The atypical DUSPs and their various aliases.
1. Introduction
The dual specificity phosphatases (DUSPs) are a subfamily within the protein tyrosine phosphatase (PTP) family, with the unique property of being able to hydrolyze phospho-serine or phospho-threonine residues and phospho-tyrosine residues [1]. All DUSPs share the characteristic Class I PTP consensus sequence, D…HC(X)5RS/T, with C representing the essential catalytic cysteine [1]. Unlike other PTPs, DUSPs lack the phospho-tyrosine recognition domain, resulting in a shallower catalytic cleft, most likely enabling DUSPs to dephosphorylate all three residues (S/T/Y) [1]. In addition to protein substrates, the DUSP subfamily contains members that dephosphorylate additional substrates including lipids, nucleic acids, and sugars [2].
DUSPs are regulators of multiple signaling pathways driving fundamental cell processes such as growth, proliferation, apoptosis, and migration, and as such they are often deregulated in a variety of diseases [2]. DUSPs can be further classified on substrate specificity and sequence homology, but all DUSPs share a highly conserved prototypical DUSP domain initially characterized in the Vaccinia virus’s VH1 gene [3]. The best-characterized DUSPs include the MAP kinase phosphatases (MKP's), which directly antagonize the activating dual phosphorylation of mitogen activated protein kinases, and PTEN that functions to dephosphorylate phosphatidyl-inositol 3,4,5 triphosphate (PIP3), the product of PI3 kinase (PI3K) [2]. As these signaling pathways are intimately implicated in cancer initiation and progression, it is not surprising that their cognate phosphatases also functionally contribute to disease progression [2,4].
In addition to DUSPs described above, the DUSP subfamily contains a distinct subgroup described as the atypical DUSPs [2,5]. In humans there are at least 16 DUSPs classified as atypical (Table 1) based on the lack of sequence similarity to better-characterized DUSPs and/or due to their substrate specificity [2,5]. Physiological substrates for several atypical
DUSPs include proteins (MAPKs), nucleic aids (RNA), and phosphorylated carbohydrates (amylopectin and glycogen), but for many atypical DUSPs physiological substrates are unknown [2,5]. However, even for cases where phosphatase-substrate relationships are known, they are somewhat complicated by the fact that several DUSPs appear to function independently of their phosphatase activity and instead function as scaffolds in signal transduction pathways [6-8].
Several atypical DUSPs have been implicated in apoptosis and proliferation [2,5], but how the DUSPs contribute to these processes is largely also unknown. Emerging roles for atypical DUSPs in malignancy are beginning to be inferred from high throughput sequencing/ genomic approaches, which have demonstrated that, like MKP's and lipid phosphatases, the atypical DUSP genes are differentially expressed in a variety of cancers and may contribute to cancer initiation and/or progression [2,4,5]. The following sections present a current synthesis of what is known about how the atypical DUSPs function, and will focus specifically on how these proteins may contribute to cancer initiation and progression. Current gaps in knowledge on the function of these proteins in both normal and cancer cell biology is highlighted to hopefully inspire new research on these poorly understood proteins.
2. Atypical DUSPs currently implicated in cancer
2.1. Laforin
Due to alternative splicing of mRNA encoded by the
A role for Laforin as a tumor suppressor was demonstrated by the observation that immunocompromised mice lacking Laforin produce spontaneous lymphomas [19]. Additionally, Laforin mRNA and protein levels were reduced in murine and human primary lymphomas [19]. In addition to the roles of Laforin in glycogen metabolism and Lafora’s disease, Laforin regulates glycogen synthase kinase 3 (GSK3β) activity, a key signaling protein in the β-catenin/WNT signaling pathway [20] by removal of the inhibitory phosphate at Ser9 [21]. Cells lacking Laforin display decreased GSK3β activity resulting in increased cyclin D1 stability, and increased WNT signaling [21,22]. As both cyclin D1 expression and WNT signaling have been implicated in a variety of cancers [20], the ability of Laforin to regulate GSK3β to inhibit cyclin D1 and WNT signaling is a possible mechanism by which Laforin may function as a tumor suppressor. In addition to a GSK3β-dependent role in promoting cell cycle progression [21,22], Laforin additionally possesses pro-survival attributes and may be a potential therapeutic target in lymphomas where low Laforin expression promotes apoptosis induced by energy deprivation, while lymphomas with high Laforin expression are resistant [18]. Laforin's ability to promote cell survival could be related to glycogen metabolism, or alternatively due to its indirect regulation of the WNT signaling pathway via activation of GSK3β [18,19].
Laforin additionally has a role in stress induced proteostasis [23-26]. Knock down of Laforin in human embryonic kidney (HEK293) cells and the neuroblastoma cell line, SH-SY5Y, resulted in increased apoptosis induced by endoplasmic reticulum (ER) stress [24]. Laforin also promotes autophagy by inhibiting the mammalian target of rapamycin (mTOR) pathway by a currently unknown mechanism to further protect cells from ER stress [25]. In addition to targeting genes involved in glycogen metabolism, recruitment of Malin further promotes ubiquitination of misfolded and aggregated proteins, thereby facilitating their proteosomal degradation [27]. Laforin also interacts with heat shock factor 1 (HSF1), an essential transcription factor in the heat shock response [26] and is necessary for up-regulation of HSF1-dependent gene expression and for protection from thermal stress in COS7 cells [26]. Accordingly, increased Laforin expression may allow cancer cells to survive in conditions where proteostasis has been perturbed.
2.2. DUSP3/VHR
Despite the ability of DUSP3 (alternatively named VHR for VH-1 related) to dephosphorylate the ERK1/2 and JNK MAPKs, it is generally not considered a MKP as it lacks the MAPK binding domain characteristic of MKPs [2,28,29]. Nevertheless, as a functional MAPK phosphatase, it is not surprising that DUSP3 is implicated in cancer, where it has been alternatively described as having both oncogenic [30-32] and tumor suppressive [33,34] properties.
DUSP3 may also inhibit tumor growth by regulating proliferation, particularly in the context of breast cancer cells expressing the oncogene,
If DUSP3 functions as a tumor suppressor or oncogene, modulators of DUSP3 function(s) could be attractive anti-cancer drug targets. The ZAP70 cytoplasmic tyrosine kinase, a key component in signaling machinery downstream of the T-cell antigen receptor, directly phosphorylates DUSP3 on tyrosine 138 (Y138) and increases it's ability to temper Erk1/2 and JNK signaling and reduce expression of a NFAT-AP1 dependent luciferase reporter, as VHRY138F functions as a dominant negative [38]. This observation is consistent with Y138 increasing the catalytic activity VHR, but this hypothesis is technically difficult to confirm due to VHR's ability to auto-dephosphorylate [38]. ZAP70 has been implicated in cancer as it is a prognostic marker for chronic lymphocytic leukemia (CLL) and B-cell acute lymphoblastic leukemia (B-ALL) where increased ZAP70 expression correlates with poor clinical outcome [39,40]. Besides being a prognostic marker, ZAP70 contributes to cancer by promoting survival and migration in both CLL and B-ALL [41,42] but whether ZAP70's modulation of DUSP3 has importance in B-ALL and CLL remains unknown. ZAP70 is not the only tyrosine kinase to target DUSP3 at tyrosine 138. TYK2, the non receptor tyrosine kinase of the Janus kinase family that regulates the expression of type 1 interferons and interleukin 12 [43] also targets this site [44]. Phosphorylation of DUSP3 by TYK2 was required for DUSP3 to dephosphorylate and inhibit signal transducer and activator of transcription 5 (STAT5) [44]. The ability of DUSP3 to inhibit STAT5 transcriptional activity may have consequences in cancer cell biology, since STAT5 activity is known to promote cancer by transcriptionally regulating genes involved in proliferation and survival [45], therefore loss of DUSP3 activity could possibly result in increased STAT5 activity thereby promoting cancer development. Furthermore, TYK2 has a suggested role in breast cancer metastasis, as analysis of 140 tissue samples from 70 breast cancer patients revealed that TYK2 protein levels are reduced in tumors that have metastasized to the regional lymph nodes [46]. Additionally, knock-down of
DUSP3’s activity is additionally activated by the pseudokinase, Vaccinia-related kinase 3 (VRK3) [47], whose expression is down-regulated in colorectal cancer [48]. VRK3 inhibits ERK1/2 signaling by the formation of a VRK3-DUSP3-ERK1/2 complex where VRK3 is able to enhance the activity of DUSP3 towards ERK1/2 in a kinase independent manner [47]. It would be interesting to examine whether tumors with decreased
2.3. DUSP11
Due to interactions with ribonucleoprotein (RNP) complexes and RNA splicing factors and its ability to dephosphorylate RNA trinucleotides, DUSP11 is thought to have a role in RNA splicing [49]. DUSP11 also associates with SAM68 (SRC-associated protein in mitotic cells), an ERK1/2 phosphorylated splicing factor that promotes the alternative splicing of cluster of differentiation 44
DUSP11 regulates proliferation as over-expression of
2.4. DUSP12
DUSP12 was initially identified as a pro-survival phosphatase from a high throughput siRNA screen in HeLa cells [62] as knock-down of
DUSP12 interacts with the heat shock protein 70 (HSP70) and the requirement of the enzymatic activity to protect cells from apoptosis activity raises the possibility that HSP70 may be a direct substrate for DUSP12. However, if DUSP12 does regulate HSP70, it does not appear to regulate HSP70’s chaperone function as demonstrated by
DUSP12 also has a role in cell cycle regulation. Transient over-expression of
To determine whether DUSP12 has oncogenic properties, we examined the oncogenic potential of DUSP12 in a cell culture model [67]. Unlike the cell cycle effects in HEK293 cells transiently over-expressing
Although it is clear that DUSP12 regulates several important cancer-relevant processes, how DUSP12 accomplishes this is largely unknown. Insights into DUSP12’s cellular function(s) can be obtained by investigating the budding yeast DUSP12 ortholog, Yvh1p.
Recent independent genetic screens in yeast have revealed that Yvh1p is a critical factor in ribosome biogenesis [77,78]. Ribosome biogenesis is an extremely complex process that is regulated both spatially and temporally [79]. Ribosomal RNA is transcribed and processed in the nucleolus and the pre-40S and pre-60S subunits, are assembled in the nucleus [79]. The pre-40S and pre-60S subunits are exported into the cytoplasm where additional maturation occurs including the binding of multiple translation initiation factors to the small ribosomal subunit to form a 48S complex [79]. Upon recognition of the Met initiation anticodon, the translation initiation factors are expelled to facilitate the joining of the large 60S ribosomal subunit to form a translationally competent 80S ribosome [79]. Defects within specific steps or association of proteins with defined complexes within this multistep process can be inferred from polysome analyses as each complex in endowed with a unique sedimentation coefficient within sucrose gradients [80]. Polysome analysis in yeast demonstrated that Yvh1p associates with pre-60S ribosomes and loss of
A similar role for DUSP12 regulating ribosome biogenesis in humans is borne from observations that knock-down of human
2.5. DUSP18
2.6. DUSP22
DUSP22 expression is down-regulated in breast cancer and lymphomas [95, 96], and is used as a prognostic marker for B cell chronic lymphocytic leukemia patients [97]. In anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphomas, the commonly found t(6;7)(p25.3;q32.3) translocation disrupts the
There are conflicting reports concerning the ability of DUSP22 to dephosphorylate MAPKs [97-100], but most studies indicate DUSP22 as a regulator of JNK [99-101]. Over-expression of both JNK and DUSP22 in COS7 suppressed JNK phosphorylation [99]. However, other reports have identified a phosphatase-dependent role for DUSP22 in promoting JNK activity [100,101]. Glutathione S-transferase (GST) pull downs and immunoprecipitations revealed that DUSP22 can bind the JNK activating kinase, MKK7, but not JNK itself, and the association with MKK7 activates MKK7's phosphorylation of JNK [99]. Exactly how DUSP22 activates MKK7 and JNK activity is unclear but the requirement is biologically significant as mouse embryonic stem cells lacking DUSP22 were unable to activate JNK in response to cytokines [100].
Another reported substrate of DUSP22 is the estrogen receptor (ERα) an important prognostic marker for breast cancer regulating proliferation and apoptosis [102,103]. DUSP22 most likely functions within a negative feedback loop to regulate ERα, as activation of ERα induces
DUSP22 may also regulate metastasis as it dephosphorylates tyrosines 576/577 and 397 of focal adhesion kinase (FAK) [104]. FAK is a key regulator of integrin-mediated attachment and FAK inhibition results in detachment and apoptosis in some cell lines [105].
2.7. DUSP23
DUSP23 dephosphorylates ERK1/2
The
2.8. DUSP26
A role for
The cellular function of DUSP26 is also unclear as the substrates for DUSP26 are debated. DUSP26 can dephosphorylate the tumor suppressor p53 at Ser20 and Ser37, inhibiting p53-mediated apoptosis induced by genotoxic stress [112], suggesting a pro-survival role. In addition to p53, several other
DUSP26 is also implicated in regulating the kinesin superfamily 3 (KIF3) microtubule-directed protein motor complex by dephosphorylating the kinesin-associated protein 3 (KAP3) [111]. The KIF3 motor complex has been implicated in cancer due to its ability to traffic cancer relevant proteins including, adenamaous polyposis coli (APC), β-catenin, cadherins, and the polarity complex, PAR3 [115,116]. Consistent with DUSP26 functioning as a positive regulator of KIF3, over-expression of
3. Less well-characterized atypical DUSPs.
The previous sections discussed the atypical DUSPs that have been described in the literature as having a relationship, however tenuous or controversial, to tumor suppressive and/or oncogenic properties and are often supported by genetic/genomic analyses of primary tumors samples. Although the previous sections should reaffirm that the function(s) of many of the atypical DUSPs are likely both cell type and context dependent, we nevertheless undertook a comparison of the expression profiles of all the atypical DUSPs in tumors of the prostate to normal prostate tissue using the cBio Cancer Genomics Portal (http://www.cbioportal.org/) and microarray data deposited by the Memorial Sloan-Kettering Cancer (MSKCC) Center’s Prostate Oncogenome Project [117]. Comparison of the transcriptome of 85 tumors to normal prostate tissue revealed that many atypical DUSPs have aberrant expression in prostate cancer (Table 2). In at least two cases this difference
Gene | Down | Up | Total |
EPM2A | 13% | 0% | 13% |
STYX | 2% | 7% | 9% |
DUSP3 | 40% | 0% | 40% |
DUSP11 | 4% | 5% | 8% |
DUSP12 | 1% | 15% | 16% |
DUSP13 | 0% | 5% | 5% |
DUSP14 | 6% | 11% | 16% |
DUSP15 | 4% | 0% | 4% |
DUSP18 | 40% | 4% | 44% |
DUSP19 | 1% | 1% | 2% |
DUSP21 | 0% | 7% | 7% |
DUSP22 | 15% | 2% | 18% |
DUSP23 | 11% | 8% | 19% |
DUSP26 | 1% | 2% | 4% |
DUSP27 | 2% | 5% | 7% |
Androgen Receptor (AR) | 2% | 7% | 9% |
was reflected clinically as patients harboring tumors with aberrant
3.1. STYX
The prototypical pseudophosphatase, STYX, contains a substitution of the catalytic cysteine for glycine, rendering it catalytically inactive [118]. As this mutation abrogates catalysis, but not substrate binding, pseudophosphatases are though to function as substrate traps preventing dephosphorylation of the target protein(s) [119]. In mice,
3.2. DUSP13A/B
The
3.3. DUSP14
3.4. DUSP15
The DUSP15 crystal structure reveals it lacks the MAPK substrate recognition domain and it has a unique additional alpha helix located at the back end of the active site suggesting that DUSP15 has unique substrate recognition mechanisms [129]. DUSP15 displays phosphatase activity against the artificial substrate pNPP
3.5. DUSP19
Like DUSP13A, DUSP19 is thought to facilitate ASK1 activation leading to MKK7 activation and in turn activating JNK as DUSP19 directly binds MKK7, but not JNK
3.6. DUSP21
Similar to DUSP18, DUSP21 contains a highly conserved mitochondrial localization signal, however DUSP21 localizes to the peripheral membrane of the inner membrane of the mitochondria, which is the opposing side to which DUSP18 is found [91]. DUSP21 exhibits activity against synthetic MAPK peptides
3.7. DUSP27
Substrates for the newest atypical DUSP, DUSP27, are unknown but solution of the DUSP27 3D structure suggests that it may have substrates other than the MAPKs [133]. The catalytic site can accommodate dually-phosphorylated residues separated by two amino acids, which differs from the catalytic site of DUSPs that can dephosphorylate the characteristic MAPK activation loop (T-X-Y) [133].
4. Conclusion
Although many atypical DUSPs display differential expression in tumor samples, significant amounts of work will be required to determine whether and how these differences contribute to malignancy, especially with the common discrepancy between
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