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The functions and regulation of the PTEN tumour suppressor

Key Points

  • PTEN (phosphatase and tensin homologue) is frequently disrupted in multiple sporadic tumours, and targeted by germline mutations in patients with cancer predisposition syndromes.

  • PTEN antagonizes the phosphoinositide 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity and governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture.

  • The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus.

  • The molecular mechanisms regulating PTEN expression and function include transcriptional regulation, post-transcriptional regulation by microRNAs (miRNAs) and competitive endogenous RNA (ceRNAs), post-translational modifications and protein interactions.

  • The increasing knowledge of PTEN and pathologies that alter its function undoubtedly informs the rational design of novel cancer therapies.

Abstract

The importance of the physiological function of phosphatase and tensin homologue (PTEN) is illustrated by its frequent disruption in cancer. By suppressing the phosphoinositide 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity, PTEN governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture. Consequently, mechanisms regulating PTEN expression and function, including transcriptional regulation, post-transcriptional regulation by non-coding RNAs, post-translational modifications and protein–protein interactions, are all altered in cancer. The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus. Our increasing knowledge of PTEN and pathologies in which its function is altered will undoubtedly inform the rational design of novel therapies.

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Figure 1: Structure of the PTEN tumour suppressor.
Figure 2: The PTEN–PI3K–AKT–mTOR pathway.
Figure 3: Functions of PTEN in the nucleus.
Figure 4: Molecular mechanisms of PTEN regulation.

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Acknowledgements

The authors are grateful to all members of the Pandolfi laboratory for insightful comments and discussion. The authors also thank H. M. Kim for providing the modified PTEN structures. L.S. was supported by fellowships from the Canadian Institutes of Health Research and the Human Frontier Science Program. This work was supported by US National Institutes of Health (NIH) grant R01 CA-82328-09 awarded to P.P.P.

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The Sanger Institute Catalogue of Somatic Mutations in Cancer (COSMIC)

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S1 (table)

Glossary

Cowden disease

An autosomal dominant multiple hamartoma syndrome that results most commonly (in 80% of cases) from a mutation in the phosphatase and tensin homologue (PTEN) gene. The disease was named after the family in which it was first reported. Although the tumours are largely benign, people with Cowden syndrome have an increased risk of developing several types of cancer, including cancers of the breast, thyroid and uterus.

Haploinsufficient tumour suppressor

A tumour suppressor gene is haploinsufficient when loss of one functional copy in a diploid organism compromises tumour suppression, because the remaining copy of the gene is incapable of providing sufficient protein for tumour suppressive function.

Two-hit model

Mutation or deletion of one allele induces cancer susceptibility (the first hit) and mutation or loss of the other allele induces cancer (the second hit).

C2 domains

Protein structural domains involved in targeting proteins to cell membranes. They are composed of eight β-strands that coordinate calcium ions, which bind in a cavity formed by the first and final loops of the domain on the membrane binding face.

PDZ domain

(Postsynaptic-density protein of 95 kDa, discs large, zona occludens-1). A protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family.

Pleckstrin homology domains

(PH domains). Protein structural domains composed of two perpendicular antiparallel β-sheets followed by a carboxy-terminal α-helix. They are capable of binding phosphatidylinositol lipids in cell membranes and thus targeting proteins to the membranes.

Metabolic reprogramming

Reprogramming of cellular metabolism allows quiescent cells to proliferate. Proliferating cells often take up nutrients in excess of bioenergetic needs (for example, ATP) and shunt metabolites into pathways that support a platform for biosynthesis (for example, amino acids, lipids and nucleic acids).

Warburg effect

A phenomenon first described by Otto Warburg in which rapidly proliferating tumour cells consume glucose at a higher rate than normal cells and secrete most of the glucose-derived carbon as lactate rather than oxidizing it completely.

Pro-senescence therapy

Novel therapeutic approach to treat cancers by inducing cellular senescence — a robust physiological antitumour response that is engaged by tissues to counteract oncogenic insults. Senescent cells can be cleared through an innate immune response.

PTEN hamartoma tumour syndromes

(PHTSs). Patients with PHTS harbour phosphatase and tensin homologue (PTEN) mutations and develop non-malignant tumours. In PHTSs the proliferation of normal cellular elements is accompanied by disordered architecture. PHTSs include Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), Proteus-like syndrome (PSL) and autism spectrum disorder with macrocephaly.

miR-1792 cluster

The miR-1792 cluster is a polycistron that generates six different miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92a) from one transcript.

ceRNA hypothesis

A unifying hypothesis introducing a new level of post-transcriptional regulation. According to this hypothesis, different RNA transcripts are competing for binding of microRNAs (miRNAs) to their miRNA-binding sites ('miRNA response elements' or 'MREs').

Acute promyelocytic leukaemia

(APL). A subtype of acute myeloid leukaemia that stems from a t(15;17)(q24;q21) translocation. APL is characterized by an abnormal accumulation of immature granulocytes called promyelocytes.

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Song, M., Salmena, L. & Pandolfi, P. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13, 283–296 (2012). https://doi.org/10.1038/nrm3330

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