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First published online November 21, 2007
doi: 10.1242/10.1242/jcs.015230

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New insights into PTEN

UCSF Cancer Research Institute, 2340 Sutter Street, San Francisco, CA 94115, USA

View larger version (71K): [in this window] [in a new window]   Fig. 1. Transcriptional regulation of PTEN. Illustrated are the pathways recently found to be involved in the regulation of PTEN transcription. Components of activating pathways are displayed as ovals and those of suppressing pathways as rectangles (note that some function as both activators and repressors). JUN was found to suppress PTEN transcription by binding to a variant activator 1 (AP-1) site, called PF1, roughly 19 kb upstream of the transcriptional start site (Hettinger et al., 2007). Activation of PPAR by its selective ligands of the glitazone (Glit) group, used in the treatment of diabetes, upregulates PTEN expression by binding to two PPAR response elements (PPREs) (Patel et al., 2001). Upregulation of PTEN by glitazones has been observed by several other groups (Han and Roman, 2006; Lee et al., 2005; Zhang, W. et al., 2006). Phytoestrogens, such as genistein from soybeans, indole-3-carbinole from cruciferous vegetables like broccoli, and resveratrol found in red wine, lead to an increase in PTEN mRNA (Waite et al., 2005) and protein (Dave et al., 2005; Waite et al., 2005). In pancreatic cancer cells, TGF positively regulates PTEN transcription in a SMAD-dependent manner and negatively controls it in a SMAD-independent way (Chow et al., 2007). Furthermore, in a mesangial cell model for diabetic nephropathy, in which high glucose levels lead to a decrease in PTEN (protein) expression, this decrease was found to be mediated by suppressive effects of TGF (Mahimainathan et al., 2006). By contrast, binding of growth factor (GF) to its receptors in the cell membrane activates, via RAS, human SPRY2 (hSPRY2) to upregulate PTEN transcription (Edwin et al., 2006). Resistin, a peptide secreted by adipocytes and other cell types during inflammation, also positively regulates PTEN transcription. Resistin leads to activation of the p38 pathway and of ATF2, as well as to the binding of ATF2 to the PTEN promoter (shown in orange) to two ATF binding sites (Shen et al., 2006). Moreover, MKK4 inhibits PTEN transcription by activating NFB, a transcriptional repressor that binds to the PTEN promoter 1.5 kb upstream of the ATG (Xia et al., 2007). p53 regulates PTEN both positively at the transcriptional level and negatively at the protein-stability level: a functional p53 response element (RE) has been found in the PTEN promoter, and p53 induction leads to elevated PTEN mRNA and protein levels (Stambolic et al., 2001; Tang and Eng, 2006b). PTEN might autoregulate its own expression through stabilization of p53 protein independently of its phosphatase activity (Tang and Eng, 2006b). EGR1 binds to the PTEN promoter and upregulates its expression in response to radiation (Virolle et al., 2001) and IGF2 (Moorehead et al., 2003). (For pathways marked with a star, no specific PTEN promoter site has been identified as being involved in the regulation observed.) Solid lines represent demonstrated direct interaction of the respective protein with DNA; broken lines indicate indirect action.

View larger version (181K): [in this window] [in a new window]   Fig. 2. Post-translational regulation of PTEN. Components of activating pathways are displayed as ovals and those of suppressing pathways as rectangles (note that some function as both activators and repressors). (A) PTEN activity, localization and stability are regulated by acetylation, ubiquitylation, oxidation and phosphorylation. In the presence of growth factors, the histone acetyltransferase PCAF acetylates PTEN at lysines 125 and 128 in the catalytic cleft. This acetylation negatively regulates PTEN activity, probably by interfering with its binding to its substrate, PtdIns(3,4,5)P3 (Okamura et al., 2006). Ubiquitylation at K289 by NEDD4-1 affects both PTEN localization and stability (see C) (Trotman et al., 2007; Wang, L. et al., 2007). Human SPRY2 (hSPRY2) decreases phosphorylation of PTEN at several sites and thereby increases PTEN levels and activity (Edwin et al., 2006). CK2 phosphorylates PTEN at S370 and S385, and GSK3 phosphorylates S362 and T366. Phosphorylation at T366 is strongly increased by prior phosphorylation of the protein by CK2 (Al-Khouri et al., 2005). GLTSCR2 interacts with PTEN to promote phosphorylation at S380 and to positively regulate its levels (Okahara et al., 2006; Yim et al., 2007). Generally, phosphorylation in the C-terminal tail of PTEN is thought to enhance stability and to decrease membrane localization and activity. However, phosphorylation at T366 is linked to destabilization of PTEN (Maccario et al., 2007). ROCK activates PTEN and targets it to the plasma membrane, presumably by direct phosphorylation of S229, T232, T319 and T321 in its C2 domain (Li et al., 2005). (B) PTEN localization, activity and stability are controlled by phosphorylation. Phosphorylation of PTEN in the C-terminal tail by GSK3, CK2 and possibly other kinases is generally thought to decrease membrane association and protein activity but to enhance protein stability. Phosphorylation of residues in the C-terminus of PTEN might cause the C-terminal tail to interact with the C2 domain, inducing a closed conformation and a predominantly cytosolic localization that inhibit PTEN activity (Odriozola et al., 2007). (C) PTEN localization and stability are controlled by interaction with other proteins. PTEN interacts with the NHERF1 and NHERF2 adaptor proteins by virtue of its PDZ-binding motif, and PTEN and NHERF proteins are found in a ternary complex with PDGFR. Activation of PI3-kinase after PDGFR stimulation is prolonged in NHERF1–/– MEFs and in NHERF2 siRNA knockdown experiments, indicating that NHERF proteins normally recruit PTEN to PDGFR in order to restrict the activation of PI3-kinase (Takahashi et al., 2006). Interactions between MAGI2 and PTEN at the cell membrane prevent PTEN degradation. Vinculin is required to maintain -catenin–MAGI2 interactions at adherens junctions and thereby limit ubiquitin-mediated degradation of PTEN (Subauste et al., 2005). Binding of PTEN to the MAST kinases MAST3 and SAST also stabilizes PTEN and facilitates its phosphorylation by these proteins (Valiente et al., 2005). Association of PTEN with MVP, a putative nucleocytoplasmatic transport protein, carries PTEN to the nucleus. This is dependent on two nuclear-localization-signal-like sequences but independent of PTEN phosphorylation and of its phosphatase activity (Chung et al., 2005). Monoubiquitylation of PTEN by NEDD4-1 increases nuclear localization (Trotman et al., 2007), whereas polyubiquitylation by NEDD4-1 promotes its degradation in the cytoplasm (Wang, X. et al., 2007). p53 also downregulates PTEN protein levels by promoting caspase-mediated degradation of PTEN (Tang and Eng, 2006a).