The atypical DUSPs and their various aliases.
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 . All DUSPs share the characteristic Class I PTP consensus sequence, D…HC(X)5RS/T, with C representing the essential catalytic cysteine . 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) . In addition to protein substrates, the DUSP subfamily contains members that dephosphorylate additional substrates including lipids, nucleic acids, and sugars .
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 . 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 . 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) . 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
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 . Additionally, Laforin mRNA and protein levels were reduced in murine and human primary lymphomas . 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  by removal of the inhibitory phosphate at Ser9 . 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 , 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 . 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 . 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 . 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 . Laforin also interacts with heat shock factor 1 (HSF1), an essential transcription factor in the heat shock response  and is necessary for up-regulation of HSF1-dependent gene expression and for protection from thermal stress in COS7 cells . Accordingly, increased Laforin expression may allow cancer cells to survive in conditions where proteostasis has been perturbed.
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 . 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 . 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  also targets this site . Phosphorylation of DUSP3 by TYK2 was required for DUSP3 to dephosphorylate and inhibit signal transducer and activator of transcription 5 (STAT5) . 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 , 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 . Additionally, knock-down of
DUSP3’s activity is additionally activated by the pseudokinase, Vaccinia-related kinase 3 (VRK3) , whose expression is down-regulated in colorectal cancer . 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 . It would be interesting to examine whether tumors with decreased
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 . 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
DUSP12 was initially identified as a pro-survival phosphatase from a high throughput siRNA screen in HeLa cells  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 . 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 . Ribosomal RNA is transcribed and processed in the nucleolus and the pre-40S and pre-60S subunits, are assembled in the nucleus . 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 . 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 . 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 . 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
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 . 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 . 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 . 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 .
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) . FAK is a key regulator of integrin-mediated attachment and FAK inhibition results in detachment and apoptosis in some cell lines .
DUSP23 dephosphorylates ERK1/2
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 , 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) . 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 . 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
|Androgen Receptor (AR)||2%||7%||9%|
was reflected clinically as patients harboring tumors with aberrant
The prototypical pseudophosphatase, STYX, contains a substitution of the catalytic cysteine for glycine, rendering it catalytically inactive . As this mutation abrogates catalysis, but not substrate binding, pseudophosphatases are though to function as substrate traps preventing dephosphorylation of the target protein(s) . In mice,
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 . DUSP15 displays phosphatase activity against the artificial substrate pNPP
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
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 . DUSP21 exhibits activity against synthetic MAPK peptides
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 . 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) .
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
and Denu J. M Dixon J. E 1995 A catalytic mechanism for the dual-specific phosphatases.Proc. Natl. Acad. Sci. U. S. A. 92 13 5910 5914
phosphatases: critical regulators with diverse cellular targets. Biochem. J. Patterson K. I Brummer T O Brien P. M Daly R. J 2009 Dual-specificity 418 475 489
Barford D Das A. K Egloff M. P 1998 The structure and mechanism of protein phosphatases: insights into catalysis and regulation.Annu. Rev. Biophys. Biomol. Struct. 127 133 164
Jeffrey K. L Camps M Rommel C Mackay C. R 2007 Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses.Nat. Rev. Drug. Discov. 6 5 391 403
and Bayon Y Alonso A 2010Atypical DUSPs: 19 phosphatases in search of a role. In: Lazo PA, editor. Emerging Signaling Pathways in Tumor Biology. Kerala: Transworld Research Network. 185 208
Takagaki K Satoh T Tanuma N Masuda K Takekawa M Shima H et al 2004 Characterization of a novel low-molecular-mass dual-specificity phosphatase-3 (LDP-3) that enhances activation of JNK and 38Biochem. J. 383(Pt. 3):447-455.
Lee do H, et al. ( Park J. E Park B. C Kim H. A Song M Park S. G 2010 Positive regulation of apoptosis signal-regulating kinase 1 by dual-specificity phosphatase 13ACell Mol. Life Sci. 67 15 2619 2629
Zama T Aoki R Kamimoto T Inoue K Ikeda Y Hagiwara M 2002 Scaffold role of a mitogen-activated protein kinase phosphatase, SKRP1, for the JNK signaling pathway.J. Biol. Chem. Jun 28; 277 26 23919 23926
Dubey D Parihar R Ganesh S 2012 Identification and characterization of novel splice variants of the human EPM2A gene mutated in Lafora progressive myoclonus epilepsy 99 1 36 43
Ganesh S Suzuki T Yamakawa K 2002 Alternative splicing modulates subcellular localization of laforinBiochem. Biophys. Res. Commun. 291 5 1134 1137
Ianzano L Young E. J Zhao X. C Chan E. M Rodriguez M. T Torrado M. V et al 2004 Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy.Hum. Mutat. 23 2 170 176
Ganesh S Puri R Singh S Mittal S Dubey D 2006 Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsyJ. Hum. Genet. 51 1 1 8
Singh S Satishchandra P Shankar S. K Ganesh S 2008 Lafora disease in the Indian population: EPM2A and NHLRC1 gene mutations and their impact on subcellular localization of laforin and malin.Hum. Mutat. 29(6):E 1 12
Worby C. A Gentry M. S Dixon J. E 2006Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J. Biol. Chem. 281 41 30412 30418
Wang J Stuckey J. A Wishart M. J Dixon J. E 2002 A unique carbohydrate binding domain targets the lafora disease phosphatase to glycogen.J. Biol. Chem. 277 4 2377 2380
Worby C. A Gentry M. S Dixon J. E 2008 Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG)J. Biol. Chem. 283 7 4069 4076
Wang J. Y Lin C. H Yang C. H Tan T. H Chen Y. R 2006 Biochemical and biological characterization of a neuroendocrine-associated phosphataseJ. Neurochem. 98 1 89 101
Wang Y Liu Y Wu C Mcnally B Liu Y Zheng P 2008Laforin confers cancer resistance to energy deprivation-induced apoptosis. Cancer Res. 68 11 4039 4044
Wang Y Liu Y Wu C Zhang H Zheng X Zheng Z et al 2006 Epm2a suppresses tumor growth in an immunocompromised host by inhibiting Wnt signaling 10 3 179 190
Polakis P 2012 Wnt Signaling in Cancer.Cold Spring Harb. Perspect. Biol. Mar 20 DOI:cshperspect.a008052.
Liu Y Wang Y Wu C Liu Y Zheng P 2006 Dimerization of Laforin is required for its optimal phosphatase activity, regulation of GSK3beta phosphorylation, and Wnt signaling.J. Biol. Chem. 281 46 34768 34774
Liu R Wang L Chen C Liu Y Zhou P Wang Y et al 2008 Laforin negatively regulates cell cycle progression through glycogen synthase kinase 3beta-dependent mechanisms.Mol. Cell Biol. 28 23 7236 7244
Liu Y Wang Y Wu C Liu Y Zheng P 2009 Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stressHum. Mol. Genet. 18 14 2622 2631
Rodriguez de Cordoba S, Sanz Vernia S Rubio T Heredia M 2009 Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforinPLoS One. 4(6):e5907.
Aguado C Sarkar S Korolchuk V. I Criado O Vernia S Boya P et al 2010 Laforin, the most common protein mutated in Lafora disease, regulates autophagyHum. Mol. Genet. 19 14 2867 2876
Sengupta S Badhwar I Upadhyay M Singh S Ganesh S 2011 Malin and laforin are essential components of a protein complex that protects cells from thermal stressJ. Cell Sci. 124(Pt 13): 2277 EOF 2286 EOF
Garyali P Siwach P Singh P. K Puri R Mittal S Sengupta S et al 2009 The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome systemHum. Mol. Genet. 18 4 688 700
Todd J. L Tanner K. G Denu J. M 1999 Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.J. Biol. Chem. 274 19 13271 13280
Todd J. L Rigas J. D Rafty L. A Denu J. M 2002 Dual-specificity protein tyrosine phosphatase VHR down-regulates c-Jun N-terminal kinase (JNK) 21 16 2573 2583
Henkens R Delvenne P Arafa M Moutschen M Zeddou M Tautz L et al 2008 Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR. 147 EOF
Wu S Vossius S Rahmouni S Miletic A. V Vang T Vazquez-rodriguez J et al 2009 Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cellsJ. Med. Chem. 52 21 6716 6723
Arnoldussen Y. J Lorenzo P. I Pretorius M. E Waehre H Risberg B Maelandsmo G. M et al 2008 The mitogen-activated protein kinase phosphatase vaccinia H1-related protein inhibits apoptosis in prostate cancer cells and is overexpressed in prostate cancerCancer Res. 68 22 9255 9264
Wang J. Y Yeh C. L Chou H. C Yang C. H Fu Y. N Chen Y. T et al 2011 Vaccinia H1-related phosphatase is a phosphatase of ErbB receptors and is down-regulated in non-small cell lung cancerJ. Biol. Chem. 286 12 10177 10184
and Hao L Elshamy W. M 2007 BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHR.Int. J. Cancer. 121 1 39 46
Rahmouni S Cerignoli F Alonso A Tsutji T Henkens R Zhu C et al 2006 Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence.Nat. Cell Biol. 8 5 524 531
and Elshamy W. M Livingston D. M 2004 Identification of BRCA1-IRIS, a BRCA1 locus product.Nat. Cell Biol. 6 10 954 967
and Howe L. R Brown P. H 2011 Targeting the HER/EGFR/ErbB family to prevent breast cancerCancer Prev. Res. (Phila). 4 8 1149 1157
Alonso A Rahmouni S Williams S Van Stipdonk M Jaroszewski L Godzik A et al 2003Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nat. Immunol. 4 1 44 48
Sagatys E. M Zhang L 2012 Clinical and laboratory prognostic indicators in chronic lymphocytic leukemia 19 1 18 25
Chiaretti S Guarini A De Propris M. S Tavolaro S Intoppa S Vitale A et al 2006 ZAP-70 expression in acute lymphoblastic leukemia: association with the E2A/PBX1 rearrangement and the pre-B stage of differentiation and prognostic implications. 107 1 197 204
L, et al. ( Deaglio S Vaisitti T Aydin S Bergui L D Arena G Bonello 2007 CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential. 110 12 4012 4021
Richardson S. J Matthews C Catherwood M. A Alexander H. D Carey B. S Farrugia J et al 2006 ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL). 107 9 3584 3592
Shimoda K Kato K Aoki K Matsuda T Miyamoto A Shibamori M et al 2000 Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. 13 4 561 571
Hoyt R Wei Z Cerignoli F Alonso A and Mustelin T David M 2007 Cutting Edge: Selective Tyrosine Dephosphorylation of Interferon-Activated Nuclear STAT5 by the VHR Phosphatase.J. Immunol. 179 6 3402 3406
Silva C. M 2004 Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. 23 8017 8023
Sang Q. X Man Y. G Sung Y. M Khamis Z. I Zhang L Lee M. H et al 2012 Non-receptor tyrosine kinase 2 reaches its lowest expression levels in human breast cancer during regional nodal metastasis.Clin. Exp. Metastasis. 29 2 143 153
and Kang T. H Kim K. T 2006 Negative regulation of ERK activity by VRK3-mediated activation of VHR phosphatase.Nat. Cell Biol. 8 8 863 869
Hennig E. E Mikula M Rubel T Dadlez M Ostrowski J 2012 Comparative kinome analysis to identify putative colon tumor biomarkersJ. Mol. Med. (Berl). 90 4 447 456
Yuan Y Li D. M Sun H 1998 PIR1, a novel phosphatase that exhibits high affinity to RNA. ribonucleoprotein complexes.J, Biol. Chem. 273 32 20347 20353
Matter N Herrlich P Konig H 2002 Signal-dependent regulation of splicing via phosphorylation of Sam68. 420 6916 691 695
Arch R Wirth K Hofmann M Ponta H Matzku S Herrlich P et al 1992 Participation in normal immune responses of a metastasis-inducing splice variant of CD44.Science. 257 5070 682 685
and Blair C. A Zi X 2011 Potential molecular targeting of splice variants for cancer treatmentIndian J. Exp. Biol. 49 11 836 839
Caprara G Zamponi R Melixetian M Helin K 2009 Isolation and characterization of DUSP11, a novelJ. Cell Mol. Med. 13(8B):2158-2170. 53target gene
and Suzuki K Matsubara H 2011 Recent advances inJ. Biomed. Biotechnol. 2011:978312. 53research and cancer treatment
Hanahan D Weinberg R. A 2011 Hallmarks of cancer: the next generationCell. 144 5 646 674
Hirai M Yoshida S Kashiwagi H Kawamura T Ishikawa T Kaneko M et al 1999 1q23 gain is associated with progressive neuroblastoma resistant to aggressive treatment.Chromosomes Cancer. 25 261 269
Gratias S Schuler A Hitpass L. K Stephan H Rieder H Schneider S et al 2005 Genomic gains on chromosome 1q in retinoblastoma: consequences on gene expression and association with clinical manifestation.Int. J. Cancer. 116 555 563
Mendrzyk F Korshunov A Benner A Toedt G Pfister S Radlwimmer B et al 2006 Identification of Gains on 1q and Epidermal Growth Factor Receptor Overexpression as Independent Prognostic Markers in Intracranial Ependymoma.Clin. Cancer Res. 12 2070 2079
Biernacki M. A Marina O Zhang W Liu F Bruns I Cai A et al 2010 Efficacious immune therapy in chronic myelogenous leukemia (CML) recognizes antigens that are expressed on CML progenitor cellsCancer Res. 70 3 906 915
Kresse S. H Berner J. M Meza-zepeda L. A Gregory S. G Kuo W. L Gray J. W et al 2005 Mapping and characterization of the amplicon near APOA2 in 1q23 in human sarcomas by FISH and array CGHMol. Cancer. 4:39.
Muda M Manning E. R Orth K Dixon J. E 1999 Identification of the Human YVH1 Protein-tyrosine Phosphatase Orthologue Reveals a Novel Zinc Binding Domain Essential for in Vivo Function.J. of Biol. Chem. 274 23991 23995
MacKeigan JPMurphy LO, Blenis J ( 2005 Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance.Nat. Cell Biol. 7 591 600
Sharda P. R Bonham C. A Mucaki E. J Butt Z Vacratsis P. O 2009 The dual-specificity phosphatase hYVH1 interacts with Hsp70 and prevents heat-shock-induced cell deathBiochem. J. 418 2 391 401
and Denu J. M Tanner K. G 1998 Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation.Biochemistry. 37 16 5633 5642
and Bonham C. A Vacratsis P. O 2009 Redox regulation of the human dual specificity phosphatase YVH1 through disulfide bond formation.J. Biol. Chem. 21; 284 34 22853 22864
Kozarova A Hudson J. W Vacratsis P. O 2011 The dual-specificity phosphatase hYVH1 (DUSP12) is a novel modulator of cellular DNA content 10 10 1669 1678
Cain E. L Braun S. E Beeser A 2011 Characterization of a human cell line stably over-expressing the candidate oncogene, dual specificity phosphatase 12PLoS One. 6(4):e18677.
Lochter A Navre M Werb Z Bissell M. J 1999a1 and a2 Integrins Mediate Invasive Activity of Mouse Mammary Carcinoma Cells through Regulation of Stromelysin-1 Expression. Mol. Biol. Cell. 10 271 282
a Unique Collagen-dependent Proliferation Pathway In Vivo. J. Cell Biol. Pozzi A Wary K. K Giancotti F. G Gardner H. A 1998 Integrin a b Mediates 142 587 594
Senger D. R Perruzzi C. A Streit M Koteliansky V. E De Fougerolles A. R Detmar M 2002 The alpha1beta1 and alpha2beta1 Integrins Provide Critical Support for Vascular Endothelial Growth Factor Signaling, Endothelial Cell Migration, and Tumor Angiogenesis. Am. J.Pathol. 160 195 204
Vande Woude GF ( Birchmeier C Birchmeier W Gherardi E 2003 Met, metastasis, motility and more. Nat. Rev. Mol. Cell Biol. 4 915 925
Fukuda T Ichimura E Shinozaki T Sano T Kashiwabara K Oyama T et al 1998Coexpression of HGF and c-MET/HGF receptor in human bone and sof tissue tumors. Pathol. Int. 48 757 762
Mueller M. M Fusenig N. E 2004Friends or foes- bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer. 4 11 839 849
Guan K Hakes D. J Wang Y Park H. D Cooper T. G Dixon J. E 1992 A yeast protein phosphatase related to the vaccinia virus VH1 phosphatase is induced by nitrogen starvation.Proc. Natl. Acad. Sci. U. S. A. 89 12175 12179
Sakumoto N Mukai Y Uchida K Kouchi T Kuwajima J Nakagawa Y et al 1999A series of protein phosphatase gene disruptants in Saccharomyces cerevisiae. Yeast. 15 15 1669 1679
and Beeser A. E Cooper T. G 2000 The Dual-Specificity Protein Phosphatase Yvh1p Regulates Sporulation, Growth, and Glycogen Accumulation Independently of Catalytic Activity in Saccharomyces cerevisiae via the Cycle AMP-Dependent Protein Kinase Cascade.J. Bacteriol. 182 3517 3528
Kemmler S Occhipiniti L Veisu M Panse V. G 2009 Yvh1 is required for a late maturation step in the 60S biogenesis pathwayJ. Cell Biol. 186 863 880
Lo K Li Z Wang F Marcotte E. M Johnson A. W 2009 Ribosome stalk assembly requires the dual-specificity phosphatase Yvh1 for the exchange of Mrt4 with 0J. Cell Biol. 186:849-862.
Kressler D Hurt E Bassler J 2010 Driving ribosome assemblyBiochim. Biophys. Acta. 1803 6 673 683
Jr ( Rotenberg M. O Moritz M Woolford J. L 1988 Depletion of Saccharomyces cerevisiae ribosomal protein L16 causes a decrease in 60S ribosomal subunits and formation of half-mer polyribosomes.Genes Dev. 2 2 160 172
and Liu Y Chang A 2009 A mutant plasma membrane protein is stabilized upon loss of Yvh1, a novel ribosome assembly factorGenetics. 181 3 907 915
Tchorzewski M Krokowski D Rzeski W Issinger O. G Grankowski N 2003The subcellular distribution of the human ribosomal "stalk" components: 1P2 and P0 proteins. Int. J. Biochem. Cell Biol. 35(2):203-211.
Sugiyama M Nugroho S Iida N Sakai T Kaneko Y Harashima S 2011 Genetic interactions of ribosome maturation factors Yvh1 and Mrt4 influence mRNA decay, glycogen accumulation, and the expression of early meiotic genes in Saccharomyces cerevisiaeJ. Biochem. 150 1 103 111
Lo K. Y Li Z Bussiere C Bresson S Marcotte E. M Johnson A. W 2010 Defining the pathway of cytoplasmic maturation of the 60S ribosomal subunitMol. Cell. 30; 39 2 196 208
Silvera D Formenti S. C Schneider R. J 2010 Translational control in cancerNat. Rev. Cancer. 10 4 254 266
Calkhoven C. F Muller C Leutz A 2002 Translational control of gene expression and disease.Trends Mol. Med. 8 12 577 583
Wu Q Huang S Sun Y Gu S Lu F Dai J et al 2006 Dual specificity phosphotase 18, interacting with SAPK, dephosphorylates SAPK and inhibits SAPK/JNK signal pathway in vivoFront Biosci. 11 2714 2724
Jeong D. G Cho Y. H Yoon T. S Kim J. H Son J. H Ryu S. E Kim S. J 2006 Structure of human DSP18, a member of the dual-specificity protein tyrosine phosphatase familyAxta. Crystallogr. D. Biol. Crystallogr. 62 582 588
Wu Q Gu S Dai J Dai J Wang L Li Y et al 2003 Molecular cloning and characterization of a novel dual-specificity phosphatase18 gene from human fetal brainBiochim. Biophys. Acta. 1625 3 296 304
Hood K. L Tobin J. F Yoon C 2002 Identification and characterization of two novel low-molecular-weight dual specificity phosphatasesBiochem. Biophys. Res. Commun. 298 4 545 551
Rardin M. J Wiley S. E Murphy A. N Pagliarini D. J Dixon J. E 2008 Dual specificity phosphatases 18 and 21 target to opposing sides of the mitochondrial inner membrane. JBiol. Chem. 283 22 15440 15450
Rennefahrt U Illert B Greiner A Rapp U. R Troppmair J 2004 Tumor induction by activated JNK occurs through deregulation of cellular growth.Cancer. Lett. 215(1): 113 124
Whitfield J Neame S. J Paquet L Bernard O Ham J 2001 Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. 29 3 629 643
Han Z Boyle D. L Chang L Bennett B Karin M Yang L et al 2001 c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis.J Clin. Invest. 108 1 73 81
Bernard-pierrot I Gruel N Stransky N Vincent-salomon A Reyal F Raynal V et al 2008 Characterization of the recurrent 8Cancer Res. 68(17):7165-7175. 11 12amplicon identifies PPAPDC1B, a phosphatase protein, as a new therapeutic target in breast cancer
Feldman A. L Dogan A Smith D. I Law M. E Ansell S. M Johnson S. H et al 2011Discovery of recurrent t(6;7)( 25q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood. 117(3):915-919.
Jantus Lewintre EReinoso Martin C, Montaner D, Marin M, Jose Terol M, Farras R, et al. ( 2009Analysis of chronic lymphotic leukemia transcriptomic profile: differences between molecular subgroups. Leuk. Lymphoma. 50 1 68 79
Alonso A Merlo J. J Na S Kholod N Jaroszewski L Kharitonenkov A et al 2002 Inhibition of T cell antigen receptor signaling by VHR-related MKPX (VHX), a new dual specificity phosphatase related to VH1 related (VHR).J. Biol. Chem. 277 7 5524 5528
Aoyama K Nagata M Oshima K Matsuda T Aoki N 2001 Molecular cloning and characterization of a novel dual specificity phosphatase, LMW-DSP2, that lacks the cdc25 homology domain.J. Biol. Chem. 276 29 27575 27583
Chen A. J Zhou G Juan T Colicos S. M Cannon J. P Cabriera-hansen M et al 2002 The dual specificity JKAP specifically activates the c-Jun N-terminal kinase pathway.J. Biol. Chem. 277 39 36592 36601
Shen Y Luche R Wei B Gordon M. L Diltz C. D Tonks N. K 2001 Activation of the Jnk signaling pathway by a dual-specificity phosphatase, JSP-1Proc. Natl. Acad. Sci. U. S. A. 98 24 13613 13618
Sekine Y Ikeda O Hayakawa Y Tsuji S Imoto S Aoki N et al 2007DUSP22/LMW-DSP2 regulates estrogen receptor-alpha-mediated signaling through dephosphorylation of Ser-118. Oncogene. 26 41 6038 6049
Chen G. G Zeng Q Tse G. M 2008 Estrogen and its receptors in cancerMed. Res. Rev. 28 6 954 974
Li J. P Fu Y. N Chen Y. R Tan T. H 2010 JNK pathway-associated phosphatase dephosphorylates focal adhesion kinase and suppresses cell migrationJ. Biol. Chem. 2010 285 8 5472
( Martin GS 2003) Cell signaling and cancer. Cancer Cell. 4 3 167 174.
- 106. Schwertassek U, Buckley DA, Xu CF, Lindsay AJ, McCaffrey MW, Neubert TA, et al. (2010) Myristoylation of the dual-specificity phosphatase c-JUN N-terminal kinase (JNK) stimulatory phosphatase 1 is necessary for its activation of JNK signaling and apoptosis. FEBS. J. 277(11):2463-2473.
Caren H Djos A Nethander M Sjoberg R. M Kogner P Enstrom C et al 2011 Identification of epigenetically regulated genes that predict patient outcome in neuroblastoma. 66 EOF
Tang J. P Tan C. P Li J Siddique M. M Guo K Chan S. W et al 2010 VHZ is a novel centrosomal phosphatase associated with cell growth and human primary cancersMol. Cancer. 9:128.
Yu W Imoto I Inoue J Onda M Emi M Inazawa J 2007A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting 38MAPK activity. Oncogene. 26(8):1178-1187.
Tanuma N Nomura M Ikeda M Kasugai I Tsubaki Y Takagaki K et al 2009 Protein phosphatase Dusp26 associates with KIF3 motor and promotes N-cadherin-mediated cell-cell adhesion 28 5 752 761
negatively affects the proliferation of epithelial cells, an effect not mediated by dephosphorylation of MAPKs. Biochim. Biophys. Acta. Patterson K. I Brummer T Daly R. J O Brien P. M 2010 Dusp 1803 9 1003 1012
Shang X Vasudevan S. A Yu Y Ge N Ludwig A. D Wesson C. L et al 2010 Dual-specificity phosphatase 26 is a novel 53phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma
Vasudevan S. A Skoko J Wang K Burlingame S. M Patel P. N Lazo J. S et al 2005 MKP-8, a novel MAPK phosphatase that inhibitsBiochem. Biophys. Res. Commun. 330(2):511-518. 38kinase.
Lee do H, Choi HK, Park BC, Ryu SE, Kim JH, Cho S ( Song M Park J. E Park S. G 2009NSC-87877, Inhibitor of SHP-1/2 PTPs, inhibits dual-specificity phosphatase 26 (DUSP26). Biochem. Biophys. Res. Commun. 381 4 491 495
Jimbo T Kawasaki Y Koyama R Sato R Takada S Haraguchi K et al 2002 Identification of a link between the tumour suppressor APC and the kinesin superfamily.Nat. Cell Biol. 4 4 323 327
Nishimura T Kato K Yamaguchi T Fukata Y Ohno S Kaibuchi K 2004 Role of the PAR-Nat. Cell Biol. 6(4):328-334. 3KIF3 complex in the establishment of neuronal polarity.
Taylor B. S Schultz N Hieronymus H Gopalan A Xiao Y Carver B. S et al 2010Integrative genomic profiling of human prostate cancer. Cancer Cell. 18 1 11 22
and Wishart M. J Dixon J. E 2002 The archetype STYX/dead-phosphatase complexes with a spermatid mRNA-binding protein and is essential for normal sperm production.Proc. Natl. Acad. Sci. U. S. A. 99 4 2112 2117
and Wishart M. J Dixon J. E 1998 Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains.Trends Biochem. Sci. 23 8 301 306
Alonso A Sasin J Bottini N Friedberg I Friedberg I Osterman A et al 2004Protein tyrosine phosphatases in the human genome. Cell. 117 6 699 711
Chen H. H Luche R Wei B Tonks N. K 2004 Characterization of two distinct dual specificity phosphatases encoded in alternative open reading frames of a single gene located on human chromosome 10q22.2.J. Biol. Chem. 279 40 41404 41413
Nakamura K Shima H Watanabe M Haneji T Kikuchi K 1999 Molecular cloning and characterization of a novel dual-specificity protein phosphatase possibly involved in spermatogenesis.Biochem. J. 344 Pt 3 819 825
Katagiri C Masuda K Nomura M Tanoue K Fujita S Yamashita Y et al 2011DUSP13B/TMDP inhibits stress-activated MAPKs and suppresses AP- 1dependent gene expression. Mol. Cell Biochem. 352(1-2):155-162.
for AP-1 in apoptosis: the case for and against. Ameyar M Wisniewska M Weitzman J. B 2003 A Role 85 8 747 752
Varis A Wolf M Monni O Vakkari M. L Kokkola A Moskaluk C et al 2002 Targets of gene amplification and overexpression at 17q in gastric cancer.Cancer Res. 62 9 2625 2629
Marti F Krause A Post N. H Lyddane C Dupont B Sadelain M et al 2001 Negative-feedback regulation of CD28 costimulation by a novel mitogen-activated protein kinase phosphatase, MKP6.J. Immunol. 166 1 197 206
Klinger S Poussin C Debril M. B Dolci W Halban P. A Thorens B 2008 Increasing GLP-1-induced beta-cell proliferation by silencing the negative regulators of signaling cAMP response element modulator-alpha and DUSP14. 57 3 584 593
Lee do H, Park SY, et al. ( Park J. E Park B. C Song M Park S. G 2009 PTP inhibitor IV protects JNK kinase activity by inhibiting dual-specificity phosphatase 14 (DUSP14)Biochem. Biophys. Res. Commun. 387 4 795 799
Yoon T. S Jeong D. G Kim J. H Cho Y. H Son J. H Lee J. W et al 2005 Crystal structure of the catalytic domain of human VHY, a dual-specificity protein phosphatase. 61 3 694 697
Alonso A Narisawa S Bogetz J Tautz L Hadzic R Huynh H et al 2004 VHY, a novel myristoylated testis-restricted dual specificity protein phosphatase related to VHX.J. Biol. Chem. 279 31 32586 32591
Jerez-timaure N. C Eisen E. J Pomp D 2005 Fine mapping of a QTL region with large effects on growth and fatness on mouse chromosome 2.Physiol. Genomics 21 3 411 422
Zama T Aoki R Kamimoto T Inoue K Ikeda Y Hagiwara M 2002 A novel dual specificity phosphatase SKRP1 interacts with the MAPK kinase MKK7 and inactivates the JNK MAPK pathway. Implication for the precise regulation of the particular MAPK pathway.J. Biol. Chem. 277 26 23909 23918
Friedberg I Nika K Tautz L Saito K Cerignoli F Friedberg I et al 2007Identification and characterization of DUSP27, a novel dual-specific protein phosphatase. FEBS Lett. 581 13 2527 2533