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The Functions and Regulation of the PTEN Tumour Suppressor: New Modes and Prospects

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The Functions and Regulation of the PTEN Tumour Suppressor: New Modes and Prospects REVIEWS The functions and regulation of the PTEN tumour suppressor: new modes and prospects Yu- Ru Lee1,2, Ming Chen1,2 and Pier Paolo Pandolfi1* Abstract | PTEN is a potent tumour suppressor, and its loss of function is frequently observed in both heritable and sporadic cancers. PTEN has phosphatase- dependent and phosphatase- independent (scaffold) activities in the cell and governs a variety of biological processes, including maintenance of genomic stability , cell survival, migration, proliferation and metabolism. Even a subtle decrease in PTEN levels and activity results in cancer susceptibility and favours tumour progression. Regulation of PTEN has therefore emerged as a subject of intense research in tumour biology. Recent discoveries, including the existence of distinct PTEN isoforms and the ability of PTEN to form dimers, have brought to light new modes of PTEN function and regulation. These milestone findings have in turn opened new therapeutic avenues for cancer prevention and treatment through restoration of PTEN tumour suppressor activity. PTEN hamartoma tumour PTEN is one of the most frequently mutated tumour are often found to be altered in cancer. Apart from syndromes suppressor genes in human cancer. It was identified mutations, the suppression of PTEN function by either (PHTS). Encompass a spectrum simultaneously by three groups in 1997 as a candidate repression of PTEN gene expression or aberrant PTEN of disorders caused by tumour suppressor gene1,2 and a novel protein tyrosine subcellular localization is tightly related to tumorigenesis germline mutations of the 3 14 PTEN gene. These disorders phosphatase . Shortly thereafter, PTEN was found to be and disease progression . Moreover, PTEN- interacting are characterized by multiple targeted by germline mutations in a group of rare auto- proteins may have important roles in cancer progres- hamartomas that can affect somal dominant syndromes that are collectively referred sion by perturbing the fine-tuning of PTEN activity14,15. various organs. Hamartoma is to as the PTEN hamartoma tumour syndromes (PHTS)4,5, Recently, PTEN was reported to be active in its dimer a general term for a benign which provided direct evidence of the deregulation of configuration within membrane compartments16, sug- tumour- like malformation composed of mature cells in PTEN in tumorigenesis. Subsequently, genetic ablation gesting that yet unknown mechanisms underlying PTEN a tissue that has grown in a of Pten in mice reaffirmed its tumour- suppressive role in dimerization are deregulated in cancer, leading to its disorganized manner as multiple tumour types6–8. Further genetic analyses also inactivation. Intriguingly, two studies recently reported a result of developmental demonstrated that Pten acts as a haploinsufficient tumour that PTEN is secreted into the extracellular environment defects. suppressor gene in some tissues9. Additionally, studies for uptake by recipient cells, thus, also functioning as of both human samples and hypomorphic Pten mice a tumour suppressor in a cell non- autonomous man- showed that even partial loss of PTEN function is suf- ner17,18. Taken together, these findings shed new light on ficient to promote some cancer types and that a reduc- PTEN biology and function and open up avenues for tion in PTEN levels below 50% further accelerates cancer the establishment of novel effective therapies for can- 1Cancer Research Institute, progression10, suggesting that a continuum model of cer prevention and treatment. While several excellent Beth Israel Deaconess Cancer PTEN tumour suppression, rather than a stepwise alter- reviews cover the molecular details of PTEN regulation Center, Department of 11 PI3K–AKT–mTOR pathway Medicine and Pathology, ation of PTEN levels, is key to tumour development . of the and its role in human 14,15,19,20 Beth Israel Deaconess Nevertheless, it should also be noted that complete loss disease , here, we highlight recent advances in our Medical Center, Harvard of Pten (Pten-null) can impede tumour growth by indu- understanding of the functions of PTEN and discuss Medical School, Boston, cing a potent fail-safe mechanism, cellular senescence, in novel modes of PTEN regulation emerging from current MA, USA. the prostate11,12 and that Pten inactivation also paradox- research. We also examine ways and opportunities to 2 These authors contributed ically increases apoptosis in the liver owing to fatty acid restore and improve PTEN function for cancer therapy. equally: Yu-Ru Lee, Ming Chen. accumulation, which leads to non- alcoholic fatty liver 13 Biochemical functions of PTEN *e- mail: ppandolf@ disease and long-latent liver tumorigenesis . bidmc.harvard.edu In line with the profound effects of subtle downreg- PTEN was initially identified as a protein tyrosine phos- https://doi.org/10.1038/ ulation of PTEN on tumour development, a plethora of phatase (PTP) on the basis of its sequence homology in s41580-018-0015-0 mechanisms regulating PTEN expression and function the catalytic domain to members of the PTP family1–3. NATURE REVIEWS | MOLECULAR CELL BIOLOGY © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. REVIEWS a PTEN N Phosphatase C2 Tail proto- oncogene tyrosine- protein kinase SRC, insulin PDZ-BD receptor substrate 1 (IRS1) and others, to exert its tumour- suppressive function29–33. Identification of mutant forms Lipid phosphatase Protein phosphatase Scaffold of PTEN, in particular G129E and Y138L, in which b lipid and protein phosphatase activities are selectively Plasma abolished34,35, has allowed the field to characterize the PIP p85 membrane c PTEN dimer 3 protein phosphatase function of PTEN in many experi- mental systems; however, the physiological relevance of PTEN open conformation protein dephosphorylation by PTEN has yet to be fully Phosphorylation Dephosphorylation established. A thorough genetic analysis of PTEN G129E and Y138L mutants in mice is warranted to understand the role of PTEN protein phosphatase in vivo. PTEN closed Scaffold function. Many studies have revealed that conformation Phosphorylation PTEN exerts part of its tumour- suppressive function independently of PIP3 and the PI3K–AKT axis by acting Fig. 1 | Structure and activity of PTEN. a | PTEN is a multi- domain protein that exerts as a scaffold protein in both the nucleus and cytoplasm, tumour- suppressive functions in a lipid phosphatase- dependent, protein phosphatase- which is as relevant as modulation of the PI3K–AKT dependent or scaffold- dependent manner. PTEN is composed of five functional domains: signalling to tumour suppression14,15. Accordingly, PTEN a short N- terminal phosphatidylinositol (PtdIns)(4,5)P2-binding domain (PBD), a catalytic phosphatase domain, a C2 lipid/membrane- binding domain, a C- terminal tail containing loss is not synonymous with AKT overexpression, as Pro, Glu, Ser and Thr (PEST) sequences and a class I PDZ-binding (PDZ-BD) motif. PEST revealed by in vivo genetic analyses in mouse mod- 36 sequences determine short intracellular half- lives and have been linked to targeting els . In the nucleus, PTEN regulates diverse processes, proteins for proteasomal degradation, while the PDZ-BD acts as a protein–protein including cell proliferation, transcription and main- interaction motif. b | Model for the conformational regulation of PTEN. Phosphorylation of tenance of genomic stability (see examples in the fol- the C- terminal of PTEN promotes an interaction between the acidic tail and C2 domain lowing section). In the cytoplasm, scaffolding by PTEN (closed conformation), which in turn masks the membrane binding of PTEN. In the modulates the activity of inositol 1,4,5-trisphosphate open conformation, dephosphorylation of PTEN reverses this closed conformation receptors (IP3Rs) and, consequently, Ca2+-mediated to an open conformation, allowing PTEN to bind to the membrane and PDZ apoptosis. Both wild-type PTEN and a catalytically dead domain- containing proteins. c | Structure modelling of PTEN dimerization. PTEN forms a PTEN mutant can compete with the F- box/LRR- repeat homodimer in vitro. The PTEN dimer is superimposed as a ribbon structure and determined 181 protein 2 (FBXL2) for IP3R3 binding in the cytosol, by small- angle X-ray scattering (SAXS) analysis (figure adapted from REF. , Elsevier). PIP3, phosphatidylinositol (PtdIns)-3,4,5-trisphosphate; p85, PI3K regulatory subunit alpha. thereby preventing FBXL2-mediated IP3R3 degrada- tion, which in turn induces persistent Ca2+ mobilization and apoptosis37. Moreover, a recent study has demon- strated that cytosolic PTEN stimulates chromodomain- However, it is now known that it majorly functions as helicase-DNA- binding protein 1 (CHD1) proteasomal a phosphatase for lipids, mainly phosphatidylinositol degradation through the recruitment of F- box/WD (PtdIns)-3,4,5-trisphosphate (PIP3). It also displays repeat- containing protein 1A (β- TRCP) E3 ubiquitin non- enzymatic (scaffold) functions. ligases, thereby suppressing CHD1-induced trimethyl lysine-4 histone H3 modification, which leads to tran- Lipid and protein phosphatase function. The crystal scriptional activation of the oncogenic tumour necrosis Haploinsufficient structure of PTEN has revealed that the PTEN protein factor (TNF)–nuclear factor- κB (NF- κB) pathway38. It A situation in a diploid organism when one copy of a consists of a short N- terminal PtdIns(4,5) P2 (PIP2)- will be important to consider these non-canonical, scaf- gene is inactivated due to binding domain (PBD), a
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