Posttranslational regulation of phosphatase and tensin homolog (PTEN) and its functional impact on cancer behaviors.

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Posttranslational regulation of phosphatase and tensin homolog (PTEN) and its functional impact on cancer behaviors.

Author(s): Wenting Xu, Zhen Yang, Shu-Feng Zhou, Nonghua Lu

Publication date: 2014

Journal: Drug Design, Development and Therapy

Keywords: PTEN, acetylation, oxidation, phosphorylation, ubiquitination

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Abstract

The incidence of cancer is increasing worldwide, but the biochemical mechanisms for the occurrence of cancer is not fully understood, and there is no cure for advanced tumors. Defects of posttranslational modifications of proteins are linked to a number of important diseases, such as cancer. This review will update our knowledge on the critical role of posttranscriptional regulation of phosphatase and tensin homolog (PTEN) and its activities and the functional impact on cancer behaviors. PTEN is a tumor suppressor gene that occupies a key position in regulating cell growth, proliferation, apoptosis, mobility, signal transduction, and other crucial cellular processes. The activity and function of PTEN are regulated by coordinated epigenetic, transcriptional, posttranscriptional, and posttranslational modifications. In particular, PTEN is subject to phosphorylation, ubiquitylation, somoylation, acetylation, and active site oxidation. Posttranslational modifications of PTEN can dynamically change its activity and function. Deficiency in the posttranslational regulation of PTEN leads to abnormal cell proliferation, apoptosis, migration, and adhesion, which are associated with cancer initiation, progression, and metastasis. With increasing information on how PTEN is regulated by multiple mechanisms and networked proteins, its exact role in cancer initiation, growth, and metastasis will be revealed. PTEN and its functionally related proteins may represent useful targets for the discovery of new anticancer drugs, and gene therapy and the therapeutic potentials should be fully explored.

Most cited references 51

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Reversible inactivation of the tumor suppressor PTEN by H2O2.

Seung-Rock Lee, Kap-Seok Yang, Jaeyul Kwon … (2002)

The tumor suppressor PTEN regulates cell migration, growth, and survival by removing the 3'-phosphate of phosphoinositides. Exposure of purified PTEN or of cells to H(2)O(2) resulted in inactivation of PTEN in a time- and H(2)O(2) concentration-dependent manner. Analysis of various cysteine mutants, including mass spectrometry of tryptic peptides, indicated that the essential Cys(124) residue in the active site of PTEN specifically forms a disulfide with Cys(71) during oxidation by H(2)O(2). The reduction of H(2)O(2)-oxidized PTEN in cells appears to be mediated predominantly by thioredoxin. Thus, thioredoxin was more efficient than glutaredoxin, glutathione, or a 14-kDa thioredoxin-like protein with regard to the reduction of oxidized PTEN in vitro. Thioredoxin co-immunoprecipitated with PTEN from cell lysates; and incubation of cells with 2,4-dinitro-1-chlorobenzene (an inhibitor of thioredoxin reductase) delayed the reduction of oxidized PTEN, whereas incubation with buthioninesulfoximine (an inhibitor of glutathione biosynthesis) did not. These results suggest that the reversible inactivation of PTEN by H(2)O(2) might be important for the accumulation of 3'-phosphorylated phosphoinositides and that the uncontrolled generation of H(2)O(2) associated with certain pathological conditions might contribute to cell proliferation by inhibiting PTEN function.

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Ubiquitination regulates PTEN nuclear import and tumor suppression.

Lloyd C. Trotman, Xinjiang Wang, Andrea Alimonti … (2007)

The PTEN tumor suppressor is frequently affected in cancer cells, and inherited PTEN mutation causes cancer-susceptibility conditions such as Cowden syndrome. PTEN acts as a plasma-membrane lipid-phosphatase antagonizing the phosphoinositide 3-kinase/AKT cell survival pathway. However, PTEN is also found in cell nuclei, but mechanism, function, and relevance of nuclear localization remain unclear. We show that nuclear PTEN is essential for tumor suppression and that PTEN nuclear import is mediated by its monoubiquitination. A lysine mutant of PTEN, K289E associated with Cowden syndrome, retains catalytic activity but fails to accumulate in nuclei of patient tissue due to an import defect. We identify this and another lysine residue as major monoubiquitination sites essential for PTEN import. While nuclear PTEN is stable, polyubiquitination leads to its degradation in the cytoplasm. Thus, we identify cancer-associated mutations of PTEN that target its posttranslational modification and demonstrate how a discrete molecular mechanism dictates tumor progression by differentiating between degradation and protection of PTEN.

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The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network

Min Sup Song, Leonardo Salmena, Arkaitz Carracedo … (2008)

Nuclear exclusion of the PTEN tumour suppressor has been associated with cancer progression 1-6 . However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear-cytoplasmic partitioning 7 . Here we show that functional PML-nuclear bodies co-ordinate PTEN localization by opposing the action of a novel PTEN-deubiquitinylating enzyme, HAUSP, and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia (APL), where PML function is disrupted by the PML-RARα fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARα degradation such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN, through a mechanism involving the adaptor protein DAXX. In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus our results delineate a novel PML-DAXX-HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization.