Phosphatase-independent functions of the tumor suppressor PTEN

PTEN (Phosphatase and tensin homolog deleted on Chromosome 10) is a major tumor suppressor with both phosphatase-dependent and -independent functions. As it dephosphorylates the second messenger phosphatidylinositol-3,4,5- triphosphate (PtdIns3 P or PI3P), PTEN regulates the activation of the proto-oncogenic PI3K-AKT signaling pathway and thereby inhibits cell proliferation and cell growth. In addition, through protein phosphatase activity, PTEN can regulate the phosphorylation of protein substrates in order to inhibit cell migration and invasion. Recently several studies have highlighted the importance of PTEN localization in cell nuclei, where it can function as a tumor suppressor in a phosphatase-independent manner. For instance, nuclear PTEN function has been associated with a PTEN scaffolding role favoring the activation of the DNA-repair machinery and ensuring chromosome stability. Further, it has been discovered that through phosphatase-independent functions PTEN also regulates cell cycle progression and key tumor-suppressive metabolic states in the nucleus. In this chapter we focus our attention on the scaffolding role of PTEN. We summarize the mechanisms involved in the regulation of nuclear and cytoplasmic PTEN shuttling, and discuss the potential clinical relevance of reported nuclear PTEN targets. Importantly, we also discuss the implications of nuclear PTEN functions to tumorigenesis, and outline their potential as targets in the development of new therapeutic approaches to cancer.