Protein phosphatase 2A (PP2A) plays a major role in maintaining cellular signaling homeostasis by dephosphorylation of a variety of signaling proteins and acts as a tumor suppressor. Protein phosphatase methylesterase-1 (PME-1) negatively regulates PP2A activity by highly complex mechanisms that are reviewed here. Importantly, recent studies have shown that PME-1 promotes oncogenic MAPK/ERK and AKT pathway activities in various cancer types. In human glioma, high PME-1 expression correlates with tumor progression and kinase inhibitor resistance. We discuss the emerging cancer-associated function of PME-1 and its potential clinical relevance.

Protein phosphatases

Protein phosphorylation is a posttranslational modification (PTM) event, which is reversibly carried out by the action of phosphorylating protein kinases and dephosphorylating protein phosphatases. There are ∼140 known protein phosphatase catalytic subunits, and on the basis of the substrate specificity, they fall into four categories: (1) serine/threonine phosphatases (PSTPs), (2) tyrosine phosphatases (PTPs), (3) dual specificity phosphatases, and (4) histidine phosphatases [1]. Protein phosphatase 2A (PP2A) along with protein phosphatases PP1, PP2B, PP2C, PP4, PP5, and PP6 comprises the major PSTP activity in a cell [2].

Protein phosphatase 2A

Structurally, PP2A consists of three subunits: a catalytic ‘C’ (PP2A-C), a scaffolding ‘A’ (PP2A-A or PR65), and a regulatory ‘B’ subunit (Figure 1A). There are two isoforms, α and β, for A and C subunits each (Figure 1A). In mammalian cells, A and C subunits mostly exist in a complex as AC dimer (also called core dimer), or as ABC trimers (also called heterotrimer or holoenzyme), and a small fraction as ‘free C’ subunits possibly stabilized by binding with other regulatory proteins [3]. The PP2A-C subunit requires the presence of two manganese (Mn2+) ions in its active site for the hydrolysis of Ser/Thr phosphate esters, although recent studies suggest the presence of zinc (Zn2+) and ferrous (Fe2+) in its bimetallic active site under physiological conditions [4,5]. PP2A B-subunits have been broadly categorized into four families: (1) PPP2R2 (PR55 or B55), (2) PPP2R5 (PR61 or B56), (3) PPP2R3, and (4) STRN or Striatin (Figure 1A). Each B-subunit subfamily contains ∼3–5 different isoforms and additional splice variants, altogether generating at least 26 different B-subunits [6]. On the basis of the number of known A, C, and B subunits, PP2A can theoretically exist in nearly 100 different trimeric holoenzyme complexes. B-subunits contain putative substrate-binding pockets and function as a regulatory partner whose binding directs a particular PP2A complex to a distinct set of substrates (i.e. regulators of substrate specificity) [7,8].

PP2A structure, function, and regulation.

Figure 1.
PP2A structure, function, and regulation.

(A) Structural components of a PP2A complex. (B) Illustration of the possible posttranslational modifications of the PP2A-C subunit carboxy-terminal tail. LCMT-1 and PME-1 carry out the methylation and demethylation of terminal Leu309 residue, respectively. Potential PP2A Thr304 and Tyr307 kinases are marked with dotted arrows. Phosphorylation of Tyr307 might inhibit the methylation at Leu309 (dotted red line). (C) PP2A complexes can dephosphorylate numerous phosphoproteins, and the PP2A complexes, in turn, are negatively regulated by cellular inhibitory proteins, some of which are highly expressed in cancers.

Figure 1.
PP2A structure, function, and regulation.

(A) Structural components of a PP2A complex. (B) Illustration of the possible posttranslational modifications of the PP2A-C subunit carboxy-terminal tail. LCMT-1 and PME-1 carry out the methylation and demethylation of terminal Leu309 residue, respectively. Potential PP2A Thr304 and Tyr307 kinases are marked with dotted arrows. Phosphorylation of Tyr307 might inhibit the methylation at Leu309 (dotted red line). (C) PP2A complexes can dephosphorylate numerous phosphoproteins, and the PP2A complexes, in turn, are negatively regulated by cellular inhibitory proteins, some of which are highly expressed in cancers.

PP2A is required for the proper functioning of many signaling pathways [6]. Particularly, cellular functions, such as cell division, cell cycle regulation, DNA damage response, stress response (for example hypoxia), growth factor response, cell adhesion, survival, and death, including apoptosis and autophagy, neuronal signaling, and brain development, are affected by PP2A [914]. It is noteworthy that the multiple PP2A functions are carried out by specific PP2A complexes directed by the B-subunits [7].

The mechanism of PP2A biogenesis and regulation of its catalytic activity have recognized an ever-increasing complexity (reviewed in ref. [15]). Overall, PP2A is regulated by various PTMs and protein–protein interactions. The hot-spot of PP2A-C subunit PTMs is at the carboxyl-terminal six amino acid residue tail (304TPDYFL309; Figure 1B). This includes a very unique methylation at free carboxyl group of the terminal Leu309 and phosphorylations at Thr304 and Tyr307. The methylation of PP2A-C Leu309 residue is reversibly modified by LCMT-1 (leucine carboxylmethyltransferase-1) and PME-1 (protein phosphatase methylesterase-1) [1618]. Very little is known about the kinases responsible for the phosphorylation of Thr304, although CDK1 has been suggested to phosphorylate this residue during mitosis [19]. Increased Tyr307 phosphorylation has been associated with active Src, glycogen synthase kinase-3β (GSK-3β), and EGFR and insulin receptor signaling [2022]. GSK-3β signaling functions via suppression of protein tyrosine phosphatase PTP1B that dephosphorylates Tyr307 [21]. Moreover, autodephosphorylation activity of PP2A has also been suggested to act on these residues and activate itself [22,23]. Interestingly, Tyr307 phosphorylation seems to negatively affect the methylation at Leu309 [24] which, as discussed more below, affects the differential binding of certain B-subunits [15]. PP2A-C phosphorylation at Thr304, instead, may inhibit the formation of PP2A complexes containing PPP2R2/PR55 family B-subunits [15,22,25]. The Tyr307 phosphorylation has been proposed to inhibit the binding of PPP2R5/PR61 family B-subunits and enhance the recruitment of STRN family B-subunits to PP2A complexes [15,22,24,25]. It should, however, be mentioned that many of the conclusions related to Tyr307 phosphorylation are based on experiments using antibody clone E155 that later has been found by distributor Abcam to recognize total PP2Ac, independently of Tyr307 phosphorylation status. Therefore, any further attempts to clarify the role of PP2Ac Tyr307 phosphorylation should be carried out using other technical approaches.

Apart from LCMT-1 and PME-1, other PP2A modulatory proteins, such as alpha4 (α4 or IGBP1), type 2A­-interacting protein (TIP or TIPRL1), and PP2A activator (PTPA), participate in the PP2A holoenzyme biogenesis and activity regulation [15]. Additionally, many proteins have been discovered, which inhibit PP2A activity (Figure 1C). These include inhibitor-1 of PP2A (I1PP2A or ANP32a), inhibitor-2 of PP2A (I2PP2A or SET), cancerous inhibitor of PP2A (CIP2A), cAMP-regulated phosphoproteins (ARPP), α-endosulfin (ENSA), TIP, and PME-1 (Figure 1C) [26]. The expression of these proteins, especially SET, CIP2A, and PME-1, is elevated in cancers, suppressing the tumor suppressor PP2A activity [26,27]. In this review, we focus on the function of PME-1 and its relevance in human cancers.

Protein phosphatase methylesterase-1

PME-1 is the first eukaryotic carboxylmethylesterase to be characterized [16] and cloned [17]. It is a 44-kDa (386 amino acids long) intracellular protein, which belongs to the subfamily of serine hydrolases containing a catalytic triad of Ser-Asp-His with Ser156 as an active site residue [17,28]. PME-1 protein encoded by PPME1 gene is conserved among eukaryotes, and its highest transcript expression has been reported in the brain and testis tissue extracts from mouse [17]. PME-1 contains an active nuclear localization signal (270KRKK273), which directs its predominant localization to the nucleus, where most of the demethylated PP2A pool has been detected in HeLa cells [29].

PME-1 methylesterase activity shows insensitivity to serine esterase inhibitors PMSF and DFP in cell-free assays [16,17]. The reason behind this was explained when the crystal structure of PME-1 was solved by Xing et al. [28]. In a free state, not bound to PP2A, catalytic site of PME-1 exists in an inactive conformation which does not bind serine esterase inhibitors [28]. PP2A-C binding induces structural rearrangement of PME-1 catalytic triad residues (Ser156, Asp181, and His349) into an active form that allows PP2A-C C-terminal 304TPDYFL309 tail binding to the active site pocket of PME-1 [28].

Various modes of PP2A regulation by PME-1

The mechanisms by which PME-1 regulates PP2A function are highly complex. However, PME-1 functions can be broadly divided into two main categories: (1) catalytic methylesterase (demethylation) activity and (2) direct inhibitory function toward PP2A-C catalytic site. However, a distinction between the functional relevance of these two PME-1 functions for some PP2A regulatory mechanisms is yet unclear because of insufficient experimental evidence.

PME-1 methylesterase regulates B-subunit binding and substrate specificity

The methylation status of PP2A-C is tightly linked with PP2A biogenesis and substrate specificity regulation. A methyltransferase enzyme LCMT-1 adds methyl group (methylation) to the free carboxyl group of PP2A-C Leu309, utilizing S-adenosylmethionine in the reaction [18]. In a reversible reaction, PME-1 removes this methyl group (demethylation) [17] (Figure 21). The PME-1 knockout (KO) mouse studies have indicated that PME-1 is the sole PP2A methylesterase, and that the demethylated PP2A is essential for normal cellular functioning in perinatal development [30].

Various modes of PP2A regulation by PME-1.

Figure 2.
Various modes of PP2A regulation by PME-1.

(1) PME-1 and LCMT-1 regulate PP2A-C methylation and B-subunit selection, and thereby influence the substrate specificity. (2A) PME-1 binding removes Mn2+ ions from the PP2A active site and inhibits its activity. (2B) PME-1 binding inhibits PP2A possibly by altering its conformation. (3) PME-1 protects PP2A-C from proteasome degradation.

Figure 2.
Various modes of PP2A regulation by PME-1.

(1) PME-1 and LCMT-1 regulate PP2A-C methylation and B-subunit selection, and thereby influence the substrate specificity. (2A) PME-1 binding removes Mn2+ ions from the PP2A active site and inhibits its activity. (2B) PME-1 binding inhibits PP2A possibly by altering its conformation. (3) PME-1 protects PP2A-C from proteasome degradation.

Biochemical and functional analyses have identified an important role for PP2A-C Leu309 methylation status in selective binding of certain B-subunits to PP2A-AC dimer (Figure 21). Initial experiments using PP2A-C Leu309 mutants and purified PP2A complexes suggested methylation to be required for the binding of PPP2R5 (PR61) and, to a great extent, for PPP2R2 (PR55) subunits [31,32]. Further studies have shown a less stringent requirement for methylated PP2A-C for the binding of PPP2R5 (PR61) and PPP2R3 (PR72) subunits under the conditions where PPP2R2 (PR55) exclusively binds methylated PP2A-C [24,33,34]. Moreover, the PME-1 KO mouse embryonic fibroblasts (MEFs) display increased association of PPP2R2A (PR55α) with PP2A-A and PP2A-C subunits when compared with wild-type MEFs, whereas no difference is observed in the PPP2R5A (PR61α) binding [35]. The binding of STRN family subunits, such as STRN and SG2NA, appears to be unaffected by the methylation status of PP2A-C [24]. Strikingly, indicative data show that some STRN family B-subunits might prefer the unmethylated PP2A-C [24]. It should be stated that several contradictory in vitro and in vivo studies have been reported over the years, confirming or disproving the above-mentioned individual findings [4,18,24,3133,36,37]. However, the overall consensus is that PP2A-C Leu309 methylation is an important regulatory mechanism that defines which of the distinct sets of B-subunits bind to PP2A-AC dimer and consequently, what type of active PP2A holoenzymes exists in cells [15,25]. This model is depicted in Figure 21.

Importantly, as different PP2A (B-subunit) complexes dephosphorylate a different set of target proteins [6,7], the altered balance between activities of LCMT-1 and PME-1 toward PP2A-C Leu309 can dynamically affect PP2A function. Consistent with this view, PME-1 knockdown in cancer cells results in dephosphorylation of PP2A targets, ERK and AKT [38,39], which is similar to the effects seen in PME-1 KO MEFs [35]. PME-1 KO mouse brain tissues also display differential phosphorylation of several proteins, especially those involved in signal transduction, transcriptional regulation, and cytoskeleton [30]. However, PME-1 down-regulation in skeletal muscle cells renders the PP2A complexes incompetent in dephosphorylating another target Na+,K+-ATPase α-subunit [40]. Thus, loss of PME-1 affects the composition of active PP2A complexes and eventually the substrate specificity.

PME-1 binding inhibits PP2A catalytic activity

Earlier studies focused on the influence of PP2A-C methylation on PP2A catalytic activity reported conflicting results [18,32,37]. The effect of PME-1 on PP2A catalytic activity remained inconclusive until the structural analysis of PME-1–PP2A complex revealed an additional mode of PP2A regulation. In this view, PME-1 binds to PP2A-C (in AC dimer) active site forming an interaction interface containing several hydrogen bonds and other covalent interactions [28]. These in vitro findings have been recently confirmed by a point mutation of PME-1 on an interaction interface residue arginine 369 (R369D), which results in complete loss of PME-1 binding to PP2A-C in prostate cancer PC-3 cells [41]. PME-1 binding-mediated eviction of catalytic manganese (Mn2+) ions from the PP2A active site was identified as the mechanism resulting in PP2A inhibition, for instance, toward phosphorylase a substrate (Figure 22A) [28,36]. It was further concluded that PME-1 binding-mediated removal of Mn2+ ions from PP2A-C requires stable and long-term interaction between PME-1 and PP2A-C [28]. In addition to this in vitro evidence, PME-1 silencing in endometrial cancer RL95-2 cells results in increased phosphatase activity of immunopurified PP2A-C complex [39]. A possible explanation for PME-1-mediated direct inhibition of PP2A-C catalytic activity could be a requirement to retain PP2A-AC dimers catalytically inactive before binding to a substrate recognizing B-subunit, so as to prevent promiscuous PP2A-C activity [15,36,42].

Interestingly, several researchers have isolated distinct pools of inactive PP2A complexes, mostly those containing core dimers and less frequently also heterotrimers bound to PME-1 [17,29,32,36,42]. PP2A-C in some of the inactive complexes was shown to be reactivated by the addition of a combination of PTPA enzyme, ATP, and Mg2+in vitro, whereas other complexes could be reactivated by only Mn2+ (Figure 22) [36]. Whereas the Mn2+-elicited PP2A-C reactivation could be attributed to balancing out the Mn2+-evicting function of PME-1 (Figure 22A), reactivation by PTPA has been explained to be mediated by at least two potentially separate functions (Figure 22B). First, PTPA activity releases PME-1 from PP2A core dimers [36]. Secondly, it is known that PP2A-C within an inactive core dimer requires a conformational change to generate an active conformation before it can bind to the B-subunits [36,43]. This activation is carried out by a peptidyl-prolyl cis/trans-isomerase activity of PTPA (Figure 22B) [36,42,44,45]. Additionally, PTPA can activate the weak intrinsic phospho-tyrosyl phosphatase (PTPase) activity of PP2A leading to dephosphorylation of PP2A-C Tyr307, which is another important player in determining B-subunit binding and its phospho-Ser/Thr phosphatase (PSTPase) activity [46,47]. Moreover, PTPA binding to PP2A core dimer has been proposed to induce a composite ATPase activity which might be required for both PTPase and PSTPase activities of PP2A [5]. Importantly, PTPA is not only relevant in the context of inhibited PP2A, but also implicated in PP2A holoenzyme biogenesis [15].

Even though the two principal mechanisms by which PME-1 affects PP2A activity, PP2A-C demethylation and active site binding seem separate, some studies indicate that they actually can be interconnected. The structural studies demonstrated that PME-1 binding to PP2A-C catalytic site activates the methylesterase activity [28]. Moreover, a mutation of the PME-1 methylesterase active site (Ser156) increases its binding to PP2A-C, which remains methylated but inactive [29,39]. It is also suggested that PME-1 dissociates from PP2A once the demethylation reaction is complete. All these evidence indicate for a sequential model where PME-1 first binds to PP2A-C catalytic site to initiate PP2A-C activity inhibition, and this binding allows a subsequent conformational change in PME-1 that activates the methylesterase activity toward PP2A-C Leu309. However, it is clear that due to very complex interplay between different factors implicated in PP2A regulation by PME-1, comprehensive understanding of this process will require substantial further research.

Other PME-1-related regulatory mechanisms

A recent report has suggested that PME-1 methylesterase activity protects PP2A-C from ubiquitin/proteasome degradation in MEFs (Figure 23) [35]. The PME-1 KO MEFs as well as the heart and liver tissue from newborn mouse demonstrate reduction in the total PP2A-C level when compared with those from wild-type mouse [30,35]. However, it is unclear whether this PME-1 function can be generalized to cancer cells as PME-1 knockdown by shRNA was shown to reduce PP2A-C protein only in one of three cancer cell lines tested [35].

Genetic alterations of PPME1 in human cancer types.

Figure 3.
Genetic alterations of PPME1 in human cancer types.

The analysis was performed at cBioPortal website using all available cancer types. Selected cancer studies with >3% total alterations in PPME1 are shown here.

Figure 3.
Genetic alterations of PPME1 in human cancer types.

The analysis was performed at cBioPortal website using all available cancer types. Selected cancer studies with >3% total alterations in PPME1 are shown here.

In addition to PP2A-C, PME-1 has also been shown to bind to the catalytic subunit of PP4 (PPP4C) in a co-immunoprecipitation experiment [39]. Given that PP4 is also methylated by LCMT-1 and its role in DNA repair and other cellular functions, future studies might reveal PP2A-independent functions of PME-1.

Regulation of PME-1

PME-1 itself is subjected to regulation by PTMs, possibly phosphorylated by Chk1 (checkpoint kinase 1), SIK1 (salt-inducible kinase 1), and CaMKI (calcium calmodulin-dependent kinase 1). PME-1 phosphorylated at Ser 15 was first identified as the potential Chk1 substrate in a phosphoproteomic screen [48]. PME-1 phosphorylation by SIK1 (at unidentified site) promotes its dissociation from PP2A [49]. On the contrary, CaMKI-mediated phosphorylation at Ser15 can possibly promote its binding to PP2A either directly or indirectly via phosphorylation and degradation of SIK2 [50]. Moreover, two conflicting reports have implicated GSK-3β in the indirect regulation of PME-1 expression and PP2A activity in neuronal cells [51,52]. Related to this, a recent study showed that brain-specific PME-1 transgene expression in mice exaggerates the β-amyloid-induced pathologies in Alzheimer's disease [53]. At transcript level, an oncofetal protein IMP1 has been suggested to stabilize PPME1 mRNA and to promote migration and invasion of choriocarcinoma JAR cells [54]. Finally, the first PME-1 interactome analysis from cancer cells has been reported [41]. Further research efforts are required to understand the role of these proteins and other mechanisms regulating PME-1 activity toward PP2A in normal and cancerous cells.

PME-1 chemical inhibitors

Two different families of nanomolar range, selective PME-1 methylesterase (serine hydrolase) activity inhibitors have been described: the aza-β-lactum inhibitor ABL127 [55] and the sulfonyl acrylonitrile inhibitor AMZ30 [56]. Both inhibitors covalently bind to the active site Ser156 of PME-1 and irreversibly inactivate it, though ABL127 (IC50 = 10 nM) is a more potent inhibitor of PME-1 methylesterase than AMZ30 (IC50 = 500 nM) [55,56]. Treatment with these inhibitors reduces demethylated PP2A-C levels in MEFs, HEK-293T, MDA-MB-231, and HeLa cells [35,5557]. However, an increase in methylated PP2A-C upon inhibitor treatment could be observed only in cells expressing exogenous PME-1 [55,56]. AMZ30 treatment (20 µM) in HeLa cells has been shown to induce abnormal shortening of metaphase spindles, mitotic arrest, and cell death in a significant fraction of cells [57]. Notably, some of the cellular effects observed with AMZ30 could be nonspecific or cell-type specific. In HEK-293T cells, much higher concentration of AMZ30 is required for cytotoxicity (CC50 = 100 µM) when compared with the concentration that inhibits PP2A demethylation (20 µM) [58].

PME-1 inhibition by either ABL127 (50 nM) or AMZ30 (25 µM) treatment inhibits the growth and migration of endometrial cancer cells in vitro, but a single-dose intratumor ABL127 treatment (5 mg/kg) has failed to suppress tumor growth in mouse xenografts [59]. Conversely, PME-1 knockdown by siRNA or shRNA inhibits cancer cell growth not only in in vitro but also in in vivo endometrial cancer xenograft models [39,59]. An acute intraperitoneal treatment with ABL127 (50 mg/kg, 2 h) has shown 35% reduction in demethylated PP2A-C in mouse brain tissue [55]. However, systemically delivered PME-1 inhibitors have not yet been tested in any human cancer xenograft study, probably due to their poor solubility as recently indicated [59].

In conclusion, a lack of clear PP2A-regulated cellular effects with PME-1 inhibitors, despite their potent inhibition of methylesterase activity, further indicates that direct PP2A-C catalytic activity inhibition might be a dominant mechanism by which PME-1 influences cellular signaling. Thereby, alternative to methylesterase inhibitors, PME-1 inhibitors capable of disrupting its binding to PP2A-C, or RNAi-mediated targeting, might provide an approach to reactivate PP2A tumor suppressor activity in cancer.

Oncogenic activities of PME-1

Using immortalized human embryonic kidney cells weakly transformed by down-regulation of PPP2R5C/PR61γ and overexpression of Ras (HEK-TERASB56γ) as a model system, LCMT-1 and PME-1 have been identified as negative and positive regulators of malignant growth in anchorage-independent conditions, respectively [60]. Alteration in the PP2A methylation by knockdown of LCMT-1 or overexpression of PME-1 contributes to malignant growth in these cells by increased phosphorylation and activation of AKT and p70/p85-S6K pathways [60]. Interestingly, none of these alterations were detectable under anchorage-dependent culture conditions [60].

An oncogenic role of PME-1 has been described in human gliomas, where MAPK/ERK signaling was identified as a PME-1-regulated PP2A target pathway [38]. PME-1 silencing in cultured cells increases the association of PP2A with MEK complex, resulting in dephosphorylation of MEK and downstream ERK and Elk-1 proteins. Furthermore, the MAPK/ERK pathway inhibition by PP2A is regulated by PME-1 at a level downstream of Ras and upstream of Raf [38]. In gliomas, PME-1 depletion inhibits the proliferation and anchorage-independent growth of cancer cell lines, without inducing apoptosis [38]. More recently, reactivation of specific PP2A complexes by PME-1 depletion has been shown to sensitize glioma cells to multikinase inhibitors [61]. In addition to synthetic lethality observed in cell culture, PME-1 negative glioma xenografts showed increased sensitivity to UCN-01 treatment in vivo. The PME-1-elicited resistance was mediated by a decrease in cytoplasmic HDAC4 activity. Importantly, both PME-1 and HDAC4 associated with human glioma progression, supporting clinical relevance of the identified mechanism. Thus, PME-1 expression confers therapy resistance in gliomas, strengthening the candidacy of PME-1 as a therapy target in this cancer type. Similar to glioma, in endometrial cancer cells, PP2A inhibition by PME-1 promotes cell proliferation and pro-survival ERK and AKT signaling [39]. These researchers also reported the first instance of in vivo tumor growth promoting the function of PME-1 using a subcutaneous ECC-1 endometrial carcinoma cell xenograft mouse model [39].

Paradoxically, PME-1 silencing in colorectal cancer (CRC) cells does not affect cell viability or inhibit phosphorylation of AKT and ERK survival proteins [62]. It can be speculated that the presence of other PP2A inactivation mechanisms may abolish the PP2A regulatory function of PME-1. For instance, mutation or deletion of PPP2R1B (PP2A-Aβ subunit) occurs in 8–15% of CRCs, altering its interaction with PP2A-C subunit and inhibiting overall PP2A activity [63]. Among the methylation-sensitive B-subunits, repressed protein expression of PPP2R2A (PR55α) subunit has been detected in ∼42% (n = 21) [64], and epigenetic silencing of PPP2R2B (PR55β) by promoter hypermethylation has been detected in >90% of CRC tumors (n = 24) [65]. Additionally, elevated expression of other PP2A inhibitory proteins, such as CIP2A, occurs in majority of CRCs (80 to >90%), and SET occurs in 25% of metastatic CRC tumors [64,66]. CIP2A and SET expression associates with chemoresistance, aggressive tumor growth, and poor patient prognosis. It is possible that ‘low’ PME-1-expressing tumors have a compensatory increase in CIPA or SET expression, which might explain the paradoxical results of PME-1 in CRC. Moreover, oncogenic B-RafV600E mutation renders the AKT-overexpressing HEK-T cells resistant to PME-1 silencing-mediated dephosphorylation of ERK and cell growth inhibition [38]. The B-RafV600E mutation occurs in 5–15% of all CRCs and ∼80% of the tumors that display microsatellite instability [67]. These alterations might also contribute to the constitutive downstream ERK pathway signaling and insensitivity of CRC cells to PME-1-regulated functions [62].

Thus, PME-1 promotes oncogenic MAPK/ERK and AKT signaling and anchorage-independent growth. Given the importance of these Ras downstream pathways in cancers, reactivation of PP2A by PME-1 inhibition might be a promising therapeutic strategy in subsets of Ras-driven cancers which do not contain activating mutations in Raf or other downstream proteins.

PME-1 expression in patient tumor material

Primary astrocytic glioma is the first cancer type where PME-1 expression has been assessed by immunohistochemical methods [38]. Approximately 50% of glioma tumor samples show PME-1 positivity. In line with the cell culture studies, PME-1 expression shows a strong correlation with phospho-MEK, phospho-Elk-1, and cell proliferation index (Ki67) in glioma patient tumor samples [38]. A strong association is found between PME-1 staining and tumor grade (grades II–IV), suggesting an oncogenic role for PME-1 with increasing malignancy of glioma tumors. The analysis of PPME1 mRNA and protein expression in a small panel (n = 30) of type I endometrioid adenocarcinoma samples has demonstrated enhanced expression of PME-1 in tumor samples when compared with matched normal adjacent tissue [39].

A study in Chinese gastric and lung cancer patient cohort has described the existence of a small subset (∼3%) of patients with amplification of PPME1 [68]. The functional studies performed using PPME1-amplified versus -non-amplified gastric and lung cancer cell lines illustrate that PME-1-regulated PP2A activity and pro-survival functions might be the driving factors in cancer cells that are dependent on PME-1 (synonymous with the oncogene addiction phenotype of cancer) [68]. PME-1 knockdown resulted in decreased PP2A-C demethylation, and AKT (Ser473) and ERK (Thr202) phosphorylation in PPME1-amplified cancer cells [68]. Similarly, inhibition of cell viability and induction of apoptosis upon PME-1 knockdown were also specifically seen in PPME1-amplified cells.

Opposite to other cancer types, high expression of PME-1 correlates with less recurrence and longer patient survival in CRC [62]. The PME-1 expression analysis at both the mRNA and protein level, from two independent patient cohorts with almost 200 or more patients per cohort, has provided a convincing evidence of the existence of an unexpected role of PME-1 in CRC [61]. As discussed, this raises the possibility that the PME-1/PP2A or PP2A/target circuit might be broken in these cells.

In the absence of any other published reports, the copy number alterations and mutations of PPME1 were analyzed in the online cancer database cBioPortal (www.cbioportal.org) (Figure 3). A very high frequency of PPME1 amplification (21%) is found in neuroendocrine prostate cancer (NEPC) tumors (www.cbioportal.org). High frequency of PPME1 amplifications is also detected in carcinomas of serous ovarian (8.7%), esophageal (8.2%), head and neck squamous cell (5%), bladder urothelial (4.7%), breast (4.5%), melanoma (4%), and lung (3.5%) from published or provisional TCGA datasets (www.cancergenome.nih.gov). The PPME1 amplifications in GBM and CRC are found in <0.5% of cases reported by TCGA network studies. No recurrent mutations of PME-1 could be detected in any cancer type (www.cbioportal.org).

Abbreviations

     
  • CaMKI

    calmodulin-dependent kinase 1

  •  
  • Chk1

    checkpoint kinase 1

  •  
  • CIP2A

    cancerous inhibitor of PP2A

  •  
  • CRC

    colorectal cancer

  •  
  • DFP

    diisopropyl fluorophosphate

  •  
  • DUSPs

    dual specificity phosphatases

  •  
  • GSK-3β

    glycogen synthase kinase-3β

  •  
  • KO

    knockout

  •  
  • LCMT-1

    leucine carboxylmethyltransferase-1

  •  
  • MEFs

    mouse embryonic fibroblasts

  •  
  • Mn2+

    manganese

  •  
  • PME-1

    phosphatase methylesterase-1

  •  
  • PMSF

    phenylmethylsulfonyl fluoride

  •  
  • PP2A

    protein phosphatase 2A

  •  
  • PSTPs

    serine/threonine phosphatases

  •  
  • PTM

    posttranslational modification

  •  
  • PTPA

    protein phosphatase 2A activator

  •  
  • PTPs

    tyrosine phosphatases

  •  
  • SIK1

    salt-inducible kinase 1

  •  
  • Striatin

    STRN

  •  
  • TIP

    type 2A­-interacting protein

Funding

The original work by authors was supported by the financial support from Sigrid Juselius Foundation, Cancer Society of Finland, Academy of Finland [grant 252572], and Jane and Aatos Erkko Foundation to J.W., and funded by Turku Doctoral Programme of Biomedical Sciences (TuBS) and Turku Doctoral Programme of Molecular Medicine (TuDMM), University of Turku, Orion Research Foundation, Instrumentarium Science Foundation, K. Albin Johanssons Foundation, and Turku University Foundation to A.K. J.W. holds a Research Professor position supported by the Foundation of Finnish Cancer Institute.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

References

References
1
Shi
,
Y.
(
2009
)
Serine/threonine phosphatases: mechanism through structure
.
Cell
139
,
468
484
doi:
2
Brautigan
,
D.L.
(
2013
)
Protein Ser/Thr phosphatases — the ugly ducklings of cell signalling
.
FEBS J.
280
,
324
325
doi:
3
Kremmer
,
E.
,
Ohst
,
K.
,
Kiefer
,
J.
,
Brewis
,
N.
and
Walter
,
G.
(
1997
)
Separation of PP2A core enzyme and holoenzyme with monoclonal antibodies against the regulatory a subunit: abundant expression of both forms in cells
.
Mol. Cell. Biol.
17
,
1692
1701
doi:
4
Xing
,
Y.
,
Xu
,
Y.
,
Chen
,
Y.
,
Jeffrey
,
P.D.
,
Chao
,
Y.
,
Lin
,
Z.
et al. 
(
2006
)
Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins
.
Cell
127
,
341
353
doi:
5
Guo
,
F.
,
Stanevich
,
V.
,
Wlodarchak
,
N.
,
Sengupta
,
R.
,
Jiang
,
L.
,
Satyshur
,
K.A.
et al. 
(
2014
)
Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone
.
Cell Res.
24
,
190
203
doi:
6
Eichhorn
,
P.J.
,
Creyghton
,
M.P.
and
Bernards
,
R.
(
2009
)
Protein phosphatase 2A regulatory subunits and cancer
.
Biochim. Biophys. Acta Rev. Cancer
1795
,
1
15
doi:
7
Slupe
,
A.M.
,
Merrill
,
R.A.
and
Strack
,
S.
(
2011
)
Determinants for substrate specificity of protein phosphatase 2A
.
Enzyme Res.
2011
,
398751
doi:
8
Hertz
,
E.P.T.
,
Kruse
,
T.
,
Davey
,
N.E.
,
López-Méndez
,
B.
,
Sigurðsson
,
J.O.
,
Montoya
,
G.
et al. 
(
2016
)
A conserved motif provides binding specificity to the PP2A-B56 phosphatase
.
Mol. Cell
63
,
686
695
doi:
9
Sontag
,
J.-M.
and
Sontag
,
E.
(
2014
)
Protein phosphatase 2A dysfunction in Alzheimer's disease
.
Front. Mol. Neurosci.
7
,
16
doi:
10
Fujiwara
,
N.
,
Usui
,
T.
,
Ohama
,
T.
and
Sato
,
K.
(
2016
)
Regulation of Beclin 1 protein phosphorylation and autophagy by protein phosphatase 2A (PP2A) and death-associated protein kinase 3 (DAPK3)
.
J. Biol. Chem.
291
,
10858
10866
doi:
11
Wong
,
P.-M.
,
Feng
,
Y.
,
Wang
,
J.
,
Shi
,
R.
and
Jiang
,
X.
(
2015
)
Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A
.
Nat. Commun.
6
,
8048
doi:
12
Janssens
,
V.
and
Rebollo
,
A.
(
2012
)
The role and therapeutic potential of Ser/Thr phosphatase PP2A in apoptotic signalling networks in human cancer cells
.
Curr. Mol. Med.
12
,
268
287
doi:
13
Junttila
,
M.R.
,
Li
,
S.-P.
and
Westermarck
,
J.
(
2008
)
Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival
.
FASEB J.
22
,
954
965
doi:
14
Kurimchak
,
A.
and
Graña
,
X.
(
2015
)
PP2A: more than a reset switch to activate pRB proteins during the cell cycle and in response to signaling cues
.
Cell Cycle
14
,
18
30
doi:
15
Sents
,
W.
,
Ivanova
,
E.
,
Lambrecht
,
C.
,
Haesen
,
D.
and
Janssens
,
V.
(
2013
)
The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity
.
FEBS J.
280
,
644
661
doi:
16
Lee
,
J.
,
Chen
,
Y.
,
Tolstykh
,
T.
and
Stock
,
J.
(
1996
)
A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain
.
Proc. Natl Acad. Sci. USA
93
,
6043
6047
doi:
17
Ogris
,
E.
,
Du
,
X.
,
Nelson
,
K.C.
,
Mak
,
E.K.
,
Yu
,
X.X.
,
Lane
,
W.S.
et al. 
(
1999
)
A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A
.
J. Biol. Chem.
274
,
14382
14391
doi:
18
De Baere
,
I.
,
Derua
,
R.
,
Janssens
,
V.
,
Van Hoof
,
C.
,
Waelkens
,
E.
,
Merlevede
,
W.
et al. 
(
1999
)
Purification of porcine brain protein phosphatase 2A leucine carboxyl methyltransferase and cloning of the human homologue
.
Biochemistry
38
,
16539
16547
doi:
19
Schmitz
,
M.H.
,
Held
,
M.
,
Janssens
,
V.
,
Hutchins
,
J.R.A.
,
Hudecz
,
O.
,
Ivanova
,
E.
et al. 
(
2010
)
Live-cell imaging RNAi screen identifies PP2A-B55α and importin-β1 as key mitotic exit regulators in human cells
.
Nat. Cell Biol.
12
,
886
893
doi:
20
Xiong
,
Y.
,
Jing
,
X.-P.
,
Zhou
,
X.-W.
,
Wang
,
X.-L.
,
Yang
,
Y.
,
Sun
,
X.-Y.
et al. 
(
2013
)
Zinc induces protein phosphatase 2A inactivation and tau hyperphosphorylation through Src dependent PP2A (tyrosine 307) phosphorylation
.
Neurobiol. Aging
34
,
745
756
doi:
21
Yao
,
X.-Q.
,
Zhang
,
X.-X.
,
Yin
,
Y.-Y.
,
Liu
,
B.
,
Luo
,
D.-J.
,
Liu
,
D.
et al. 
(
2011
)
Glycogen synthase kinase-3β regulates Tyr307 phosphorylation of protein phosphatase-2A via protein tyrosine phosphatase 1B but not Src
.
Biochem. J.
437
,
335
344
doi:
22
Chen
,
J.
,
Martin
,
B.L.
and
Brautigan
,
D.L.
(
1992
)
Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation
.
Science
257
,
1261
1264
doi:
23
Guo
,
H.
and
Damuni
,
Z.
(
1993
)
Autophosphorylation-activated protein kinase phosphorylates and inactivates protein phosphatase 2A
.
Proc. Natl Acad. Sci. USA
90
,
2500
2504
doi:
24
Yu
,
X.X.
,
Du
,
X.
,
Moreno
,
C.S.
,
Green
,
R.E.
,
Ogris
,
E.
,
Feng
,
Q.
et al. 
(
2001
)
Methylation of the protein phosphatase 2A catalytic subunit is essential for association of Bα regulatory subunit but not SG2NA, striatin, or polyomavirus middle tumor antigen
.
Mol. Biol. Cell
12
,
185
199
doi:
25
Janssens
,
V.
,
Longin
,
S.
and
Goris
,
J.
(
2008
)
PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)
.
Trends Biochem. Sci.
33
,
113
121
doi:
26
Lambrecht
,
C.
,
Haesen
,
D.
,
Sents
,
W.
,
Ivanova
,
E.
and
Janssens
,
V.
(
2013
)
Structure, regulation, and pharmacological modulation of PP2A phosphatases
.
Methods Mol. Biol.
1053
,
283
305
doi:
27
Khanna
,
A.
,
Pimanda
,
J.E.
and
Westermarck
,
J.
(
2013
)
Cancerous inhibitor of protein phosphatase 2A, an emerging human oncoprotein and a potential cancer therapy target
.
Cancer Res.
73
,
6548
6553
doi:
28
Xing
,
Y.
,
Li
,
Z.
,
Chen
,
Y.
,
Stock
,
J.B.
,
Jeffrey
,
P.D.
and
Shi
,
Y.
(
2008
)
Structural mechanism of demethylation and inactivation of protein phosphatase 2A
.
Cell
133
,
154
163
doi:
29
Longin
,
S.
,
Zwaenepoel
,
K.
,
Martens
,
E.
,
Louis
,
J.V.
,
Rondelez
,
E.
,
Goris
,
J.
et al. 
(
2008
)
Spatial control of protein phosphatase 2A (de)methylation
.
Exp. Cell Res.
314
,
68
81
doi:
30
Ortega-Gutiérrez
,
S.
,
Leung
,
D.
,
Ficarro
,
S.
,
Peters
,
E.C.
and
Cravatt
,
B.F.
(
2008
)
Targeted disruption of the PME-1 gene causes loss of demethylated PP2A and perinatal lethality in mice
.
PLoS ONE
3
,
e2486
doi:
31
Bryant
,
J.C.
,
Westphal
,
R.S.
and
Wadzinski
,
B.E.
(
1999
)
Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory Bα subunit
.
Biochem. J.
339
(
Pt 2
),
241
246
doi:
32
Tolstykh
,
T.
,
Lee
,
J.
,
Vafai
,
S.
and
Stock
,
J.B.
(
2000
)
Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits
.
EMBO J.
19
,
5682
5691
doi:
33
Xu
,
Y.
,
Xing
,
Y.
,
Chen
,
Y.
,
Chao
,
Y.
,
Lin
,
Z.
,
Fan
,
E.
et al. 
(
2006
)
Structure of the protein phosphatase 2A holoenzyme
.
Cell
127
,
1239
1251
doi:
34
Longin
,
S.
,
Zwaenepoel
,
K.
,
Louis
,
J.V.
,
Dilworth
,
S.
,
Goris
,
J.
and
Janssens
,
V.
(
2007
)
Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic subunit
.
J. Biol. Chem.
282
,
26971
26980
doi:
35
Yabe
,
R.
,
Miura
,
A.
,
Usui
,
T.
,
Mudrak
,
I.
,
Ogris
,
E.
,
Ohama
,
T.
et al. 
(
2015
)
Protein phosphatase methyl-esterase PME-1 protects protein phosphatase 2A from ubiquitin/proteasome degradation
.
PLoS ONE
10
,
e0145226
doi:
36
Longin
,
S.
,
Jordens
,
J.
,
Martens
,
E.
,
Stevens
,
I.
,
Janssens
,
V.
,
Rondelez
,
E.
et al. 
(
2004
)
An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator
.
Biochem. J.
380
,
111
119
doi:
37
Ikehara
,
T.
,
Ikehara
,
S.
,
Imamura
,
S.
,
Shinjo
,
F.
and
Yasumoto
,
T.
(
2007
)
Methylation of the C-terminal leucine residue of the PP2A catalytic subunit is unnecessary for the catalytic activity and the binding of regulatory subunit (PR55/B)
.
Biochem. Biophys. Res. Commun.
354
,
1052
1057
doi:
38
Puustinen
,
P.
,
Junttila
,
M.R.
,
Vanhatupa
,
S.
,
Sablina
,
A.A.
,
Hector
,
M.E.
,
Teittinen
,
K.
et al. 
(
2009
)
PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma
.
Cancer Res.
69
,
2870
2877
doi:
39
Wandzioch
,
E.
,
Pusey
,
M.
,
Werda
,
A.
,
Bail
,
S.
,
Bhaskar
,
A.
,
Nestor
,
M.
et al. 
(
2014
)
PME-1 modulates protein phosphatase 2A activity to promote the malignant phenotype of endometrial cancer cells
.
Cancer Res.
74
,
4295
4305
doi:
40
Benziane
,
B.
,
Bjornholm
,
M.
,
Pirkmajer
,
S.
,
Austin
,
R.L.
,
Kotova
,
O.
,
Viollet
,
B.
et al. 
(
2012
)
Activation of AMP-activated protein kinase stimulates Na+, K+-ATPase activity in skeletal muscle cells
.
J. Biol. Chem.
287
,
23451
23463
doi:
41
Pokharel
,
Y.R.
,
Saarela
,
J.
,
Szwajda
,
A.
,
Rupp
,
C.
,
Rokka
,
A.
,
Lal Karna
,
S.K.
et al. 
(
2015
)
Relevance rank platform (RRP) for functional filtering of high content protein-protein interaction data
.
Mol. Cell. Proteomics
14
,
3274
3283
doi:
42
Hombauer
,
H.
,
Weismann
,
D.
,
Mudrak
,
I.
,
Stanzel
,
C.
,
Fellner
,
T.
,
Lackner
,
D.H.
et al. 
(
2007
)
Generation of active protein phosphatase 2A is coupled to holoenzyme assembly
.
PLoS Biol.
5
,
e155
doi:
43
Stanevich
,
V.
,
Jiang
,
L.
,
Satyshur
,
K.A.
,
Li
,
Y.
,
Jeffrey
,
P.D.
,
Li
,
Z.
et al. 
(
2011
)
The structural basis for tight control of PP2A methylation and function by LCMT-1
.
Mol. Cell
41
,
331
342
doi:
44
Jordens
,
J.
,
Janssens
,
V.
,
Longin
,
S.
,
Stevens
,
I.
,
Martens
,
E.
,
Bultynck
,
G.
et al. 
(
2006
)
The protein phosphatase 2A phosphatase activator is a novel peptidyl-prolyl cis/trans-isomerase
.
J. Biol. Chem.
281
,
6349
6357
doi:
45
Leulliot
,
N.
,
Vicentini
,
G.
,
Jordens
,
J.
,
Quevillon-Cheruel
,
S.
,
Schiltz
,
M.
,
Barford
,
D.
et al. 
(
2006
)
Crystal structure of the PP2A phosphatase activator: implications for its PP2A-specific PPIase activity
.
Mol. Cell
23
,
413
424
doi:
46
Fellner
,
T.
,
Lackner
,
D.H.
,
Hombauer
,
H.
,
Piribauer
,
P.
,
Mudrak
,
I.
,
Zaragoza
,
K.
et al. 
(
2003
)
A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo
.
Genes Dev.
17
,
2138
2150
doi:
47
Luo
,
Y.
,
Nie
,
Y.-J.
,
Shi
,
H.-R.
,
Ni
,
Z.-F.
,
Wang
,
Q.
,
Wang
,
J.-Z.
et al. 
(
2013
)
PTPA activates protein phosphatase-2A through reducing its phosphorylation at tyrosine-307 with upregulation of protein tyrosine phosphatase 1B
.
Biochim. Biophys. Acta Mol. Cell Res.
1833
,
1235
1243
doi:
48
Blasius
,
M.
,
Forment
,
J.V.
,
Thakkar
,
N.
,
Wagner
,
S.A.
,
Choudhary
,
C.
and
Jackson
,
S.P.
(
2011
)
A phospho-proteomic screen identifies substrates of the checkpoint kinase Chk1
.
Genome Biol.
12
,
R78
doi:
49
Sjostrom
,
M.
,
Stenstrom
,
K.
,
Eneling
,
K.
,
Zwiller
,
J.
,
Katz
,
A.I.
,
Takemori
,
H.
et al. 
(
2007
)
SIK1 is part of a cell sodium-sensing network that regulates active sodium transport through a calcium-dependent process
.
Proc. Natl Acad. Sci. USA
104
,
16922
16927
doi:
50
Lee
,
C.-W.
,
Yang
,
F.-C.
,
Chang
,
H.-Y.
,
Chou
,
H.
,
Tan
,
B.C.-M.
and
Lee
,
S.-C.
(
2014
)
Interaction between salt-inducible kinase 2 and protein phosphatase 2A regulates the activity of calcium/calmodulin-dependent protein kinase I and protein phosphatase methylesterase-1
.
J. Biol. Chem.
289
,
21108
21119
doi:
51
Wang
,
Y.
,
Yang
,
R.
,
Gu
,
J.
,
Yin
,
X.
,
Jin
,
N.
,
Xie
,
S.
et al. 
(
2015
)
Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation
.
Neurobiol. Aging
36
,
188
200
doi:
52
Yao
,
X.-Q.
,
Li
,
X.-C.
,
Zhang
,
X.-X.
,
Yin
,
Y.-Y.
,
Liu
,
B.
,
Luo
,
D.-J.
et al. 
(
2012
)
Glycogen synthase kinase-3β regulates leucine-309 demethylation of protein phosphatase-2A via PPMT1 and PME-1
.
FEBS Lett.
586
,
2522
2528
doi:
53
Nicholls
,
R.E.
,
Sontag
,
J.-M.
,
Zhang
,
H.
,
Staniszewski
,
A.
,
Yan
,
S.
,
Kim
,
C.Y.
et al. 
(
2016
)
PP2A methylation controls sensitivity and resistance to β-amyloid-induced cognitive and electrophysiological impairments
.
Proc. Natl Acad. Sci. USA
113
,
3347
3352
doi:
54
Hsieh
,
Y.-T.
,
Chou
,
M.-M.
,
Chen
,
H.-C.
and
Tseng
,
J.-J.
(
2013
)
IMP1 promotes choriocarcinoma cell migration and invasion through the novel effectors RSK2 and PPME1
.
Gynecol. Oncol.
131
,
182
190
doi:
55
Bachovchin
,
D.A.
,
Mohr
,
J.T.
,
Speers
,
A.E.
,
Wang
,
C.
,
Berlin
,
J.M.
,
Spicer
,
T.P.
et al. 
(
2011
)
Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors
.
Proc. Natl Acad. Sci. USA
108
,
6811
6816
doi:
56
Bachovchin
,
D.A.
,
Zuhl
,
A.M.
,
Speers
,
A.E.
,
Wolfe
,
M.R.
,
Weerapana
,
E.
,
Brown
,
S.J.
et al. 
(
2011
)
Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1
.
J. Med. Chem.
54
,
5229
5236
doi:
57
Xia
,
X.
,
Gholkar
,
A.
,
Senese
,
S.
and
Torres
,
J.Z.
(
2015
)
A LCMT1-PME-1 methylation equilibrium controls mitotic spindle size
.
Cell Cycle
14
,
1938
1947
doi:
58
Bachovchin
,
D.A.
,
Speers
,
A.E.
,
Zuhl
,
A.M.
,
Brown
,
S.J.
,
Cravatt
,
B.F.
,
Fernandez
,
V.
et al. 
(
2010
) Probe report for PME-1 inhibitors. In
Probe Reports From the NIH Molecular Libraries Program
,
National Center for Biotechnology Information (USA)
,
Bethesda (MD)
59
Pusey
,
M.
,
Bail
,
S.
,
Xu
,
Y.
,
Buiakova
,
O.
,
Nestor
,
M.
,
Yang
,
J.-J.
et al. 
(
2016
)
Inhibition of protein methylesterase 1 decreased cancerous phenotypes in endometrial adenocarcinoma cell lines and xenograft tumor models
.
Tumour Biol.
doi:
60
Jackson
,
J.B.
and
Pallas
,
D.C.
(
2012
)
Circumventing cellular control of PP2A by methylation promotes transformation in an Akt-dependent manner
.
Neoplasia
14
,
585
599
doi:
61
Kaur
,
A.
,
Denisova
,
O.
,
Qiao
,
X.
,
Jumppanen
,
M.
,
Peuhu
,
E.
,
Ahmed
,
S.U.
et al. 
(
2016
)
PP2A inhibitor PME-1 drives kinase inhibitor resistance in glioma cells
.
Cancer Res.
, Sep 26. [Epub ahead of print] doi:
62
Kaur
,
A.
,
Elzagheid
,
A.
,
Birkman
,
E.-M.
,
Avoranta
,
T.
,
Kytölä
,
V.
,
Korkeila
,
E.
et al. 
(
2015
)
Protein phosphatase methylesterase-1 (PME-1) expression predicts a favorable clinical outcome in colorectal cancer
.
Cancer Med.
4
,
1798
1808
doi:
63
Wang
,
S.S.
,
Esplin
,
E.D.
,
Li
,
J.L.
,
Huang
,
L.
,
Gazdar
,
A.
,
Minna
,
J.
et al. 
(
1998
)
Alterations of the PPP2R1B gene in human lung and colon cancer
.
Science
282
,
284
287
doi:
64
Cristobal
,
I.
,
Manso
,
R.
,
Rincon
,
R.
,
Carames
,
C.
,
Senin
,
C.
,
Borrero
,
A.
et al. 
(
2014
)
PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential
.
Mol. Cancer Ther.
13
,
938
947
doi:
65
Tan
,
J.
,
Lee
,
P.L.
,
Li
,
Z.
,
Jiang
,
X.
,
Lim
,
Y.C.
,
Hooi
,
S.C.
et al. 
(
2010
)
B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer
.
Cancer Cell
18
,
459
471
doi:
66
Cristobal
,
I.
,
Rincon
,
R.
,
Manso
,
R.
,
Carames
,
C.
,
Zazo
,
S.
,
Madoz-Gurpide
,
J.
et al. 
(
2015
)
Deregulation of the PP2A inhibitor SET shows promising therapeutic implications and determines poor clinical outcome in patients with metastatic colorectal cancer
.
Clin. Cancer Res.
21
,
347
356
doi:
67
Thiel
,
A.
and
Ristimäki
,
A.
(
2013
)
Toward a molecular classification of colorectal cancer: the role of BRAF
.
Front. Oncol.
3
,
281
doi:
68
Li
,
J.
,
Han
,
S.
,
Qian
,
Z.
,
Su
,
X.
,
Fan
,
S.
,
Fu
,
J.
et al. 
(
2014
)
Genetic amplification of PPME1 in gastric and lung cancer and its potential as a novel therapeutic target
.
Cancer Biol. Ther.
15
,
128
134
doi: