Phosphatase Subfamily DSP3

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.

Evolution

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).

Domain

DSP3 subfamily has a single domain: phosphatase domain.

Function

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 (BEDP/TMDP/MDSP/SKRP4)

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 (MKP8/SKRP3/LDP4/NEAP)

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

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

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].

References

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2. Alonso A, Saxena M, Williams S, and Mustelin T. Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. J Biol Chem. 2001 Feb 16;276(7):4766-71. DOI:10.1074/jbc.M006497200 |
3. Rahmouni S, Cerignoli F, Alonso A, Tsutji T, Henkens R, Zhu C, Louis-dit-Sully C, Moutschen M, Jiang W, and Mustelin T. Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. Nat Cell Biol. 2006 May;8(5):524-31. DOI:10.1038/ncb1398 |
4. Alonso A, Rahmouni S, Williams S, van Stipdonk M, Jaroszewski L, Godzik A, Abraham RT, Schoenberger SP, and Mustelin T. Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nat Immunol. 2003 Jan;4(1):44-8. DOI:10.1038/ni856 |
5. Hoyt R, Zhu W, Cerignoli F, Alonso A, Mustelin T, and David M. Cutting edge: selective tyrosine dephosphorylation of interferon-activated nuclear STAT5 by the VHR phosphatase. J Immunol. 2007 Sep 15;179(6):3402-6. DOI:10.4049/jimmunol.179.6.3402 |
6. Wang JY, Yeh CL, Chou HC, Yang CH, Fu YN, Chen YT, Cheng HW, Huang CY, Liu HP, Huang SF, and Chen YR. Vaccinia H1-related phosphatase is a phosphatase of ErbB receptors and is down-regulated in non-small cell lung cancer. J Biol Chem. 2011 Mar 25;286(12):10177-84. DOI:10.1074/jbc.M110.163295 |
7. Ishibashi T, Bottaro DP, Chan A, Miki T, and Aaronson SA. Expression cloning of a human dual-specificity phosphatase. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12170-4. DOI:10.1073/pnas.89.24.12170 |
8. Pavic K, Rios P, Dzeyk K, Koehler C, Lemke EA, and Köhn M. Unnatural amino acid mutagenesis reveals dimerization as a negative regulatory mechanism of VHR's phosphatase activity. ACS Chem Biol. 2014 Jul 18;9(7):1451-9. DOI:10.1021/cb500240n |
9. Henkens R, Delvenne P, Arafa M, Moutschen M, Zeddou M, Tautz L, Boniver J, Mustelin T, and Rahmouni S. Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR. BMC Cancer. 2008 May 27;8:147. DOI:10.1186/1471-2407-8-147 |
10. Arnoldussen YJ, Lorenzo PI, Pretorius ME, Waehre H, Risberg B, Maelandsmo GM, Danielsen HE, and Saatcioglu F. The mitogen-activated protein kinase phosphatase vaccinia H1-related protein inhibits apoptosis in prostate cancer cells and is overexpressed in prostate cancer. Cancer Res. 2008 Nov 15;68(22):9255-64. DOI:10.1158/0008-5472.CAN-08-1224 |
11. Amand M, Erpicum C, Bajou K, Cerignoli F, Blacher S, Martin M, Dequiedt F, Drion P, Singh P, Zurashvili T, Vandereyken M, Musumeci L, Mustelin T, Moutschen M, Gilles C, Noel A, and Rahmouni S. DUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase. Mol Cancer. 2014 May 15;13:108. DOI:10.1186/1476-4598-13-108 |
12. Singh P, Dejager L, Amand M, Theatre E, Vandereyken M, Zurashvili T, Singh M, Mack M, Timmermans S, Musumeci L, Dejardin E, Mustelin T, Van Ginderachter JA, Moutschen M, Oury C, Libert C, and Rahmouni S. DUSP3 Genetic Deletion Confers M2-like Macrophage-Dependent Tolerance to Septic Shock. J Immunol. 2015 May 15;194(10):4951-62. DOI:10.4049/jimmunol.1402431 |
13. Yuvaniyama J, Denu JM, Dixon JE, and Saper MA. Crystal structure of the dual specificity protein phosphatase VHR. Science. 1996 May 31;272(5266):1328-31. DOI:10.1126/science.272.5266.1328 |
14. Schumacher MA, Todd JL, Rice AE, Tanner KG, and Denu JM. Structural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein Phosphatase. Biochemistry. 2002 Mar 5;41(9):3009-17. DOI:10.1021/bi015799l |
15. Pavic K, Duan G, and Köhn M. VHR/DUSP3 phosphatase: structure, function and regulation. FEBS J. 2015 May;282(10):1871-90. DOI:10.1111/febs.13263 |
16. Chen HH, Luche R, Wei B, and Tonks NK. 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. 2004 Oct 1;279(40):41404-13. DOI:10.1074/jbc.M405286200 |
17. Nakamura K, Shima H, Watanabe M, Haneji T, and Kikuchi K. Molecular cloning and characterization of a novel dual-specificity protein phosphatase possibly involved in spermatogenesis. Biochem J. 1999 Dec 15;344 Pt 3(Pt 3):819-25.
18. Katagiri C, Masuda K, Nomura M, Tanoue K, Fujita S, Yamashita Y, Katakura R, Shiiba K, Nomura E, Sato M, Tanuma N, and Shima H. DUSP13B/TMDP inhibits stress-activated MAPKs and suppresses AP-1-dependent gene expression. Mol Cell Biochem. 2011 Jun;352(1-2):155-62. DOI:10.1007/s11010-011-0749-x |
19. Kim SJ, Jeong DG, Yoon TS, Son JH, Cho SK, Ryu SE, and Kim JH. Crystal structure of human TMDP, a testis-specific dual specificity protein phosphatase: implications for substrate specificity. Proteins. 2007 Jan 1;66(1):239-45. DOI:10.1002/prot.21197 |
20. Takagaki K, Shima H, Tanuma N, Nomura M, Satoh T, Watanabe M, and Kikuchi K. Characterization of a novel low-molecular-mass dual specificity phosphatase-4 (LDP-4) expressed in brain. Mol Cell Biochem. 2007 Feb;296(1-2):177-84. DOI:10.1007/s11010-006-9313-5 |
21. Vasudevan SA, Skoko J, Wang K, Burlingame SM, Patel PN, Lazo JS, Nuchtern JG, and Yang J. MKP-8, a novel MAPK phosphatase that inhibits p38 kinase. Biochem Biophys Res Commun. 2005 May 6;330(2):511-8. DOI:10.1016/j.bbrc.2005.03.028 |
22. Yu W, Imoto I, Inoue J, Onda M, Emi M, and Inazawa J. A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Oncogene. 2007 Feb 22;26(8):1178-87. DOI:10.1038/sj.onc.1209899 |
23. Wang JY, Lin CH, Yang CH, Tan TH, and Chen YR. Biochemical and biological characterization of a neuroendocrine-associated phosphatase. J Neurochem. 2006 Jul;98(1):89-101. DOI:10.1111/j.1471-4159.2006.03852.x |
24. Patterson KI, Brummer T, Daly RJ, and O'Brien PM. DUSP26 negatively affects the proliferation of epithelial cells, an effect not mediated by dephosphorylation of MAPKs. Biochim Biophys Acta. 2010 Sep;1803(9):1003-12. DOI:10.1016/j.bbamcr.2010.03.014 |
25. Shang X, Vasudevan SA, Yu Y, Ge N, Ludwig AD, Wesson CL, Wang K, Burlingame SM, Zhao YJ, Rao PH, Lu X, Russell HV, Okcu MF, Hicks MJ, Shohet JM, Donehower LA, Nuchtern JG, and Yang J. Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma. Oncogene. 2010 Sep 2;29(35):4938-46. DOI:10.1038/onc.2010.244 |
26. Lokareddy RK, Bhardwaj A, and Cingolani G. Atomic structure of dual-specificity phosphatase 26, a novel p53 phosphatase. Biochemistry. 2013 Feb 5;52(5):938-48. DOI:10.1021/bi301476m |
27. Kim H, Lee HJ, Oh Y, Choi SG, Hong SH, Kim HJ, Lee SY, Choi JW, Su Hwang D, Kim KS, Kim HJ, Zhang J, Youn HJ, Noh DY, and Jung YK. The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth. Nat Commun. 2014;5:3351. DOI:10.1038/ncomms4351 |
28. Tanuma N, Nomura M, Ikeda M, Kasugai I, Tsubaki Y, Takagaki K, Kawamura T, Yamashita Y, Sato I, Sato M, Katakura R, Kikuchi K, and Shima H. Protein phosphatase Dusp26 associates with KIF3 motor and promotes N-cadherin-mediated cell-cell adhesion. Oncogene. 2009 Feb 5;28(5):752-61. DOI:10.1038/onc.2008.431 |
29. Hu Y and Mivechi NF. Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Mol Cell Biol. 2006 Apr;26(8):3282-94. DOI:10.1128/MCB.26.8.3282-3294.2006 |
30. Friedberg I, Nika K, Tautz L, Saito K, Cerignoli F, Friedberg I, Godzik A, and Mustelin T. Identification and characterization of DUSP27, a novel dual-specific protein phosphatase. FEBS Lett. 2007 May 29;581(13):2527-33. DOI:10.1016/j.febslet.2007.04.059 |
31. Lountos GT, Tropea JE, and Waugh DS. Structure of human dual-specificity phosphatase 27 at 2.38 Å resolution. Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):471-9. DOI:10.1107/S090744491100970X |