dependent PTEN-MVP interaction is not related to MVP's tyrosil phosphorylation but rather due to its conformational modification. Our observations suggest that Ca²⁺ regulates PTEN's nuclear entry through a tyrosil phosphorylation–independent conformational change in MVP. Collectively, our data present evidence of a novel crosstalk between the Ca²⁺ signaling–mediated regulation of the cell cycle and MVP-mediated nuclear PTEN localization and function. (Cancer Res 2006; 66(24): 11677-82)

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