Phosphatase Subfamily DSP3

The subfamily DSP3 consists of five genes in human, DUSP3, DUSP13, DUSP26 (chr 8, also called MKP8, DUSP24), DUSP27 (chr 1), DUPD1 (chr 10, it has an alias of DUSP27). It is found in eumetazoan but lost in nematodes.

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

summary

Function

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 was one of the first phosphatases whose crystal structure was solved [12, 13].

References

1. Todd JL, Tanner KG, and Denu JM. 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. 1999 May 7;274(19):13271-80. DOI:10.1074/jbc.274.19.13271 |
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. 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 |
13. 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 |