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From Mammalian Cell Genetics, Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec H4P 2R2, Canada and ¶Department of Medicine, McGill University, Montreal, Quebec H3G 1A4, Canada
PTEN is a tumor suppressor that primarily dephosphorylates phosphatidylinositol 3,4,5-trisphosphate to down-regulate the phosphoinositide 3-kinase/Akt signaling pathway. Although the cellular functions of PTEN as a tumor suppressor have been well characterized, the mechanism by which PTEN activity is modulated by other signal molecules in vivo remains poorly understood. In searching for potential PTEN modulators through protein-protein interaction, we identified the major vault protein (MVP) as a dominant PTEN-binding protein in a yeast two-hybrid screen. MVP is the major structural component of vault, the largest intracellular ribonucleoprotein particle. Co-immunoprecipitation confirmed the interaction between PTEN and MVP in transfected mammalian cells. More importantly, we found that a significant portion of endogenous PTEN associates with vault particles in human HeLa cells. Deletion mutation analysis demonstrated that MVP binds to the C2 domain of PTEN and that PTEN interacts with MVP through its EF hand-like motif. Furthermore, the in vitro binding experiments revealed that the interaction of PTEN with MVP is Ca2+-dependent.
Received for publication July 29, 2002.
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Nuclear Localization of PTEN Is Regulated by Ca2+ through a Tyrosil Phosphorylation-Independent Conformational Modification in Major Vault Protein.