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The PTEN tumour suppressor is a phosphatase that dephosphorylates phosphatidylinositol 3, 4, 5 triphosphate (PIP3) and protein substrates. PTEN function is modulated by its carboxy-terminal region, which contains several clustered phosphorylation sites and a PDZ-binding motif (PDZbm). Although PTEN growth suppression effect is well demonstrated, its additional biological roles are less well understood. DAF-18, a Caenorhabditis elegans homologue PTEN, is a component of the insulin/IGF-I signalling pathway that controls entry to the dauer larval stage and adult longevity. To further explore the role of PTEN in the insulin signalling cascade and its possible involvement in the mechanisms of ageing, we undertook a study of PTEN function in C. elegans. We now report that human PTEN can substitute for DAF-18 and restores the dauer and longevity phenotypes in worms devoid of DAF-18. Furthermore, we provide genetic and biochemical evidence that dauer and lifespan control depends on PTEN-mediated regulation of PIP3 levels. Finally, we established that phosphorylation sites in the C-terminus of PTEN and its PDZbm are necessary for PTEN control of the insulin/IGF-I pathway. These results demonstrate that PTEN negatively regulates the insulin/IGF pathway in a whole organism and raise the hypothesis that PTEN may be involved in mammalian ageing.Oncogene (2005) 24, 20-27. doi:10.1038/sj.onc.1207978 [ABSTRACT FROM AUTHOR]

The human PTEN/MMAC1/TEP1 (PTEN) tumor suppressor gene encodes a phosphatase with specificity towards the D3 phosphate of phosphatidylinositides. PTEN mutations have been reported in the endometrioid type of uterine tumors which are associated with frequent activations of the Ras oncogenes. In this study, we report the ability of PTEN to potently inhibit H-Ras induced morphological transformation and anchorage-independent growth in NIH3T3 cells. This novel activity of PTEN was correlated more with its ability to suppress the phosphatidylinositol 3-kinase (PI3-K)-dependent signaling cascade, but not the mitogen-activated protein kinase (MAPK) pathway. To define the minimal region in PTEN protein that is responsible for this anti-oncogenic activity, a panel of carboxyl-terminal truncation mutants was generated. While deletions of 4 and 33 amino acids do not have marked effects, removal of up to 68 amino acids drastically reduced the ability of PTEN to inhibit Ras transformation. The propensity of these mutants to suppress Ras transformation is correlated with their relative ability to dephosphorylate inositol (1,3,4,5)-tetrakisphosphate in vitro, and to suppress Akt kinase activity in cultured cells. In addition, we have evidence to suggest that the C-terminal region of PTEN contributes to the stability of the encoded gene product. Oncogene (2000) 19, 680–689. [ABSTRACT FROM AUTHOR]

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene frequently found to be inactivated in over 30% of human cancers. PTEN encodes a 54-kDa lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3-kinase pathway involved in the promotion of multiple pro-tumorigenic phenotypes. Although the PTEN protein plays a pivotal role in carcinogenesis, cumulative evidence has implicated it as a key signaling molecule in several other diseases as well, such as diabetes, Alzheimer's disease, and autism spectrum disorders. This finding suggests that diverse cell types, especially differentiated cells, express PTEN. At the cellular level, PTEN is widely distributed in all subcellular compartments and organelles. Surprisingly, the cytoplasmic compartment, not the plasma membrane, is the predominant subcellular location of PTEN. More recently, the finding of a secreted 'long' isoform of PTEN and the presence of PTEN in the cell nucleus further revealed unexpected biological functions of this multifaceted molecule. At the regulatory level, PTEN activity, stability, and subcellular distribution are modulated by a fascinating array of post-translational modification events, including phosphorylation, ubiquitination, and sumoylation. Dysregulation of these regulatory mechanisms has been observed in various human diseases. In this review, we provide an up-to-date overview of the knowledge gained in the last decade on how different functional domains of PTEN regulate its biological functions, with special emphasis on its subcellular distribution. This review also highlights the findings of published studies that have reported how mutational alterations in specific PTEN domains can lead to pathogenesis in humans. [ABSTRACT FROM AUTHOR]

The regulation of PTEN intrinsic biochemical properties has not been fully elucidated. In this report, we investigated the role of the PTEN carboxyl-terminal tail domain in regulating its membrane targeting and catalytic functions. Characterization of a panel of PTEN phosphorylation site mutants revealed that mutating Ser-385 to alanine (S385A) promoted membrane localization in vivo and phosphatase activity in vitro. Furthermore, S385A mutation was associated with a substantial reduction in the phosphorylation of the Ser-380/Thr-382/Thr-383 cluster. Therefore, Ser-385 could prime additional dephosphorylation events to regulate PTEN catalytic activity. Moreover, substituting Ser-380/Thr-382/Thr-383 to phosphomimic residues reversed the phosphatase activity of the S385A mutation. Next, we further defined the underlying mechanisms responsible for the COOH-terminal tail region in modulating PTEN biological activity. We have identified an interaction between the 71-amino acid carboxyl-terminal tail region and the CBRIII motif of the C2 domain, which has been implicated in membrane binding. In addition, a synthetic phosphomimic peptide encompassing the phosphorylation site cluster between amino acids 368 and 390 within the tail region mediated the suppression of PTEN catalytic activity in vitro. This same peptide when expressed in cultured cells also impeded PTEN membrane localization and enhanced phospho-Akt levels. Thus, our data suggest that the COOH-terminal tail can act as an autoinhibitory domain to control both PTEN membrane recruitment and phosphatase activity. [ABSTRACT FROM AUTHOR]