Phosphatase Subfamily DSP3

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Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily DSP3

DSP3 is a subfamily abundantly expressed in skeletal muscle and heart. It emerged in eumetazoan, lost in nematodes and duplicated in deuterostomia and vertebrates. Human has five members: DUSP3 (VHR), DUSP13 (BEDP/TMDP/MDSP/SKRP4), DUSP26 (MKP8), DUSP27, DUPD1.


DSP3 is conserved in eumetazoan but lost in nematodes. It duplicated in deuterostomia and vertebrates. Human has five members: DUSP3, DUSP13, DUSP26, DUSP27 and DUPD1. DUSP13 and DUPD1 are neighboring genes in most vertebrate genomes, implies one of them (probably DUPD1) emerged by duplication (see Genomicus or UCSC genome browser).


DSP3 subfamily has a single domain: phosphatase domain.


Human has five members of DSP3 subfamily. They have different substrates and are strictly expressed in certain normal tissues. One feature in common is their abundant expression in skeletal muscle and heart.

DUSP3 (VHR, vaccinia H1-related)

DUSP3 (VHR, vaccinia H1-related) is constitutively expressed, localized to the nucleus. It is widely expressed in different tissues (see GTEx). It specifically dephosphorylates and inactivates ERK1 and ERK2 in vitro and in vivo. It does not dephosphorylate p38 or JNK [1]. Later study also suggested DUSP3 does not dephosphorylate p38, but probably dephosphorylate JNK in T cells [2]. By modulating MAP kinases ERKs and JNKs, DUSP3 is involved in cell-cycle progression as it modulates MAP kinase activation in a cell-cycle phase-dependent manner [3]. DUSP3 activity towards ERK2 is dependent on phosphorylation at Tyr138 by tyrosine kinase ZAP-70 of Syk family. The phosphorylation was required for DUSP3 to inhibit the Erk2-Elk-1 pathway [4].

DUSP3 selectively dephosphorylates IFN-alpha- and beta-activated, tyrosine-phosphorylated STAT5, leading to the subsequent inhibition of STAT5 function. DUSP3 activity towards STAT5 is also dependent on phosphorylation at Tyr138, but by tyrosine kinase Tyk2 of Jak family, which mediates the phosphorylation of STAT5. Besides phosphorylation at Tyr138 of DUSP3, Src homology 2 domain of STAT5 was required for the effective dephosphorylation of STAT5 [5] (note: SH2 domain of STAT5 binds to Tyr138 of DUSP3?).

DUSP3 dephosphorylates EGFR/ERBB1 and ERBB2. In particular, it probably dephosphorylates Tyr-992 [6]. DUSP3 dephosphorylated several activated growth factor receptors, as well as serine-phosphorylated casein, in vitro [7].

DUSP3 is regulated by dimerization. DUSP3 can dimerize inside cells, and its catalytic activity is reduced upon dimerization. Dimerization could occlude the active site, thereby blocking its accessibility to substrates. Transient self-association of DUSP3 may act as a means for the negative regulation of its catalytic activity [8].

DUSP3 is implicated in human cancer, but it has been alternatively described as having tumor suppressive and oncogenic properties. DUSP3 is upregulated in (pre) neoplastic lesions (squamous intraepithelial lesions; SILs) of the uterine cervix mainly in high grade SIL (H-SIL) compared to normal exocervix. In the invasive cancer, it is also highly expressed with nuclear localization in the majority of cells compared to normal tissue where it is always in the cytoplasm. DUSP3 is highly expressed in several cervix cancer cell lines such as HeLa, SiHa, CaSki, C33 and HT3 compared to primary keratinocytes [9]. DUSP3 inhibits apoptosis in prostate cancer cells and is overexpressed in prostate cancer. DUSP3 may therefore have a role in prostate cancer progression [10]. Expression of DUSP3 suppressed tumor formation in a mouse xenograft model. Its expression was significantly lower in non-small cell lung cancer tissues in comparison to that in normal lung tissues [6]. In addition, DUSP3 is a pro-angiogenic [11].

DUSP3 is involved in innate immune system. It is strongly expressed in human and mouse monocytes and macrophages, and that its deficiency in mice promotes tolerance to LPS-induced endotoxin shock and to polymicrobial septic shock after cecal ligation and puncture [12].

DUSP3 was one of the first phosphatases whose crystal structure was solved [13, 14].

In sum, DUSP3/VHR plays important roles in cell-cycle regulation, DNA damage response, angiogenesis, platelet activation and MAPK signaling. Its involvement in different pathways appears to be highly cell-type specific [15].


DUSP13 is expressed only in certain tissues, including skeletal muscle, testis, white blood and heart according to RNA-seq data from GTEx. It is abundantly expressed in skeletal muscle and testis in two distinct isoforms [16] (also in GTEx). The two isoforms are named skeletal muscle-specific dual specificity phosphatase (TMDP/DUSP13B) and muscle-restricted dual specificity phosphatase (MDSP/DUSP13A), respectively. TMDP may be involved in the regulation of meiosis and/or differentiation of testicular germ cells during spermatogenesis [17]. TMDP inactivates MAPK activation in the order of selectivity, JNK = p38 > ERK in cells, while DUSP13A did not show MAPK phosphatase activity [18]. The structure of TMDP is available [19].


DUSP26 is expressed in many tissues, particularly abundant in skeletal muscle, brain [20], heart, ovary and artery (see GTEx).

It is controversial whether MAPKs are DUSP26's physiological substrate. DUSP26 is able to inhibit p38 kinase phosphorylation and downstream activity [21]. It effectively dephosphorylates p38 and has a little effect on ERK in anaplastic thyroid cancer (ATC) cells. It therefore promotes survival of ATC cells by inhibiting p38-mediated apoptosis [22]. In another study, DUSP26 did not dephosphorylate p38 or JNK, either [23]. But, the primary substrates of DUSP26 are not MAPKs [24].

DUSP26 binds to p53 and dephosphorylates p53 at Ser20 and Ser37 [25, 26].

DUSP26 form complex with adenylate kinase 2 (AK2) which dephosphorylates fas-associated protein with death domain (FADD) and suppresses cell proliferation [27].

DUSP26 is recruited to the KIF3 protein complex, a microtubule-directed protein motor, in subcellular transport of several cancer-related proteins, including the beta-catenin-cadherin(s) complex. DUSP26 associates with KIF3 complex by binding to Kif3a subunit of the complex, and thereby dephosphorylates Kap3 subunit [28].

DUSP26 and ERK1 simultaneously interact with heat shock transcription factor 4b (HSF4b). DUSP26 does not dephosphorylate HSF4b, directly, but by binding to ERK1, which phosphorylates HSF4b, it regulates the phosphorylation state of HSF4b [29].

DUSP26 mainly localizes to nucleus and Golgi apparatus [20]. DUSP26 is expressed in embryonal cancers (retinoblastoma, neuroepithelioma, and neuroblastoma) and has limited expression in normal tissues [21].


DUSP27 function is unknown. According to GTEx data, DUSP27 is abundantly expressed in skeletal muscle and heart. It is also expressed artery but almost not expressed in other tissues.

DUSP27 orthologs are found from fish to human, and all of them are predicted to be catalytically inactive due to the substitution at cysteine by serine/aspartic acid/valine (not arginine) at the catalytic motif (internal data). DUSP27 has a long C-terminal domain (around 700 aa), which is conserved from fish to human. It has no sequence similarity with any other human proteins (using HHPred). It has several coiled coils according COILS program.


DUPD1 is strictly expressed in skeletal muscle according to GTEx. It is a cytosolic enzyme. Besides skeletal muscle, it has been shown to be expressed in liver and adipose tissue [30]. DUPD1 has an alias of DUSP27, which is misleading since there is a gene whose official symbol is DUSP27. Its physiological substrate is unclear, though its crystal structure has been solved [31].


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