The PTEN tumor suppressor gene and its role in lymphoma pathogenesis

Structure and function of PTEN

PTEN structure

PTEN is a tumor suppressor gene located on chromosome 10q23.31 that encodes for a 403-amino acid protein that has both lipid and protein phosphatase activities. PTEN gene and protein structures are shown in Figure 1. The PTEN protein contains a sequence motif that is highly conserved in members of the protein tyrosine phosphatase family. Structurally, the PTEN protein is composed of two major functional domains (a phosphatase domain and a C2 domain) and three structural regions (a short N-terminal phosphatidyl-inositol [4,5]-bisphosphate [PIP₂]-binding domain, a C-terminal tail containing proline-glutamic acid-serine-threonine sequences, and a PDZ-interaction motif) [11]. The PIP₂-binding site and adjacent cytoplasmic localization signal are located at the protein's N-terminal [12, 13].

Figure 1. PTEN gene and protein structures. The PTEN protein is composed of 403 amino acids and contains an N-terminal PIP₂-binding domain (PBD), a phosphatase domain, a C2 domain, a C-terminal tail containing proline–glutamic acid–serine–threonine sequences, and a PDZ interacting motif at the end. *Mutations on the phosphatase domain that disrupt PTEN's phosphatase activity include the C124S mutation, which abrogates both the lipid and protein phosphatase activity of PTEN, and the G129E mutation, which abrogates only the lipid phosphatase activity of PTEN. The C-terminal tail residues phosphorylated by glycogen synthase kinase 3β (GSK3β) and casein kinase 2 (CK2) are shown. Mutations of S380, T382, and T383 (referred to as the STT) can destabilize PTEN and increase its phosphatase activity. The PIP₂-binding site and adjacent cytoplasmic localization signal are located at the N-terminal. The N-terminal poly-basic region appears to selectively interact with PIP₂ and contribute to the nuclear accumulation of PTEN. Ubiquitination of PTEN has also been found on K13 and K289.

The PI3K/PTEN/AKT/mTOR pathway

PTEN's tumor-suppressing function largely relies on the protein's phosphatase activity and subsequent antagonism of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. Following PTEN loss, excessive PIP₃ at the plasma membrane recruits and activates a subset of pleckstrin homology domain–containing proteins to the cell membrane. These proteins include phosphoinositide-dependent kinase-1 and AKT family members [14, 15]. AKT activation also leads to the activation of the mTOR kinase complex 1 through the inhibition of the phosphorylation of tuberous sclerosis complex tumor suppressors and consequent activation of the small GTPase rat sarcoma (RAS) homologue enriched in brain. The active mTOR complex 1 phosphorylates the p70 ribosomal protein S6 kinase (S6K) and inhibits 4E-binding protein 1 to activate protein translation [16]. Accordingly, the PTEN/PI3K/AKT/mTOR pathway is emerging as a vital target for anti-cancer agents, especially in tumors with mTOR pathway activation.

AKT-independent roles of PTEN

Although AKT pathway activation can explain many of the phenotypes associated with PTEN inactivation, PTEN gene targeting and genetic activation of AKT do not have completely overlapping biological consequences. Using transcriptional profiling, Vivanco et al. identified a new PTEN-regulated pathway, the Jun-N-terminal kinase (JNK) pathway, which was constitutively activated upon PTEN knockdown [17]. In the study, PTEN null cells had higher JNK activity than PTEN positive cells did, and genetic analysis indicated that JNK functioned parallel to and independently of AKT. Thus, the blockade of PI3K signaling may shift the survival signal to the AKT-independent PTEN-regulated pathway, implicated JNK and AKT as complementary signals in PIP₃-driven tumorigenesis and suggest that JNK may be a therapeutic target in PTEN null tumors.

In addition to its lipid phosphatase function, PTEN also has lipid phosphatase–independent roles. PTEN has been shown to inhibit cell migration through its C2 domain, independent of PTEN's lipid phosphatase activity [18]. In breast cancer, PTEN deficiency has been shown to activate, in a manner dependent on its protein phosphatase activity, the SRC proto-oncogene, non-receptor tyrosine kinase (SRC), thereby conferring resistance to human epidermal growth factor receptor 2 inhibition [19]. Furthermore, PTEN has been shown to directly bind to tumor protein 53 (p53), regulate its stability, and increase its transcription, thereby increasing P53 protein levels [20].

PTEN regulation

Genetic alteration of PTEN

PTEN loss of function occurs in a wide spectrum of human cancers through various genetic alterations that include point mutations (missense and nonsense mutations), large chromosomal deletions (homozygous/heterozygous deletions, frameshift deletions, in-frame deletions, and truncations), and epigenetic mechanisms (e.g., hypermethylation of the PTEN promoter region) [21]. Somatic mutations are the main drivers of PTEN inactivation in human cancers, and have been reviewed extensively [22].

PTEN's tumor suppressor function is usually abrogated following mutations in its phosphatase domain, which is encoded by exon 5 [23] (Figure 1). These mutations typically include a C124S mutation that abrogates both lipid and protein phosphatase activity and a G129E mutation that abrogates lipid phosphatase but not protein phosphatase activity [24]. Although the N-terminal phosphatase domain is principally responsible for PTEN's physiological activity, approximately 40% of tumorigenic PTEN mutations occur in the C-terminal C2 domain (corresponding to exons 6, 7, and 8) and in the tail sequence (corresponding to exon 9), which encode for tyrosine kinase phosphorylation sites. This suggests that the C-terminal sequence is critical for maintaining PTEN function and protein stability [21, 23, 25, 26]. However, many tumor-derived PTEN mutants retain partial or complete catalytic function, suggesting that alterative mechanisms can lead to PTEN inactivation.

Transcriptional regulation

In addition to gene mutations, complete or partial loss of PTEN protein expression may impact PTEN's tumor suppression ability. The regulation of PTEN's functions and signaling pathway is shown in Figure 2. Positive regulators of PTEN gene expression include early growth response protein 1, peroxisome proliferator-activated receptor γ (PPARγ) and P53, which have been shown to directly bind to the PTEN promoter region [27–29]. Early growth response protein 1, which regulates PTEN expression during the initial steps of apoptosis, has been shown to directly upregulate the expression of PTEN in non–small cell lung cancer. PPARγ is a ligand-activated transcription factor with anti-inflammatory and anti-tumor effects. The activation of its selective ligand, rosiglitazone, leads to the binding of PPARγ at two PTEN promoter sites, PPAR response element 1 and PPAR response element 2, thus upregulating PTEN and inhibiting PI3K activity. Negative regulators of PTEN gene expression include mitogen-activated protein kinase kinase-4, transforming growth factor beta (TGF-β), nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB), IGF-1, the transcriptional cofactor c-Jun proto-oncogene, and the B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) proto-oncogene, which have been shown to suppress PTEN expression in several cancer models [30–32]. Research found that IGF-1 could affect cell proliferation and invasion by suppressing PTEN's phosphorylation. In pancreatic cancers, TGF-β significantly suppresses PTEN protein levels concomitant with the activation of AKT through transcriptional reduction of PTEN mRNA–induced growth promotion. c-Jun negatively regulates the expression of PTEN by binding to the activator protein 1 site of the PTEN promoter, resulting in the concomitant activation of the AKT pathway. PTEN transcription is also directly repressed by the leukemia-associated factor ecotropic virus integration site 1 protein in the hematopoietic system [33].

Figure 2. Mechanisms of PTEN regulation. PTEN is regulated at different levels. (A) PTEN mRNA transcription is activated by early growth response protein 1, P53, MYC, PPARγ, C-repeat binding factor 1, and others, and inhibited by NF-κB, proto-oncogene c-Jun, TGF-β, and BMI-1. (B) PTEN mRNA is also post-transcriptionally regulated by PTEN-targeting miRNAs, including miR-21, miR-17-92, and others. (C) Active site phosphorylation, ubiquitination, oxidation, acetylation, and protein-protein interactions can also regulate PTEN activity. The phosphorylation leads to a “closed” state of PTEN and maintains PTEN stability. Dephosphorylation of the C-terminal tail opens the PTEN phosphatase domain, thereby activating PTEN.

Intriguingly, recent studies reported a complex crosstalk between PTEN and other pathways. For example, RAS has been found to mediate the suppression of PTEN through a TGF-β dependent mechanism in pancreatic cancer [34], and the mitogen-associated protein kinase/extracellular signal-related kinase pathway has been found to suppress PTEN transcription through c-Jun [35]. Finally, the stress kinase pathways including mitogen-activated protein kinase kinase kinase 4 and JNK promote resistance to apoptosis by suppressing PTEN transcription via direct binding of NF-κB to the PTEN promoter [36]. These findings suggest that the pathways that are negatively regulated by PTEN can in turn regulate PTEN transcription, indicating a potential feedback loop. Studies have also shown that CpG islands hypermethylated in the PTEN promoter lead to the silencing of PTEN transcription in human cancer [37].

Translational and post-translational regulation

MicroRNAs (miRNAs) are a class of endogenous, 20- to 25-nucleotide single-stranded non-coding RNAs that repress mRNA translation by base-pairing with target mRNAs [38]. Various miRNAs are known to impact PTEN expression in both normal and pathological conditions. In multiple human cancers, PTEN expressions are downregulated by miRNAs, which are shown in Table 1.

Table 1. MiRNAs which downregulate PTEN expression in human cancers

miRNA	Locus	Expression status	Tumor type	Reference
MiR-21	17q23.1	Upregulated	Colorectal, bladder, and hepatocellular cancer	[112–114]
MiR-19a	13q31.3	Upregulated	Lymphoma and CLL	[87, 115]
MiR-19b	Xq26.2	Upregulated	Lymphoma	[87]
MiR-22	17p13.3	Upregulated	Prostate cancer and CLL	[116, 117]
MiR-32	9q31.3	Upregulated	Hepatocellular carcinoma	[118]
MiR-93	7q22.1	Upregulated	Hepatocellular carcinoma	[119]
MiR-494	14q32.31	Upregulated	Cervical cancer	[120]
MiR-130b	22q11.21	Upregulated	Esophageal carcinoma	[121]
MiR-135b	1q32.1	Upregulated	Colorectal cancer	[122]
MiR-214	1q24.3	Upregulated	Ovarian cancer	[123]
MiR-26a	3p22.2 (MIR26A1) 12q14.1(MIR26A2)	Upregulated	Prostate cancer	[113]
MiR-23b	9q22.32	Upregulated	Prostate cancer	[114]
Abbreviations: CLL, chronic lymphocytic leukemia.

Post-translational modifications, such as active site phosphorylation, ubiquitination, oxidation, and acetylation, can also regulate PTEN activity [39]. In its inactivated state, PTEN is phosphorylated on a cluster of serine and threonine residues located on its C-terminal tail, leading to a “closed” PTEN state in which PTEN protein stability is maintained. As PTEN is being activated, dephosphorylation of its C-terminal tail opens its phosphatase domain, thereby increasing PTEN activity (Figure 2). The phosphorylation of PTEN at specific residues of the C-terminal tail (Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385) is associated with increased protein stability, whereas phosphorylation at other sites may decrease protein stability. Although S370 and S385 have been identified as the major sites for PTEN phosphorylation, mutations of these residues have minimal effects on PTEN function, whereas mutations of S380, T382, and T383 can destabilize PTEN and increase its phosphatase activity, thereby enhancing PTEN's interaction with binding partners [40]. The “open” state of PTEN is more susceptible to ubiquitin-mediated proteasome degradation [13]. One recently identified E3 ligase of PTEN is neural precursor cell-expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase 1 (NEDD4-1), which mediates PTEN mono- and poly-ubiquitination [41] (Figure 3). In cancer, the inhibition of NEDD4-1, whose expression has been found to be inversely correlated with PTEN levels in bladder cancer, may upregulate PTEN levels [42]. Two major conserved sites for PTEN are K13 and K289, and ubiquitination of these sites is indispensable for the nuclear-cytoplasmic shuttling of PTEN (Figure 1).

Figure 3. PTEN's cytoplasmic and nuclear functions. In the cytoplasm, PI3K is activated downstream of receptors that include receptor tyrosine kinases, G protein–coupled receptors, cytokine receptors, and integrins. PI3K activation converts PIP₂ to PIP₃, thereby leading to AKT activation, which enhances cell growth, proliferation, and survival. PTEN dephosphorylates PIP₃ and consequently suppresses the PI3K pathway. NEDD4-1 is an E3 ligase of PTEN that mediates PTEN ubiquitination. Polyubiquitination of PTEN leads to its degradation in the plasma, whereas monoubiquitination of PTEN increases its nuclear localization. PTEN can translocate into the nucleus through various mechanisms, including passive diffusion, Ran- or major vault protein–mediated import, and a monoubiquitination-driven mechanism. In the nucleus, PTEN promotes p300-mediated P53 acetylation in response to DNA damage to control cellular proliferation. Nuclear PTEN is also involved in maintaining genomic integrity by binding to centromere protein C (CENPC) and in DNA repair by upregulating RAD51 recombinase (RAD51).

Protein-protein interactions

PTEN contains a 3–amino acid C-terminal region that is able to bind to PDZ domain–containing proteins [43, 44]. PDZ domains are involved in the assembly of multi-protein complexes that may control the localization of PTEN and its interaction with other proteins. A number of PTEN-interacting proteins have been shown to regulate PTEN protein levels and activities. These interactions, which help recruit PTEN to the membrane, can be negatively modulated by the phosphorylation of PTEN on its C terminus [40, 45]. The phosphorylation of the C terminal end of PTEN has been attributed to the activities of casein kinase 2 and glycogen synthase kinase 3β [46, 47]. In addition, evidence suggests that the C2 domain of PTEN can be phosphorylated by RhoA-associated kinase, which may have important roles in the regulation of chemoattractant-induced PTEN localization [48] (Figure 2).

Acetylation and oxidation also contribute to PTEN activity regulation. PTEN's interaction with nuclear histone acetyltransferase–associated p300/cAMP response element-binding protein (CREB)-binding protein (CBP)–associated factor can promote PTEN acetylation, and this acetylation negatively regulates the catalytic activity of PTEN [49]. Studies have shown that the PTEN protein becomes oxidized in response to the endogenous generation of the reactive oxygen species (ROS) stimulated by growth factors and insulin, and this oxidation correlates with a ROS-dependent activation of downstream AKT phosphorylation [50, 51]. Other studies have shown that the PIP₃-dependent Rac exchange factor 2 and SHANK-associated RH domain interactor proteins bind directly to PTEN to inhibit its lipid phosphatase activity [52, 53]. High P53 expression triggers proteasome degradation of the PTEN protein [54]. In addition to antagonizing the AKT–mouse double minute 2 homolog pathway in a phosphatase-dependent manner, PTEN also can interact with P53 directly in a phosphatase-independent manner, thereby stabilizing P53 [55, 56].

Therapies targeting functional loss of PTEN in lymphoma

PI3K/AKT/mTOR pathway inhibitors

Owing to PI3K's critical roles in human cancers, PI3K targeting is one of the most promising areas of anticancer therapy development. Since the absent of PTEN is concomitant with PI3K signaling activation, inhibitors that targeting this pathway might play a significant role in the treatment of PTEN-deficient tumors. Growing evidence indicates that multiple solid tumor cell lines and several lymphoid malignancy cell lines with PTEN-deficient are hypersensitive to PI3K inhibitors, which are summarized in Tables 3 and Figure 4.

Table 3. Preclinical studies of targeted therapeutics in PTEN-deficient tumors

Inhibitor type	Drug	Study notes	Ref
Class I-PI3K
Pan	Buparlisib (BKM120)	The drug elicited response in some PTEN-deficient tumors and induced cell death in DLBCL cell lines.	[124]
Pan	SAR245408 (XL147)	The drug significantly inhibited tumor growth in a PTEN-deficient prostate cancer model.	[109]
p110α	BYL719	The drug had antitumor activity in cell lines harboring PIK3CA mutations but not in PTEN-deficient solid tumors	[110]
p110β	AZD6482 (KIN-193)	The drug substantially inhibited tumor growth in PTEN-deficient cancer models.	[98]
p110β	GSK2636771	PTEN-mutant EEC cell lines were resistant to the drug; the drug decreased cell viability only when combined with a p110α selective inhibitor.	[93]
p110β/δ	AZD8186	The drug inhibited the growth of PTEN-deficient prostate tumors.	[102]
p110α/β	CH5132799	The drug inhibited the growth of some PTEN-deficient tumors in vitro.	[103]
p110γ/δ	IPI-145	The drug significantly inhibited the Loucy cell lines in T-ALL.	[100]
PI3K/mTOR	SF1126	The drug significantly reduced the viability of PTEN-deficient but not PTEN-positive GCB-DLBCL cells.	[104]
PI3K/HDAC	CUDC-907	The drug inhibited growth in multiple cell lines; cell lines with PIK3CA or PTEN-mutation induced loss of PTEN were markedly sensitive to the drug.	[105]
AKT	MK-2206	The drug had antitumor activity in breast cancer cell lines with PTEN or PIK3CA mutations.	[106]
mTORC1	Everolimus (RAD001)	PTEN-deficient prostate cancer had greater sensitivity to the drug; glioblastoma cell lines were resistant to the drug.	[107]
	Temsirolimus (CCI-779)	Multiple PTEN-deficient cell lines were remarkably sensitive to the drug.	[108]
Abbreviations: DLBCL, diffuse large B-cell lymphoma; EEC, endometrioid endometrial carcinoma; MCL, mantle cell lymphoma; GCB, germinal B-cell–like.

Figure 4. Actions of therapeutics targeting PTEN deficiency in lymphoid malignancies. PTEN deficiency is associated with increased sensitivity to PI3K, AKT, and mTOR inhibitors. In addition, because PI3K is involved in BCR signaling activation, BCR pathway inhibitors may also be effective in PTEN-deficient lymphoid malignancies. SRC family kinase inhibitors include dasatinib (which can also inhibit BTK), saracatinib, bosutinib, SU6656, CGP76030, and KX-01. BTK inhibitors include ibrutinib and AVL-292. Sotrastaurin is a PKCβ inhibitor; A20, a MALT1 paracaspase inhibitor; and MLN120B, an IKKβ inhibitor. SYK inhibitors include fostamatinib and PRT062607. Idelalisib is a PI3Kδ-specific inhibitor. MK-2206 is an AKT inhibitor. mTOR inhibitors include everolimus and temsirolimus.

In addition to PI3K pan-inhibition, several isoform-selective PI3K inhibitors have been shown to repress the viability of PTEN-deficient tumors. Notably, the p110β-specific PI3K inhibitor AZD6482 (KIN-193) displayed remarkable antitumor activity in PTEN-null tumors but failed to block the growth of PTEN–wild-type tumors in mouse models [98]. However, another separate study showed that endometrioid endometrial cancer with PTEN mutation were resistant to p110β-selective inhibition, cell lines' viability was decreased only when p110β-selective inhibition was combined with p110α-selective inhibition. Recent findings have highlighted that there is a complex interplay between the Class I PI3K isoforms, inhibition of either α or β single isoform might be compensated by reactivation of another isoform at last [99]. Furthermore, it has been proposed that the dual γ/δ inhibitor CAL-130, specifically targeting p110γ and p110δ isoforms in PTEN deleted T-ALL cell lines [100]. By contrast, Lonetti et al. recently indicated that PI3K pan-inhibition developed the highest cytotoxic effects when compared with both selective isoform inhibition and dual p110γ/δ inhibition, in T-ALL cell lines with or without PTEN deletion [101]. Nevertheless, which class of agents among isoform-specific or pan-inhibitors can achieve better efficacy is still controversial. Other target treatments including AKT, mTOR, dual PI3K/AKT and dual PI3K/mTOR inhibitors also show promising antitumor activity in cell line studies, and some of them have been testing under clinical trials [102–111] (Table 3, 4).

Table 4. Preclinical studies of targeted therapeutics in PTEN-deficient tumors

Inhibitor type	Drug	Patient population	Phase	Identifier
PI3K	GSK2636771	Patients with advanced solid tumors with PTEN deficiency	1/2a	NCT01458067
	BKM120	Patients with recurrent glioblastoma with PTEN mutations or homozygous deletion of PTEN or with PTEN-negative disease	1b/2	NCT01870726
	BKM120	Patients with advanced, metastatic, or recurrent endometrial cancers with PIK3CA gene mutation, PTEN gene mutation, or null/low PTEN protein expression	2	NCT01550380
	AZD8186	Patients with advanced CRPC, sqNSCLC, TNBC, or known PTEN-deficient advanced solid malignancies	1	NCT01884285
PI3K/mTOR	BEZ235	Patients with advanced TCC; group 1 includes patients with no PI3K pathway activation, no loss of PTEN, and no activating PIK3CA mutation; group 2 includes patients with PI3K pathway activation as defined by PIK3CA mutation and/or PTEN loss	2	NCT01856101
	BEZ235	Patients with relapsed lymphoma or multiple myeloma	1	NCT01742988
AKT	MK-2206	Patients with previously treated metastatic colorectal cancer enriched for PTEN loss and PIK3CA mutation	2	NCT01802320
	MK-2206	Patients with advanced breast cancer with a PIK3CA mutation, AKT mutation, and/or PTEN loss or mutation	2	NCT01277757
	Pazopanib + everolimus	Patients with PI3KCA mutations or PTEN loss and advanced solid tumors refractory to standard therapy	1	NCT01430572
	Trastuzumab +RAD001	Patients with HER-2–overexpressing, PTEN-deficient metastatic breast cancer progressing on trastuzumab-based therapy	1/2	NCT00317720
	GDC-0068/ GDC-0980 +abiraterone	Patients previously treated prostate cancer with PTEN loss (currently in phase II)	1b/2	NCT01485861
	Rapamycin (Temsirolimus)	Patients with advanced cancer and PI3K mutation and/or PTEN loss	1/2	NCT00877773
	Ipatasertib (GDC-0068) + paclitaxel	Patients with PTEN-low metastatic TNBC	2	NCT02162719
Abbreviations: CRPC, castrate-resistant prostate cancer; sqNSCLC, squamous non-small cell lung cancer; TNBC, triplenegative breast cancer; TCC, transitional cell carcinoma; HER-2, human epidermal growth factor receptor 2.

Author Contributions

Conception, design, manuscript writing and final approval of manuscript: XW and KHY.

Funding

This study was supported by the National Cancer Institute/National Institutes of Health (R01CA138688 and 1RC1CA146299 to KHY). XW is a recipient of hematology and oncology scholarship award. KHY is supported by The University of Texas MD Anderson Cancer Center Lymphoma Moonshot Program and Institutional Research and Development Award, an MD Anderson Cancer Center Lymphoma Specialized Programs on Research Excellence (SPORE) Research Development Program Award, an MD Anderson Cancer Center Myeloma SPORE Research Development Program Award, a Gundersen Lutheran Medical Foundation Award, and partially supported by the National Cancer Institute/National Institutes of Health (P50CA136411 and P50CA142509), and by MD Anderson's Cancer Center Support Grant CA016672.

Conflicts of Interest

KHY receives research support from Roche Molecular System, Gilead Sciences Pharmaceutical, Seattle Genetics, Dai Sanyo Pharmaceutical, Adaptive Biotechnology, Incyte Pharmaceutical and HTG Molecular Diagnostics.

Editorial Note

Key points:

PTEN deficiency is related to poor clinical outcomes in patients with a variety of tumors Nuclear and cytoplasmic PTEN has distinct functions in tumor suppression

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