The role of protein tyrosine phosphatases in colorectal cancer

Biochimica et Biophysica Acta 1826 (2012) 179–188

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Review

The role of protein tyrosine phosphatases in colorectal cancer Elmer Hoekstra, Maikel P. Peppelenbosch, Gwenny M. Fuhler ⁎ Department of Gasteroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's Gravendijkwal 230, Rotterdam, The Netherlands

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Article history: Received 8 February 2012 Received in revised form 3 April 2012 Accepted 4 April 2012 Available online 13 April 2012 Keywords: Protein tyrosine phosphatases Colorectal cancer Signaling pathways Novel treatment targets

a b s t r a c t Colorectal cancer is one of the most common oncogenic diseases in the Western world. Several cancer associated cellular pathways have been identified, in which protein phosphorylation and dephosphorylation, especially on tyrosine residues, are one of most abundant regulatory mechanisms. The balance between these processes is under tight control by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Aberrant activity of oncogenic PTKs is present in a large portion of human cancers. Because of the counteracting role of PTPs on phosphorylation-based activation of signal pathways, it has long been thought that PTPs must act as tumor suppressors. This dogma is now being challenged, with recent evidence showing that dephosphorylation events induced by some PTPs may actually stimulate tumor formation. As such, PTPs might form a novel attractive target for anticancer therapy. In this review, we summarize the action of different PTPs, the consequences of their altered expression in colorectal cancer, and their potential as target for the treatment of this deadly disease. © 2012 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . PI3K–PKB–mTOR pathway . . . . . . . . . . . . . 2.1. PTEN . . . . . . . . . . . . . . . . . . . 2.1.1. Characteristics of PTEN . . . . . . . 2.1.2. Role of PTEN in colorectal cancer . . 2.2. PRL-3 . . . . . . . . . . . . . . . . . . . 2.2.1. Characteristics of PRL-3 . . . . . . . 2.2.2. Role of PRL-3 in colorectal cancer . . JAK–STAT-signaling . . . . . . . . . . . . . . . . 3.1. LMWPTP . . . . . . . . . . . . . . . . . . 3.1.1. Characteristics of LMWPTP . . . . . 3.1.2. Role of LMWPTP in colorectal cancer 3.2. PTPRT . . . . . . . . . . . . . . . . . . . 3.2.1. Characteristics of PTPRT . . . . . . 3.2.2. Role of PTPRT in colorectal cancer . . 3.3. PTP1B . . . . . . . . . . . . . . . . . . . 3.3.1. Characteristics of PTP1B . . . . . . 3.3.2. Role of PTP1B in colorectal cancer . . RAS–RAF–ERK pathway . . . . . . . . . . . . . . 4.1. PTPRJ . . . . . . . . . . . . . . . . . . . 4.1.1. Characteristics of PTPRJ . . . . . . . 4.1.2. Role of PTPRJ in colorectal cancer . . 4.2. PTPRH . . . . . . . . . . . . . . . . . . . 4.2.1. Characteristics of PTPRH . . . . . . 4.2.2. Role of PTPRH in colorectal cancer . .

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⁎ Corresponding author at: Dept. of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 's Gravendijkwal 230, 3015CE, Rotterdam, Room L-456, The Netherlands. Tel.: + 31 107035821; fax: + 31 107032793. E-mail address: [email protected] (G.M. Fuhler). 0304-419X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2012.04.001

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4.3.

PTPN13 . . . . . . . . . . . . . . . . . . 4.3.1. Characteristics of PTPN13 . . . . . 4.3.2. Role of PTPN13 in colorectal cancer 4.4. PTPα . . . . . . . . . . . . . . . . . . . 4.4.1. Characteristics of PTPα . . . . . . 4.4.2. Role of PTPα in colorectal cancer . 5. Cell cycle proteins . . . . . . . . . . . . . . . . 5.1. Cdc25 . . . . . . . . . . . . . . . . . . 5.1.1. Characteristics of Cdc25 . . . . . . 5.1.2. Role of Cdc25 in colorectal cancer . 6. Conclusions . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Colorectal cancer (CRC) is a common form of cancer and a lethal disease. Approximately 945,000 new cases of colorectal cancer were diagnosed worldwide in the year 2000. In almost half of the cases this proves to be fatal [1]. Although CRC mortality has been progressively declining since 1990, it still remains the second most common cause of cancer death in the US and Europe [2,3]. There are environmental and genetic factors that contribute to the development of CRC. Although inherited susceptibility results in the most striking increases in risk, the majority of CRCs are sporadic rather than familial. Familial adenomatous polyposis (FAP), a relatively common form of familial colon cancer syndrome, accounts for less than 1% of the total CRC cases [4]. Many different genes and signaling pathways are involved in the development of colorectal cancer. These signaling pathways are involved in the control of cell proliferation, adhesion and migration and are under control of a delicate balance between protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) [5]. Disturbance of this balance has been shown to play a role in the pathogenesis of numerous inherited or acquired human diseases such as cancer, immune deficiencies and inflammation [6]. Regulation of protein tyrosine phosphorylation contributes to many important physiological processes including cell growth, differentiation, and migration as well as glucose metabolism, synaptic transmission, and the immune response [5]. As such, the importance of protein kinases in health and disease has been extensively investigated and reviewed. These studies are boosted by the wide ranging efforts made to develop the large panel of kinase inhibitors currently available, of which some show clinical promise. In contrast, the equally important phosphatases have received much less attention. However, because of their role in human disease, it is also vitally important to gain more understanding in the function of PTPs in these processes. The PTP gene superfamily is a large group of highly specific enzymes and comprises a total of 107 PTP genes in the human genome [7] (Table 1). They are composed of four main families based on their amino acid sequence in the phosphatase catalytic domains (Table 1). By far the largest family is the Class I cysteine based PTPs. These can be further divided into the classical PTPs, including the receptor PTPs (RPTPs) and nonreceptor PTPs (NRPTPs), and the dual specificity phosphatases (DUSPs), which can dephosphorylate serine and threonine in addition to tyrosine residues. Class II cysteine based PTPs are the smallest class of PTPs; presently only the low molecular weight phosphatase (LMWPTP) is known to belong to this group. Class III cysteine based PTPs are tyrosine/threonine specific phosphatases. In humans, this class contains three CDC25 phosphatase genes. Lastly, the four enzymes included in the Class IV aspartate based PTPs are shown to have Tyr/Ser phosphatase activity [7]. Several genetic modifications in genes encoding PTPs have been observed, and emerging evidence suggests that these alterations play a role in various human cancers. Wang and colleagues performed a systematic screen for mutations in genes

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encoding PTPs in different human cancers. They identified 83 somatic mutations in six PTPs (PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14) affecting 26% of colorectal cancers. With a frequency of 17%, PTPRT was most frequently mutated [8]. Interestingly, in their mutational screen on cancers with high level of microsatellite instability, Korff et al. described frameshift mutations in five different PTP genes (PTPRA, PTPRS, PTPN5, PTPN23, PTPN21, as well as the PTPN13 found in the screen by Wang et al.) affecting 32% of colorectal cancers [9]. In this review we will summarize the structure and role of different PTPs in the development of colorectal cancer.

2. PI3K–PKB–mTOR pathway The phosphatidyl inositol 3-OH kinase (PI3K)–protein kinase B (PKB/Akt)–mammalian target of rapamycin (mTOR) pathway is an important signal transduction axis which regulates survival, growth and proliferation in different human cells (Fig. 1). The PI3K family are lipid kinases capable of phosphorylating the hydroxyl group at the 3′ position of inositol rings. After activation by various cytokines and growth factor receptors, this enzyme catalyzes the formation of phosphatidylinositol (3,4,5) trisphosphate (PtdIns (3,4,5) P3) by phosphorylation of PtdIns (4,5) P2. PtdIns (3,4,5) P3 is a critical second messenger in the membrane recruitment of several proteins, and binds to PKB through its pleckstrin homology (PH) domain. PKB plays a major role in cell survival by phosphorylating mTOR, GSK-3β and forkhead transcription factors (reviewed in [10]). The PI3K pathway is regulated by the dual specificity phosphatase PTEN (see Section 2.1), as well as the lipid phosphatases SHIP1 and SHIP2.

Table 1 Classification and substrate specificity of the 107 PTPs. PTP family

Members (N)

Substrate specificity

Class I cys-based PTPs

Receptor PTPs (21) Non-receptor PTPs (17) MKPs (11) Atypical DUSPs (19) Slingshots (3) PRLs (3) Cdc14 (4) PTENs (5) Myotubularins (16) LMWPTP (1) Cdc25 (3) Eya (4)

pTyr pTyr pTyr, pThr pTyr, pThr, mRNA pSer pTyr pSer, pThr D3-phosphoinositides D3-phosphoinositides pTyr pTyr, pThr pTyr, pSer

Class II cys-based PTPs Class III cys-based PTPs Class IV asp-based PTPs

The table shows an overview of the PTP family, which is subdivided in 4 classes. PTP: protein tyrosine phosphatase; MKP: mitogen-activated protein kinases phosphatase; DUSP: dual-specificity phosphatase; PRL: phosphatase of regenerating the liver; CDC: cell division cycle; PTEN: phosphatase and tensin homolog; LMWPTP: low molecular weight protein tyrosine phosphatase; Eya: Eyes absent homolog. Based on Alonso et al. [7].

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2.1. PTEN 2.1.1. Characteristics of PTEN The tumor suppressor gene, phosphatase and tensin homolog (PTEN), originally described as MMAC (mutated in multiple advanced cancers), is located on chromosome 10q23.3 [11,12]. Mutations in PTEN are the second most common genetic alterations in human cancers, behind p53 mutations. Germline mutations in this gene lead to the development of rare autosomal dominant inherited disorders such as Cowden disease, Lhermitte–Duclos disease, and Bannayan– Zonana syndrome [13–15]. These syndromes are characterized by numerous tumor-like growths, called hamartomas, and give rise to an increased risk of developing certain forms of cancer, including CRC. The PTEN protein is a DUSP, which acts on both proteins and lipids, with a greater affinity for the latter. In its capacity as a lipid phosphatase, it serves as a negative regulator of the PI3K/PKB/mTOR pathway by converting PtdIns (3,4,5) P3 to PtdIns (4,5) P2 at the plasma membrane. It has been shown that inactivation of PTEN results in constitutive activation of the PI3K/PKB pathway and increases cell proliferation, cell survival, migration and metastasis [16], all well known characteristics of tumor cells. 2.1.2. Role of PTEN in colorectal cancer As part of the PI3K/PKB/mTOR pathway, PTEN alterations are found in many different human neoplasms, including colorectal cancer. Langlois and colleagues observed that PTEN protein expression as determined by Western blot analysis is reduced by 40% in approximately 60% of CRC samples [17]. This is in accordance with immunohistochemical reports from Li et al. and Jiang et al. who found PTEN expression in colorectal carcinoma to be statistically lower than the adjacent noncancerous mucosa [18,19]. As it has been suggested that PTEN activity in vivo is modulated through its expression pattern and that reduced PTEN activity seems likely in CRC cells [20]. In vitro studies have confirmed that knocking down PTEN in colorectal cancer cell lines increases PKB phosphorylation, showing that the PI3K-pathway is preferentially activated in PTEN-deficient cells. In these cells, migration and invasion capacity was also increased, thereby resulting in a higher oncogenic potential. In addition, PTEN knockdown was associated with a change in E-cadherin expression, showing that loss of PTEN induces cellular changes consistent with epithelial to mesenchymal transition (EMT), a common phenomenon in tumorigenesis [21]. The oncogenic role of PTEN has also been studied in mouse models. The importance of PTEN in cell survival is evident, as PTEN null mice die during embryogenesis between gestation days 6.5 to 9.5 [22]. However, heterozygous models are highly susceptible to development of several types of tumors, including breast cancer, endometrial cancer, prostate tumors and lymphoma [23]. More recently, an in vivo model for PTEN deficiency in adult mice was developed. Using Cre-loxP conditional genetics, tissue specific PTEN inactivation was accomplished. In this PTEN deficient background, the lymphoid lineages, as well as the epithelium of the epidermis, prostate, endometrium and intestine, are highly susceptible to tumorigenesis. In addition, 18% of PTEN deficient mice develop spontaneous intestinal cancer, compared to none in the control group [24]. Together, overwhelming evidence suggests that loss of PTEN expression is involved in pathogenesis, invasion and metastasis of colorectal carcinomas and that PTEN expression may be a good marker for prognosis of colorectal carcinoma. 2.2. PRL-3 2.2.1. Characteristics of PRL-3 Phosphatase of regenerating the liver-3 (PRL-3, also known as PTP type IVA and encoded by PTP4A3) is part of a subfamily of PTPs which also contain PRL-1 and PRL-2. PRLs have a core PTP domain with a C(X)5R active site motif and are the only PTPs known to carry the membrane-targeting CAAX motif at their COOH-terminus [7,25,26].

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Among normal adult human tissues, PRL-3 mRNA is expressed primarily in the skeletal muscle and heart, with lower expression levels in the lung, pancreas, spleen, and testis. The exact function of PRL-3 in these tissues is currently unknown [27–29]. 2.2.2. Role of PRL-3 in colorectal cancer Using global gene expression profiling of colorectal cancer (CRC) samples, PRL-3 expression levels were recently shown to be increased in metastatic colorectal carcinomas, in comparison to normal epithelium and non-metastatic tumors [30]. This enhanced PRL-3 expression is associated with poor prognosis in CRC, and an independent prognostic factor for lymphnode metastasis [31]. Overexpression of PRL-1 and PRL-2 has been shown to be sufficient for transformation of epithelial cells and fibroblasts, indicating that this class of phosphatases indeed has oncogenic potential [26,32]. Several proteins have been identified as possible PRL-3 target proteins. Forte et al. found evidence that indicates Ezrin pThr567 as a direct substrate of PRL-3 in the HCT116 colon cancer cell line. The identification of Ezrin as a target of PRL-3 action is of interest because of the role of the ERM family members (Ezrin–Radixin–Moesin) in several cellular processes involved in tumorigenesis, such as cell survival, proliferation, invasiveness and migration. Ezrin inactivation by PRL3 may enhance downstream activation of targets such as the Src kinase and Rho family of cytoskeletal proteins [33]. Both RhoA and RhoC family GTPases may act downstream of PRL-1 and PRL-3 to promote motility and invasion, although the direct substrate of PRL activity in this pathway remains unclear [34]. Other investigations led to the conclusion that PRL-3 is a direct target of TGF-β signaling in colon cancer cells. The loss of TGF-β signaling leads to the upregulation of PRL-3 and activation of the PI3K/PKB pathway [35]. In turn, PI3K/PKB activation as a result of PRL-3 activity can promote EMT. On further examination, PTEN protein expression was shown to be downregulated by PRL-3. Consequently, PI3K and PKB are activated, whereas GSK-3β is inhibited, which leads to the upregulation of mesenchymal markers and downregulation of epithelial markers [36]. An adverse role for PRL-3 in PI3K signaling has also been suggested. PRL-3 is structurally similar to the lipid phosphatase PTEN, and carries a C-terminal CAAX box, which is not only featured in known lipid phosphatases but also localizes PRL-3 to the cellular compartments rich in phosphoinositides (PIPs). Indeed, a novel role for PRL-3 as lipid phosphatase possessing phosphatidylinositol 5-phosphatase activity has recently been demonstrated [37]. This would suggest that, like PTEN, PRL-3 may act as tumor suppressor by counteracting the PI3K/Akt pathway. Nevertheless, as described earlier, other studies imply that PRL-3 and PTEN counteract each other both on protein level and in terms of PKB activation. In addition, while PTEN activity in cancer is most often decreased, PRL-3 expression is increased in CRC and can therefore possibly act as target for treatment. The recent generation of a conditional Cre-mediated PRL-3 knockout mouse opens up novel avenues of investigation into the exact role of PRL3 and its potential treatment targets in colorectal cancer [38]. 3. JAK–STAT-signaling The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is an important signaling module triggered by a large number of cytokines and growth factors, and is involved in cell proliferation, differentiation, cell migration and apoptosis, as well as drug resistance. Cytokine receptor engagement activates receptorassociated JAKs, which in turn mediate phosphorylation of specific receptor tyrosine residues. This allows the recruitment of STATs, present in the cytoplasm. Activation of STATs occurs through their tyrosine phosphorylation, which permits them to dimerize, translocate to the nucleus and bind to specific regulatory DNA sequences resulting in activation or repression of target gene transcription (reviewed in [39]).

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Fig. 1. Schematic overview of the role of PTPs in colorectal cancer. Three main signaling pathways commonly over-activated in cancer are the PI3K–PKB–mTOR, the JAK–STAT and the Ras–Raf–MEK–ERK pathways (described in detail in the main body of the text). These pathways are generally activated through engagement of growth factors to receptor tyrosine kinases (RTK). Indicated in black are the phosphatases reviewed, and their interaction with these three important pathways.

Enhanced STAT3 pathway activation is a characteristic of CRC and is associated with poor prognosis [40]. 3.1. LMWPTP 3.1.1. Characteristics of LMWPTP The family of low molecular weight protein tyrosine phosphatases (LMWPTP), represented by a single gene called ACP1, is a group of 18-kDa cytosolic enzymes that are widely expressed in different tissues [41]. LMWPTP is involved in cell growth regulation, in most instances as a negative regulator of growth factor-induced cell proliferation, but in some cases it may have an opposite role. Modulation of the activity of LMWPTP is based on its phosphorylation/dephosphorylation as well as reversible oxidation of its cysteine residues. LMWPTP contains two tyrosines, Tyr131 and Tyr132, which are preferential sites for phosphorylation by protein tyrosine kinases, such as Src [42–44]. While Tyr131 phosphorylation causes a dramatic increase in enzymatic activity, phosphorylation of Tyr132 serves as a scaffold for the SH2 domain of growth factor receptor-bound protein 2 (Grb2), which may activate the Ras– ERK pathway (see below), but has no affect on its phosphatase activity [42]. In the presence of reactive oxygen species (ROS), oxidation of the cysteine residue in the catalytic site leads to oxidative inactivation of the enzyme. The ensuing prevention of LMWPTP auto-dephosphorylation causes an increase of Tyr132 phosphorylation, and may induce a prosurvival response [45,46]. LMWPTP interacts with several cancer relevant proteins. For example, dephosphorylation of the platelet derived growth factor receptor (PDGFR) by LMWPTP results in enhanced PI3K signaling activity [47,48]. In addition, through interaction with β-catenin, LMWPTP is thought to play a role in maintaining cadherin/catenin complexes and remodeling of cell–cell contacts, two important mechanisms involved in tumor progression and metastasis [49]. Another important signaling pathway modulated by LMWPTP is the JAK–STAT pathway, as LMWPTP directly binds to, and dephosphorylates STAT5. Oxidation of LMWPTP

prevents dephosphorylation and inactivation of JAK2 and STAT5, which contributes to LMWPTP tumorigenicity [50]. LMWPTP oncogenic potential may also be associated with the receptor tyrosine kinase EphA2, as LMWPTP is a critical negative regulator of EphA2 tyrosine phosphorylation. EphA2 in its unphosphorylated form acts as a powerful oncogene by regulating tumor cell growth, survival, migration, and invasion [51]. 3.1.2. Role of LMWPTP in colorectal cancer When comparing the expression levels of LMWPTP mRNA in different human carcinomas (breast, colon, and lung) to their paired adjacent non-affected tissues, Malentacchi et al. found increased expression of LMWPTP mRNA in breast and colon cancers, but not in lung cancers [52]. This difference was most predominant in patient groups expressing negative predictive markers, such as G2–G4 patients, patients with lymph node involvement or advanced Dukes' stage, and in patients with a lower differentiation grade. Patients whose cancer LMWPTP mRNA expression is higher than that in paired non-affected tissue, have a significantly reduced survival probability in comparison to subjects who do not show an increase in LMWPTP mRNA in their tumors. The elevated mRNA also corresponded with an increase in LMWPTP protein, which was increased 2- to 20-fold in tumor samples compared to normal tissue. In the same light, Marzocchini et al. found a significant increase in LMWPTP expression in rat adenocarcinomas induced by DMH, especially proximal tumors, although the observed 2-fold increase did not reach statistical significance [53]. These results suggest that overexpression of LMWPTP is a phenomenon associated with the onset of malignancy. Whether this is related to enhanced LMWPTP phosphatase activity or mediated through phosphatase-independent functions such as ERK1/2 pathway activation remains to be elucidated, although some evidence for the latter has been presented. There are three common ACP1 alleles; A, B, and C, which give rise to six phenotypes. Subsequent alternative splicing of the ACP1 mRNA results in two isoforms of the LMWPTP protein, a slow migrating form (S) and a

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fast migrating form (F) [54]. The different genotypes of LMWPTP show different enzymatic activities and other molecular properties. While the S-forms seem to be associated with enhanced LMWPTP catalytic activity, the F-variants appear to play a role in cell adhesion, migration and extracellular matrix degradation by metalloproteinases. In colorectal cancer, the LMWPTP genotype is shifted from ACP1 S-forms to ACP1 F-forms, which may contribute to tumor invasiveness and metastasis potential through phosphatase-independent mechanisms [55]. Giving the possible oncogenic and metastatic roles in colorectal cancer, and the recent development of LMWPTP-inhibitors [56], it is tempting to speculate that there might be a future role for the modulation of LMWPTP activities in a therapeutic setting. 3.2. PTPRT 3.2.1. Characteristics of PTPRT Protein tyrosine phosphatase receptor T (also designed as PTPρ) is a frequently mutated PTP in several human neoplasms, such as lung, gastric, skin and colorectal cancers [8]. Together with PTPRM, PTPRK and PTPRU, it belongs to the receptor type IIB PTP family. They share the same domain architecture, with an extracellular domain, a juxtamembrane region and two tandem intracellular catalytic domains (D1 and D2). The large extracellular domain contains a MAM (meprinA5 antigen-PTP) domain, Ig-like domain and fibronectin type III-repeats [57]. The precise role of this PTP in signaling pathways has not been identified clearly yet. 3.2.2. Role of PTPRT in colorectal cancer In the mutational screen performed by Wang et al. described earlier, PTPRT was found to be the most frequently mutated PTP in colorectal carcinomas. A large fraction of these mutations include nonsense and frameshift mutations, suggesting inactivating mutations. Many of the missense mutations in the catalytic domains (both D1 and D2) of PTPRT lead to diminished phosphatase activity. In addition, overexpression of PTPRT inhibits CRC cell growth, suggesting a tumor suppressive role for this PTP [8]. Recently, both paxillin and STAT3 were identified as substrates of PTPRT. Paxillin is a signal transduction adaptor protein which plays a role in cell–cell adhesion. Dephosphorylation of paxillin at Y88 by PTPRT plays an important role in CRC tumorigenesis and cell migration through established signaling pathways such as PKB, p130CAS and SHP2 [58]. STAT3 dephosphorylation by PTPRT negatively regulates its translocation to the nucleus and transcriptional activation of target genes such as SOCS3 and Bcl-XL [59]. These in vitro data support the notion that decreased PTPRT activity in CRC cells results in enhanced activation of oncogenic signaling pathways. In order to provide in vivo evidence that PTPRT acts as a tumor suppressor gene, PTPRT knockout mice were developed. These knockout mice, and WT littermates, were treated with Azoxymethane (AOM) to chemically induce colon tumors. Strikingly, 17 of 20 homozygous PTPRT knockout mice developed colon tumors, while none of their wild type littermates showed cancer development [58]. Hence, inactivation of PTPRT in colorectal cancer may contribute to the survival signals induced by STAT3 in these cells.

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growth factor I receptor (IGF-IR) [66], p210 Bcr-Abl [67], Janus kinase 2 (JAK2), and TYK2 [68]. Given the central role that PTP1B plays in the negative regulation of oncogenic signaling, through dephosphorylation of PTKs such as p210 Bcr-Abl, PTP1B inhibition is generally thought to act as carcinogenic [67]. In contrast, PTP1B has also been identified as one of the major phosphatases that activate Src in breast cancer cells [69]. Similarly, in vivo approaches using PTP1B knockout models or PTP1B inhibitors have demonstrated a delayed mammary tumorigenesis and protection of mice from lung metastasis [69,70]. Thus, PTP1B appears to have tumor promoting capacity, and may potentially serve as target for treatment of cancers. 3.3.2. Role of PTP1B in colorectal cancer By evaluating distinct genomic DNA alterations for a large number of candidate oncogenes and tumor suppressor genes in 22 colorectal cancer samples, Lassmann et al. identified DNA amplifications of PTP1B in 22% of the cases, with the highest percentage in CIN-positive tumors [71]. As for breast cancer, PTP1B was shown to be the major tyrosine phosphatase capable of specifically dephosphorylating Src at its negative regulatory site Y530 in six of seven human epithelial colon cancer cell lines. PTP1B phosphatase activities were greatly elevated in these colon cancer cell lines compared to a normal colon epithelial cell line, thus resulting in enhanced Src activity in these tumor cells. Moreover, knockdown and inhibitor experiments for PTP1B resulted in decreased Src activity. The in vivo oncogenic potential of PTP1B was subsequently confirmed by the ability of PTP1B siRNA to reduce the tumor growth in NOD/SCID mice as compared to control cells [72]. Enhanced Src activity is associated with the majority of CRC, and directs downstream activation of the PI3K–PKB, JAK–STAT, and Ras–ERK pathways [73,74]. Interestingly, increased Src activity is based on increased expression/ activity modulation rather than on Src mutations, since these are very rare, suggesting a role for PTPs in this process. Modulation of this important kinase through PTPs may therefore find clinical relevance. Giving the oncogenic role for PTP1B in this respect, PTP1B-inhibitors might be a useful therapeutic target for these malignancies. 4. RAS–RAF–ERK pathway The Ras/Raf/MEK/ERK cascade is another important signaling system that controls fundamental cellular processes such as proliferation, differentiation, survival and apoptosis. Ras acts as a molecular switch by cycling between an active, GTP bound state, and an inactive, GDP bound state. A wide array of stimuli can recruit nucleotide exchange factors, such as the well characterized son of sevenless (SOS), to the cell membrane where it binds to the adaptor protein growth-factorreceptor-bound protein 2 (Grb2). Once at the cell membrane, SOS promotes the exchange of GDP for GTP, thereby converting Ras into its active conformation. Activated Ras will result in a cascade of mitogenactivated protein kinase (MAPK) activation. The first to become activated is the MAPK kinase kinase (Raf), which subsequently activates MAPK kinase (MEK1/2), which in turn is followed by phosphorylation and activation of MAPK (ERK1/2). ERK1/2 phosphorylates numerous substrates involved in the regulation of proliferation, differentiation and survival. (reviewed in [75]).

3.3. PTP1B 4.1. PTPRJ 3.3.1. Characteristics of PTP1B PTP1B (or PTPN1) is the first mammalian PTP identified and is widely expressed [60]. The gene is located on human chromosome 20q13.1– q13.2 and has a molecular weight of approximately 50 kDa [61]. PTP1B is prototypic for the PTP superfamily, with an N-terminal catalytic (PTP) domain, followed by two proline-rich motifs, and localizes to the ER through a hydrophobic domain in its C-terminus [62]. PTP1B is involved in the regulation of a variety of cellular events through different molecular pathways, such as those involving the epidermal growth factor receptor (EGFR) [63], PDGFR [64], insulin receptor (IR) [65], insulin

4.1.1. Characteristics of PTPRJ Protein tyrosine phosphatase receptor type J, also designated as DEP-1 (high cell density-enhanced phosphatase-1) or CD148, is encoded by the PTPRJ gene located on human chromosome band 11p11. PTPRJ is a class III transmembrane protein tyrosine phosphatase that contains multiple fibronectin type III repeat domains in the extracellular portion, one transmembrane domain, and a single phosphatase domain in the intracellular portion [76]. PTPRJ can be activated by binding various growth factors to its extracellular domain, and activated PTPRJ plays a

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role in several tyrosine kinase receptor pathways such as VEGF [77], PDGFR [78,79] and HGFR [80] which are implicated in carcinogenesis. For instance, PDGFR mediated activation of Ras and Src, and to a lesser extent PI3K–PKB, can be inhibited by PTPRJ [79]. In addition, oncogenic Ras transformation of cells is inhibited by PTPRJ, and PTPRJ may directly dephosphorylate ERK1/2 [81,82]. 4.1.2. Role of PTPRJ in colorectal cancer Different PTPRJ haplotype-associated single nucleotide polymorphisms (SNPs) have been identified, one of which reduces breast cancer risk [83]. However, there is no significant evidence for PTPRJ haplotype SNPs being either risk-conferring or protective in colorectal cancer [84]. Research by Ruivenkamp and collaborators showed PTPRJ to be the only candidate gene for the mouse susceptibility locus to colon cancer, Scc1 [85]. In humans they screened sporadic colorectal adenomas for genetic alterations along chromosome 11p11–11p12 and discovered the PTPRJ containing region to be deleted in 49% of the carcinomas, suggesting a tumor suppressive role for PTPRJ. In more advanced stages of CRC, loss of the second copy of the PTPRJ gene (loss of heterozygosity; LOH) was observed [82]. As no PTPRJ mutations were observed after sequence analysis of the individuals with and without LOH, it was suggested that loss of one copy of PTPRJ is sufficient to provide a growth advantage [86]. In line with this suggestion, reduction of PTPRJ protein expression by shRNA confers growth advantage in colorectal cancer cell lines [87]. Decreased PTPRJ expression was indeed observed in immunohistochemical stainings of high grade tumors, including some adenocarcinomas [88]. Based on the above, PTPRJ appears to have an antiproliferative effect in epithelial cells from the colon, where loss of a gene copy may contribute to cancer development. To study this in an in vivo setting, PTPRJ-deficient mice were developed. These mice show no growth defects or spontaneous tumor development, suggesting that loss of PTPRJ alone is not sufficient for oncogenic transformation of cells [89]. Other genetic alterations are likely required for successful tumor formation, as is the case in human CRC, where the ‘multiple hit’ model predicts that one single mutation is rarely sufficient to induce cancer. 4.2. PTPRH 4.2.1. Characteristics of PTPRH Receptor-type protein tyrosine phosphatase H (PTPRH), also known as stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1) was originally identified as a PTP expressed in a human stomach cancer cell line. This PTP with a molecular weight of 107 kDa is located on chromosome 19q13, and is structurally similar to PTPRJ [90]. It binds to Grb2, and as such may play a role in Ras signaling [91]. PTPRH is specifically overexpressed in human colon and pancreatic cancers [92], suggesting a role in carcinogenesis. In contrast, overexpression of this PTP in cultured fibroblasts inhibits cell proliferation, either through inhibition of growth factor-induced activation of MAP kinase or by caspasedependent apoptosis [93,94]. Based on this, and the earlier finding that there is a reduced expression of PTPRH in advanced cancers [92,95], it has also been suggested that PTPRH may act as a tumor suppressor. 4.2.2. Role of PTPRH in colorectal cancer As mentioned above, PTPRH overexpression has been found in colorectal cancers. Seo and co-workers examined PTPRH expression by immunohistochemistry in specimens from 65 patients, and demonstrated PTPRH expression in colonic adenomas showing moderate or severe dysplasia, but not in normal colonic epithelial cells or adenomas with mild dysplasia [92]. Thus, PTPRH expression appears to promote intestinal tumorigenesis. This is supported by functional in vivo studies showing that loss of PTPRH inhibits tumorigenesis in mice that are heterozygous for a mutation of APC that induces tumors of the colon [96]. The mutation of APC leads to stabilization and the accumulation

of β-catenin, which initiate transformation and promote tumorigenesis through activation of transcription factor 4 (reviewed in [97]). It thus appears that PTPRH cooperates with the canonical Wnt-signaling pathway in the formation of tumors, although the exact mechanism remains elusive. However, the importance of accumulation of mutations, amongst the first of which is the APC1 mutation in human CRC, has long been recognized, and PTPRH may be one of the ‘second hit’ mutations that give rise to these cancers. 4.3. PTPN13 4.3.1. Characteristics of PTPN13 Non-receptor type protein tyrosine phosphatase 13 (PTPN13), also known as FAP-1 and PTPL1, is a cytoplasmic PTP located on chromosome 4q21, and the largest among all PTPs with a molecular weight of 270 kDa [98–101]. It contains a phosphatase domain in the C-terminal portion and many non-catalytic domains, including five PSD-95/ Drosophila disk large zonula occluden (PDZ) domains, an N-terminal kinase non-catalytic C-lobe (KIND) domain [102] and a four-pointone/ezrin/radixin/moesin (FERM) domain [103]. These non-catalytic domains can interact with several different proteins, causing PTPN13 to have diverse functions. For instance, the third PDZ domain (PDZ2) intracellularly inhibits FasR-mediated apoptosis by interacting with the cytoplasmic death domain of Fas receptors [101]. In addition, PTPN13 is a negative modulator of Src–ERK signaling in cancer cells [104]. 4.3.2. Role of PTPN13 in colorectal cancer Several studies on the role of PTPN13 in colorectal cancer have shown conflicting results, as either a tumor suppressive or an oncogenic protein (reviewed in [105]). Elevated levels of PTPN13 expression have been seen in Ewing's sarcoma family tumors (ESFT), as it is a direct transcriptional target of the ESFT oncogene, EWS–FL11 [106]. In the same light, a high incidence of PTPN13 expression in colon carcinomas is related to resistance to FasR-mediated apoptosis, thus acting as a survival mechanism and enhancing tumor growth [107]. In complete contrast, others found that ectopic expression of PTPN13 enhances, rather than decreases, apoptotic cell death in colon adenocarcinomas, suggesting a more tumor suppressive role for PTPN13 [108]. These observations are further supported by the previously mentioned reports by Wang et al. and Korff et al., who identified PTPN13 among the PTPs most frequently mutated in colorectal cancer, and therefore supposed this phosphatase to act as a tumor suppressor gene [8,9]. However, as PTPN13 has both enzymatic and non-enzymatic activities in the cell, it is conceivable that such mutations affect only one of these functions, leaving the protein free to perform its other functions. PTPN13 knock down mice have so far not been described, and the exact mechanism of action of this phosphatase as well as its role in colorectal cancer development thus awaits further elucidation. 4.4. PTPα 4.4.1. Characteristics of PTPα PTPα is a transmembrane tyrosine phosphatase with a short, unique extracellular domain and two tandem catalytic domains. In comparison to other receptor-like PTPs which are often restricted to a lineagespecific expression, PTPα is widely expressed [109,110]. Two isoforms of PTPα exist, only differing in their extracellular domain, which arise by alternative splicing. The major substrates of PTPα are the Src family kinases (SFKs) [111,112]. By dephosphorylating the inhibitory COOHterminal tyrosine residue of SFKs, PTPα is capable of activating Src family members such as Src and Fyn. Homozygous knockout mice for PTPα (PTPα−/−) are viable, fertile and show no growth abnormalities. Brain lysates of these mice however, show enhanced Src Tyr527 phosphorylation, and reduced activity of the Src family kinases Src and Fyn, confirming results obtained from overexpression studies [113].

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4.4.2. Role of PTPα in colorectal cancer Tabiti et al. first explored the possible involvement of PTPα in colorectal cancer by looking at the mRNA levels of PTPα in tumors compared to adjacent healthy colon mucosa [114]. In the Dukes' D stage carcinoma they found a 2- to 10-fold increase in mRNA levels. As mentioned above, a large fraction of human colon cancers present with increased Src protein tyrosine kinase activity. RNAi against PTPα reduces Src specific activity in different breast cancer and colorectal cancer cell lines, which suppresses anchorage-independent growth and induces apoptosis [115]. More recently, it was shown that in normal tissue PTPα expression was restricted to smooth muscle cells, whereas over 70% of the colon cancer samples showed expression of PTPα. These data support a role for PTPα Src activation in colorectal cancer, and identify this PTP as a potential target for treatment [116]. 5. Cell cycle proteins 5.1. Cdc25 5.1.1. Characteristics of Cdc25 Cdc25 (cell division cycle) phosphatase is a family of human cyclin-dependent kinase activating phosphatases composed of three different members, Cdc25A, Cdc25B, and Cdc25C. They serve as Cdk/ cyclin-activating phosphatases, by removing inhibitory phosphates from the threonine and/or tyrosine residues of these cell cycle proteins. This action is imperative for normal cell cycle progression [117]. Cdc25A is expressed in late G1 phase, where it is essential for G1/S transition through the activation of the cyclin E/CDK2 complex, while Cdc25B and C mainly regulate G2 and G2/M transition [118]. Hence, all three phosphatases seem to be key regulators of mitosis and cell cycle transition. Their relative importance remains controversial though, as knockout models for Cdc25B and double knockouts for both Cdc25B and C seem to develop normally, while Cdc25A knockout mice are embryonically lethal [119]. 5.1.2. Role of Cdc25 in colorectal cancer Different studies have indicated that Cdc25A and B, specifically, may have oncogenic potential. Overexpression of these two phosphatases has been observed in different cancer cell lines and human tumors, suggesting that these PTPs are implicated in human neoplasms [120]. The structure and expression of Cdc25A, B, C, and several splice variants were investigated in a series of 34 paired tumor and normal colorectal tissues. Cdc25B mRNA was overexpressed in 56% of the tumors, whereas Cdc25A and C were overexpressed in 12% and 26% of cases, respectively [121]. Takesama et al. confirmed a 60% overexpression of Cdc25B mRNA level by RT-PCR in colorectal carcinoma [122]. In their unpublished data of a preliminary study they found that Cdc25B expression was relatively low in hepatocellular carcinoma and in esophageal squamous cell carcinoma, although these carcinomas frequently expressed Cdc25A at high levels. They speculated that high levels of Cdc25B may be a characteristic for colorectal carcinoma and went on to demonstrate high Cdc25B in CRC as an independent predictive factor of death with a relative risk of 3.7. As this risk is higher than the relative risk for lymph node metastasis (2.4), which is considered one of the strongest predictors of poor prognosis in colorectal carcinoma, they proposed Cdc25B as a novel prognostic marker in patients with colorectal carcinoma. On the other hand, others did not find statistical evidence for Cdc25B as a good marker for colorectal carcinoma [123]. Recently, the epidermal growth factor receptor has been identified as a target of the Cdc25 proteins. In BRAF mutated colon cancers there seems to be a strong synergistic interaction between BRAF and EGFR. Inhibition of mutated BRAF results in upregulation of EGFR (and PKB) by inhibiting the negative regulatory signal from Cdc25C. Combining BRAF and EGFR inhibitors in several CRC-cell lines results in clear growth inhibition. The same holds true for mouse xenograft models where this combination leads to lack of tumor progression [124].

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Table 2 PTPs discussed in this review with their potential role in colorectal cancer. Phosphatase Role in colorectal cancer

Key ref.

PTEN

[17–20,23]

PRL-3 LMWPTP PTPRT

PTP1B

PTPRJ PTPRH PTPN13 PTPα CDC25

Tumor suppressor gene, inactivated in CRC. Acts as negative regulator of the PI3K/PKB/mTOR pathway by converting PtdIns (3,4,5) P3 to PtdIns (4,5) P2. Oncogene, increased expression in metastatic colorectal cancers. Oncogene, increased levels in colorectal tumors with negative predictors. Tumor suppessor gene, negative regulator of paxillin and STAT3. Inactivating mutations in CRC. Oncogenic potential, activates Src-family members. Gene amplification, enhanced activity in CRC Tumor suppressor gene, LOH in 49% of CRC Oncogenic potential, possibly through canonical Wnt-pathway Dual role, through FAS-mediated apoptosis Oncogene, upgerulation in CRC causes increased Scr activity Oncogene, prognostic marker for survival

[29–35] [49–52] [8,55,56]

[68–71]

[81–86] [89,93] [8,9,102,104,105] [88,111–113] [117–121]

Clearly, Cdc25 is not only involved in mitosis signaling, but has multiple effector function. Further studies are required to specify the role of the different Cdc25 proteins in CRC. 6. Conclusions Protein phosphorylation and dephosphorylation, and in particular phosphorylation on tyrosine, play an important role in several cellular processes, such as the control of cell proliferation, adhesion and migration. These processes are controlled by a tight balance between protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). So far, most research has focussed on the PTKs. In part, this is probably due to historical reasons, as the first PTP was only purified [125] ten years after the first PTK [126]. A variety of PTKs have since been linked to tumorigenesis, and overexpression of PTK activity results in malignant transformation [127]. Because of their antagonistic role on PTKs, PTPs have long been thought to act solely as tumor suppressors, and have received far less attention than they deserve. The lack of interest in the role of PTPs in colorectal cancer is reflected by the relatively low number of PTP knockout models crossed with APC mutants, or knockout animals treated with AOM. The elucidation of the in vivo role of PTPs in CRC development thus awaits the development of new animal models and reanalysis of PTP knockout mice for intestinal carcinogenesis. Emerging evidence, some of which has been discussed in this review, suggests that PTPs have dual roles, both as tumor suppressor genes and oncogenes. Thanks to comprehensive screens, such as those from Wang et al. and Korff et al. [8,9], the role of PTPs in colorectal cancer is now starting to receive more attention. Here, we discuss the role of different PTPs in colorectal cancer (summarized in Table 2). Based on the studies included, we conclude that PTPs not only play an imperative role in oncogenesis, but that some of these phosphatases may also form an attractive target in the battle against colorectal cancer. Acknowledgements G.M.F. was supported by the Dutch Cancer Society (grant EMCR 2010–4737). References [1] D.M. Parkin, F. Bray, J. Ferlay, P. Pisani, Estimating the world cancer burden: Globocan 2000, Int. J. Cancer 94 (2001) 153–156.

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