ReviewMechanisms of PTEN loss in cancer: It’s all about diversity
Introduction
PTEN is a ubiquitously expressed tumour suppressor that is commonly inactivated in human sporadic cancers. It was firstly identified in 1997 by two independent research groups while studying the chromosomal location 10q23, which appeared to show frequent deletion in tumours of the brain, prostate and bladder [1,2]. Shortly thereafter, PTEN mutations were also found in the germline of patients with a group of autosomal dominant syndromes, termed collectively as PTEN hamartoma tumour syndromes (PHTS) that are characterized by the presence of multiple hamartomas, an increased cancer predisposition and neurological symptoms. The role of PTEN as a tumour suppressor has been extensively studied since its initial discovery [3,4] and it was identified as the locus with greatest selection pressure for deletion in an analysis of 746 human cancer genomes [5].
In many cases, PTEN appears to be a haploinsufficient tumour suppressor. In contrast to classical tumour suppressor models that need a complete inactivation to induce cancer and were based upon studies of the Retinoblastoma gene, [6] partial loss of PTEN function can have a dramatic impact on tumorigenesis and cancer progression. Studies using hypomorphic mouse models expressing reduced PTEN levels have shown that even subtle reductions in PTEN expression can significantly increase cancer susceptibility [[7], [8], [9]]. This is also in accordance with evidence that the diverse mechanisms controlling PTEN stability and function can have substantial impacts on cancer development [[10], [11], [12], [13], [14]] and with the observation that loss of one copy of PTEN is far more common than mutation or deletion of both copies (Tables 1 and S1).
PTEN is a major negative regulator of the signalling pathway defined by class I phosphoinositide 3 kinase (PI3K), AKT and the mechanistic target of rapamycin (mTOR) and which plays a key role controlling a wide range of essential cellular processes including cell proliferation, growth, survival and metabolism [[15], [16], [17]]. The PI3K-AKT-mTOR signalling pathway is evolutionarily conserved within metazoans although the linked functions of the class I PI3Ks and PTEN appear to have evolved earlier as regulators of cell polarity and membrane remodelling [18].
The activation of intracellular class I PI3Ks is caused by diverse cell surface receptors which promote cell growth and proliferation, including many growth factor-activated members of the receptor tyrosine kinases (RTK) cytokine receptors, some integrins and a subset of G-protein coupled receptors which includes several chemokine receptors [19]. These activated receptors directly or indirectly recruit and activate class I PI3K which in turn phosphorylates a small fraction of plasma membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), a membrane-associated lipid that acts as a second messenger driving downstream signalling (Fig. 1). Increases in local PIP3 levels facilitate the binding of a large number of proteins that carry selective PIP3-binding domains which in turn promote the effects of pathway activation on cell metabolism, growth, proliferation, etc [[20], [21], [22]]. The best studied of these PIP3-binding effector proteins are the AKT protein kinases, which have a large and diverse range of substrates and are important proto-oncogenes in their own right. However, other proteins directly regulated by PIP3 binding include the BTK/TEC family of tyrosine kinases and several regulators of small GTPase of the ARF and RHO families [19,22].
PTEN’s role within the pathway is as a lipid phosphatase, directly opposing the activation of the PI3K signalling by converting the PIP3 generated by PI3K back to PIP2. Loss of PTEN results in the lack of regulation of PIP3 levels which in turn promote the hyper-activation of the pathway thus leading to cellular transformation and tumorigenesis, as observed in studies with PTEN-null tumour cell lines, immortalized fibroblasts and tumours arising in PTEN-deficient mice [3,23,24]. The PI3K/AKT/mTOR signalling axis is one of the most frequently deregulated pathways in cancer with mutations occurring in most of the major components of the network [15,[25], [26], [27]]. Therefore, targeting the pathway has become an attractive strategy for cancer therapy and this has led to the development of numerous compounds designed to counteract activated PI3K signalling, although to date clinical success has been limited to the approval of the PI3K delta inhibitor idelalisib for the treatment of B cell malignancies [15].
Even though its main biological activity relies on its ability to dephosphorylate lipid substrates, PTEN has also been reported to display phosphatase activity against tyrosine, serine and threonine residues towards protein substrates in vitro as well as on itself [28] although the biological significance of these functions is still controversial. In addition, PTEN has been proposed to exert some of its biological functions in a catalysis-independent manner through protein-protein interactions [29,30]. Both phosphatase-dependent and independent functions appear related to PTEN’s subcellular localization: interestingly, loss of the nuclear pool of PTEN seems to correlate with cancer progression and poor clinical outcome in certain types of tumours thus highlighting the importance of its nuclear localisation [13,31,32]. However, the molecular mechanisms through which PTEN exerts its tumour-suppressor functions in the nucleus and its biological relevance still remain unclear.
The PTEN gene is located on chromosome 10q23 and its 9 exons encode a predominant protein product of 403 amino acids and 48 kDa that shares sequence homology with the tyrosine phosphatase superfamily as well as with tensin and auxilin. Therefore it was named Phosphate and Tensin Homolog deleted from chromosome ten (PTEN) when first discovered [1]. The protein sequence is highly conserved within vertebrates with only one amino acid difference between the human and murine orthologs. The first analysis of a crystal structure of human PTEN revealed the existence of 2 tightly associated domains: a catalytic N-terminal phosphatase domain (amino acids 6–185) and a C2 domain required for membrane binding (amino acids 186–351) [33]. The protein also includes an extreme N-terminal PtdIns(4,5)P2 binding sequence (amino acids 6–15) that enables the interaction with substrate-containing membrane surfaces and cytoplasmic and nuclear localization signals (amino acids 19–25) that helps dictate its subcellular localization [[34], [35], [36]]. Furthermore, the C-terminal portion of PTEN has a less-structured C-terminal tail (amino acids 352–403) that contributes to the post-translational regulation of the PTEN protein, containing two clusters of phosphorylation sites and a PDZ binding sequence [33].
In addition to the most abundant 403 amino acid form of PTEN, many cells contain lower levels of N-terminally extended isoforms of the enzyme [37,38]. The first of these to be discovered, PTEN-L, has an additional 173 amino acid N-terminal region translated from an alternate upstream start codon which notably includes a signal peptide. This leads to the secretion of PTEN-L and suggested the hypothesis that active PTEN-L protein may be shared between cells to suppress PI3K/AKT signalling [39]. However, the functions of these longer forms of PTEN remains somewhat mysterious.
Section snippets
Changes in PTEN activity in health and disease
Given the biological importance of its functions and the profound pathological effects that arise as a consequence of subtle disruptions on its expression and activity, it is unsurprising that PTEN levels are tightly regulated through multiple physiological mechanisms [40,41]. These mechanisms of PTEN regulation act at transcriptional, post-transcriptional and post-translational levels. Significantly, these physiological mechanisms appear to be subverted in some cancers to suppress PTEN
Tumour type-specific patterns of PTEN loss
Stark changes in PTEN activity are seen in tumours that display changes in the PTEN gene, mutating or deleting the gene in many cases leading to complete loss of activity or of expression. PTEN shows different patterns of loss in different tumour types and these are discussed in individual sections below and illustrated in Table 1 and Table S1. It should be noted that despite work to compare antibodies and advise best practice [108], sources of uncertainty within datasets analysing PTEN loss
Conclusion
The spectrum of changes and processes which contribute to the loss of PTEN function in different types of tumours is diverse and as discussed reveals some specific patterns. In many cases, the source and consequence of these patterns are unclear. It seems likely that some may be driven by mutational processes, such as tumour cells which are deficient in mismatch repair, identifiable by microsatellite instability. However, other patterns of PTEN loss seem likely to be driven by selection,
Acknowledgements and conflict of interest statement
The authors declare they have no conflict of interest with publication of this manuscript. Work in the NRL laboratory is funded by Medical Research Scotland (Grant number: 1034-2016), Prostate Cancer UK (PG14-006), CRUK (C50604/A28050) and PTEN Research.
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Present address: Cancer Research UK Edinburgh Centre, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XR, UK.