%0 Journal Article
%T Nongenomic Mechanisms of PTEN Regulation
%A Jimmie E. Fata
%A Shawon Debnath
%A Edmund C. Jenkins Jr.
%A Marcia V. Fournier
%J International Journal of Cell Biology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/379685
%X A large amount of data supports the view that PTEN is a bona fide tumor suppressor gene. However, recent evidence suggests that derailment of cellular localization and expression levels of functional nonmutated PTEN is a determining force in inducing abnormal cellular and tissue outcomes. As the cellular mechanisms that regulate normal PTEN enzymatic activity resolve, it is evident that deregulation of these mechanisms can alter cellular processes and tissue architecture and ultimately lead to oncogenic transformation. Here we discuss PTEN ubiquitination, PTEN complex formation with components of the adherens junction, PTEN nuclear localization, and microRNA regulation of PTEN as essential regulatory mechanisms that determine PTEN function independent of gene mutations and epigenetic events. 1. PTEN: A Unique Dual-Specificity Phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome ten)/MMAC (mutated in multiple advanced cancers) has been identified simultaneously by two research groups as a candidate tumor suppressor gene located at 10q23 and encoding 403 amino acids [1, 2]. Another group identified the same gene in the search for new dual-specific phosphatases and named it TEP-1 (TGF-¦Â regulated and epithelial cell-enriched phosphatase) [3]. PTEN is one of the most common targets of mutation in human cancer, with a mutation frequency approaching that of the tumor suppressor gene p53, and it is also mutated in inherited cancer predisposition disorders. PTEN belongs to the protein tyrosine phosphatase family with phosphatase activity on both lipids and proteins. PTEN¡¯s lipid phosphatase catalyzes the conversion of phosphatidylinositol-(3,4,5)-triphosphate (PIP3) to phosphatidylinositol-4,5-bisphosphate (PIP2) [4, 5] and plays an important role in the PI3K pathway by catalyzing degradation of PIP3 generated by PI3K. This inhibits PI3K downstream targets, mainly PKB-Akt [6¨C10]. It should be noted, however, that lipid phosphatase attenuated or inactive PTEN mutants have been reported to still retain some tumor suppressing properties [11¨C15]. So far there is no report of redundancy for PTEN function, which could explain the high frequency with which PTEN inactivation is selected during tumor development [16]. By virtue of PTEN¡¯s ability to attenuate and control the extent of PI3K signaling, PTEN influences many cellular functions, including cell growth, survival, proliferation, and metabolism [8]. PTEN contributes to cell cycle regulation by blocking cells entering the S-phase of the cell cycle and by upregulation of p27kip1, which is
%U http://www.hindawi.com/journals/ijcb/2012/379685/