The human DUSP26 gene is located on chromosome 8p12, starting at 33600028 and ending at 33591330 and comprises 4 exons (NCBI, 2015)

According to Ensemble, three splicing variants have been reported for Dusp26 transcripts. The longest isoform comprises four exons and is considered the canonical sequence. The second isoform also comprises four exons, and gives rise to a protein of the same length (211 aa), however it has shorter regulative sequences both at 3 and 5. The third variant instead, consists of two exons and transcribes for a shorter protein, lacking 70 aminoacids at the C-terminus. In uniprot database this third variant is annotated in a different entry (E5RHD0), while a shorter isoform lacking the first 125 aminoacids is reported, which is not considered in ensemble.

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Dusp26 protein consists of 211 aminoacids with a predicted molecular mass of 23.945 kDa. The phosphatase is an atypical DUSP able to dephoshorylate both phosphotyrosine and phosphothreonine/phosphoserine residues, thanks to the 126 aminoacids DSP catalytic domain (Vasudevan et al, 2005). This domain consists of five beta -sheets sandwiched between six alpha -helices (alpha 3-8), with a shallow catalytic site pocket. As shown in the diagram, the catalytic domain is surrounded by two N-terminal alpha -helices (alpha 1 and alpha 2) and one C-terminal helix (alpha 9)(Lokareddy et al, 2013). The central core contains a PTP signature motif with the consensus Cys-(X)5-Arg-(Ser/Thr) conserved among the PTP class I members, where Cys152 and Arg158 form, together with Asp120, the catalytic triad. The catalytic residue Cys152 which primes the reaction, is buried 7 ÅA below the enzyme surface, at the bottom of the catalytic site pocket (Lokareddy et al, 2013; Won, et al., 2013). Dusp26 also presents an "AYLM" motif that is typical of MKPs, but lacks the CDC25 homology domain (Patterson et al, 2009; Vasudevan et al, 2005).

Dusp26 is expressed in the brain, heart, skeletal muscle, adrenal gland and spinal cord (Hu and Mivechi, 2006; Takagaki et al, 2007; Vasudevan et al, 2005; Wang et al, 2006). It is also expressed at lower levels in the testis and thyroid gland (Wang et al, 2006)

Dusp26 localizes to the nucleus and the cytoplasm (Takagaki et al, 2007; Vasudevan et al, 2005; Wang et al, 2006)

At the molecular level, several Dusp26 substrates have been reported and we will briefly summarize them. Dusp26 was reported to dephosphorylate MAPKs such as p38, Erk and JNK, as well as Akt kinase,and to regulate their activity (Hu and Mivechi, 2006; Vasudevan et al, 2005; Wang et al, 2006; Wang et al, 2008; Yu et al, 2007). However, other authors have reported no effect of Dusp26 on MAPK, which suggests that this activity might not be the major function of the phosphatase, or that it might behave differently in different cell types (Patterson et al, 2010). Notably Hsf4b and Scrib have been proposed as regulators to bridge the protein with MAPK substrates (Hu and Mivechi, 2006; Sacco et al, 2014). A similar role was proposed for the Adenylate Kinase (AK2), which was shown to form a complex with Dusp26 and to stimulate its phosphatase activity toward Fas-associated protein with death domain (FADD),although the molecular mechanism of this activation is unknown (Kim et al, 2014). However, the authors specify that this complex does not modulate apoptosis and that Fadd phosphorylation level is irrelevant to cell death, while it is involved in the control of cell proliferation. The Kif3a subunit of the KIF3 protein-motor complex might be another scaffold subunit that leads the phosphatase to act on Kap3(Tanuma et al, 2009). It is not unfrequent that the catalityc activity of enzymes is increased upon binding to interactors that function as coactivators, and the organization of complexes could be a refined mechanism to control the specificity. Notably, the structural comparison of Dusp26 with other Dusps reveals two gaps nearby the catalytic domain which could be targeted for the binding of physiological interactors or allosteric regulators (Won et al, 2013). Dusp26 was also reported to directly bind and dephosphorylate Ser20 and Ser37 of the tumour suppressor p53, both in vitro and in vivo (Shang et al, 2010).
As a result of its function as MAPKs, KIF3 and p53 regulator, modulation of its activity and/or its expression has been proposed, as well as that of other atypical Dusps, as a promising anti-cancer therapy (Nunes-Xavier et al, 2011; Song et al, 2009). The challenge for the future infact, is to complement various therapeutical targets, to treat patients with specific and more effective therapies. A current priority is the elucidation of the molecular basis for the insorgece of acquired drug resistance during therapy, and for the selection of apoptosis-resistant cells. Although more than 50% of all human cancers have p53 deletion or mutation, neuroblastoma (NB) is known to maintain functional p53, but to defect in apoptotic pathways. It was shown that Dusp26 has an important role in the chemoresistance of NB cancer cells, and inhibits doxorubicin- and genotoxic-stress-induced apoptosis by dephosphorylation and inactivation of p53. In Dusp26 knockdown cells there is a significant enhancement of apoptosis and a concomitant iperphosphorylation of p53, while the overexpression of the phosphatase promotes cell resistance (Shang et al, 2010). Althought Dusp26 is overexpressed in neuroblastoma cells, as described below, no specific drug has been developed yet to selectively target Dusp26 (Song et al, 2009). However it is reasonable to think that interfering Dusp26 dephosphorylation of p53 would promote NB cells apoptosis and help chemosensitivity (Shang et al, 2010). Similarly, in anaplastic tyroid cancer cells (ATC), the phosphatase downregulates apoptosis by inhibiting p38 MAPK (Yu et al, 2007). In PC12 cells, however, low levels of the phosphatase are required for differentation, while Dusp26 overexpression down-regulates the PI3K/Akt pathway. In these conditions, NGF-induced phosphorylation of mTOR on Ser2448, the Akt specific targeted serine, is decreased, and PC12 cells are more sensible to cisplatin-induced apoptotic stimuli (Wang et al, 2006).
Beyond regulating cell differentiation and apoptosis in these cell systems, Dusp26 was also hypothesized to control cell transformation in other human malignancies, by exerting a tumour-suppressor activity enhancing cell-cell adhesion. Dephosphorylation of the Kap3 subunit of the KIF3 microtubule-dependent protein motor infact, results, by unknown mechanism, to N-cadherin/beta-catenin colocalization in membrane ruffles and in sites of cell contacts (Tanuma et al, 2009).
These findings suggest that the final effect of the phosphatase depends on tissue-specific substrates and a fine characterization of its fuctional role in different cancer cells is necessary to develop selective therapies. While the catalytic core of the atypical Dusps is well conserved among the members of the family, the binding of ligands to more specific N and C terminal regions (Sacco et al, 2014) allows for the design of selective inhibitors.

Dusp26 is a member of the dual specificity family of protein phosphatases. It shares the highest homology with Dusp13, Dusp 27 and Dusp3/VHR protein phosphatases (Patterson et al, 2009; Pavic et al, 2015; Takagaki et al, 2007; Vasudevan et al, 2005; Won et al, 2013).
The human Dusp26 protein is highly conserved within Mammalia, and shows 100%, 98%, 97% and 94% of identity with chimpanzee, rat, mouse and pig orthologs, respectively (percentages according to Blast bl2seq). Dusp26 also shows high similarity with chicken, chamaleon, western clawed frog, Japanese ricefish and zebrafish homologous proteins.

Several point mutations of Dusp26 coding region are reported in Cosmic database (Forbes et al, 2015). The analysis of 19779 samples led to the identification of 41 missense mutations, 16 synonymous and 2 nonsense mutations (Forbes et al, 2015) (april 2015 release). None of them are associated with a specific phenotype.
The mutation C152S instead, inactivates the phosphatase function of the protein (Vasudevan et al, 2005; Wang et al, 2006).
Amplification of genomic copy number of DUSP26 gene, overexpression of its transcript, as well as downregulation, have all been reported to be related to human cancers (see also below). Actually, the amplification of the genomic copy number of DUSP26 was reported in Anaplastic Thyroid Cancer cells, and the consequential overexpression of the transcript was determined by RT-PCR (Yu et al, 2007). Overexpression of DUSP26 was determined at RNA and protein level in neuroblastoma cell lines and in primary tumour samples(Shang et al, 2010). Downregulation of Dusp26 RNA was also observed in ovarian cancer, medulloblastoma and glioblastoma cell lines (Patterson et al, 2010)