Phosphatase Subfamily DSP1

Phosphatase Classification: Superfamily CC1: Family DSP: Subfamily DSP1

DSP1 is an inducible nuclear MAP Kinase phosphatase (MKP) conserved throughout eukaryotes. As a key player in MAPK pathway, it is implicated in immune regulation and cancer.

Evolution

DSP1 subfamily is widely found across eukaryotes. It is present in animals, plants, amoeba, and some basal eukaryotes, but is absent from ecdysozoa (nematodes and arthropods), most fungi and Monosiga (unpublished data, DUSP1, DUSP2, DUSP4, DUSP5).

Domain Structure

DSP1 has an inactive rhodanese domain, followed by a phosphatase domain. In general, a kinase interaction motif (KIM) embedded in rhodanese domain mediates the interaction between DSP1 and MAPK (i.e. ERK, JNK, p38 kinase subfamilies) [1, 2, 3, 4].

Dictyostelium has four DSP1s. Two (mkpB-1 and mkpB-2) have the typical domain combination of rhodanese domain and phosphatase domain. Another two have different domain combination. Both of them have a long N-terminal region. One of the two, mkpA, has three weak hits to Gelsolin domain, an actin-binding protein that is a key regulator of actin filament assembly and disassembly.

Functions

In general, DSP1 are inducible nuclear MAP Kinase phosphatases (MKPs). Given the MAPKs modules many different biological processes, it is not surprising that DSP1 subfamily functions in cancer and immune system. Human members are DUSP1, DUSP2, DUSP4 and DUSP5. Their substrate specificity, subcellular localization and etc have been summarized in Table 1 in review paper [5]. Although they have overlapping substrate specificity, there are differences in their mRNA regulation, response to extracellular stimuli, and tissue-specific expression, suggesting they serve specific roles in cellular function [6].

DUSP1 (MKP1/hVH1)

DUSP1 is the best characterized phosphatase within this subfamily. It prefers to dephosphorylates p38 and JNK over ERK. DUSP1 is involved in immune regulation and cancer. DUSP1 is an important negative-feedback regulator of macrophage function (possibly by modulating mRNA-destabilizing protein tristetraprolin [7]) and the inflammatory response to TLR signalling, and plays key regulatory roles in both innate and adaptive immune responses via inactivation of p38 and JNK (reviewed in [5]). DUSP1 is an important negative regulator of pro-allergic responses in airway epithelium [8].

DUSP1 (MKP1) also mediates G1-specific dephosphorylation of H3Serine10P in histone in response to DNA damage. The phosphorylation at H3S10 plays a dual role in a cell by maintaining relaxed chromatin for active transcription in interphase and condensed chromatin state in mitosis [9].

(Note: It is worthy pointing out that DUSP1 expression is strictly regulated at low level in brain (see GTEx)).

DUSP2 (PAC1)

As a MKP, DUSP2 has preference toward ERK=p38 > JNK. DUSP2 is inactive when alone in vitro, and dephosphorylates extracellular signal-regulated kinase 2 (ERK2) but not p38alpha or c-Jun NH(2)-terminal kinase 2 (JNK2). ERK2 dephosphorylation by DUSP2 requires association of its rhodanese domain and ERK2 that results in catalytic activation of the phosphatase. p38alpha interacts with but does not activate DUSP2, whereas JNK2 does not bind to or cause catalytic activation by DUSP2 [2, 3].

It has been shown that individual mutation of the conserved Arg294 and Arg295 that likely comprise the phosphothreonine-binding pocket in DUSP2 to either alanine or lysine results in a nearly complete loss of its phosphatase activity even in the presence of ERK2 [3]. (PS: However, the conservation is not found within DSP1 subfamily. On the other hand, they are found in other subfamilies no matters they dephosphorylate ERK or not, which suggested the two arginine residues do not determine phosphatase activity or the specific phosphatase activity towards ERK.)

DUSP2 is expressed in various tissues (see GTEx). Its expression is regulated by p53 which binds to palindromic site in DUSP2 promoter [10]. Its expression is regulated, or more precisely speaking, inhibited by hypoxia inducible factor-1 (HIF-1) [11, 12].

DUSP4 (MKP2/TYP)

DUSP4 prefers ERK and JNK over p38 [13, 14, 15]. Further studies has shown the catalytic activity of DUSP4 was enhanced dramatically by ERK and JNK but was affected only minimally by p38. By contrast, p38 and ERK bound DUSP4 with comparably strong affinities, whereas JNK and DUSP2 interacted very weakly [16]. DUSP4's substrate in vivo is controversial. As reported in [17], DUSP4 selectively dephosphorylates JNK, or different DUSP4 isoforms have different substrate specificity as shown in [18].

DUSP4 dephosphorylates ERK, and on the other hand, ERK can phosphorylates DUSP4 (on Ser386 and Ser391 at its C-terminus) which leads to stabilization of DUSP4 protein, as blockage of ERK activation results in enhanced proteasomal degradation of DUSP4 protein [19]. (Note: Ser386 and Ser391 are also found in DUSP1, which preferential dephosphorylates p38 and JNK but NOT ERK. DUSP2 has Ser386 but position 391 is Ala; DUSP5 does not align at C-terminal region.)

DUSP4 is involved in cancer. For instance, it is a common epigenetically silenced gene in glioma [20]. DUSP4 is frequently upregulated in breast malignancy [21].

DUSP4 is also involved in inflammation. It is a negative regulator of macrophage M1 activation through JNK and p38 and inhibits inflammation during macrophage-adipocyte interaction [22].

(Note: look into the conservation of basic motif mentioned in [16, 23], which is supposed to mediate the interaction between DUSP4 (or even other DSP1 or MKPs) with ERK (or MAPKs in general).

DUSP5 (hVH3)

DUSP5 is an inducible nuclear ERK-specific MKP that functions as both an inactivator of and a nuclear anchor for ERK2 in mammalian cells [1, 24]. Thus, it modules T-cell development and function [25], modules corneal epithelial cell proliferation [26], is implicated in angiogenesis [27], and influences myeloid cell fate by M-CSF pathway [28]. It may be involved in carcinogenesis, since DUSP5 is down-regulated in gastric cancer by promoter CpG island hypermethylation [29], up-regulated in MCF-7 human breast carcinoma cells by transcription factor c-Jun [30] and its down-regulation predicts poor prognosis of patients with prostate cancer [31].

Similar with DUSP4, DUSP5 is also stabilized by binding to and be phosphorylated by ERK. The accumulation of DUSP5 protein is regulated by rapid proteasomal degradation. DUSP5 is phosphorylated by ERK1/2 both in vitro and in vivo on three sites (Thr321, Ser346 and Ser376) at C-terminus. Co-expression of ERK2 results in significant stabilisation of DUSP5, which is accompanied by reduced levels of DUSP5 ubiquitination. However, there is no evidence that phosphorylation of DUSP5 by ERK2 significantly affects either the half-life of the DUSP5 protein or its ability to bind to, inactivate or anchor ERK2 in the nucleus. These changes are independent of ERK2 kinase activity but absolutely depend on the ability of ERK2 to bind to DUSP5 [4].

DUSP5 is regulated by p53 binding to DUSP5 promoter [32] (same mechanism as DUSP2).

References

1. Mandl M, Slack DN, and Keyse SM. Specific inactivation and nuclear anchoring of extracellular signal-regulated kinase 2 by the inducible dual-specificity protein phosphatase DUSP5. Mol Cell Biol. 2005 Mar;25(5):1830-45. DOI:10.1128/MCB.25.5.1830-1845.2005 |
2. Farooq A, Plotnikova O, Chaturvedi G, Yan S, Zeng L, Zhang Q, and Zhou MM. Solution structure of the MAPK phosphatase PAC-1 catalytic domain. Insights into substrate-induced enzymatic activation of MKP. Structure. 2003 Feb;11(2):155-64. DOI:10.1016/s0969-2126(02)00943-7 |
3. Zhang Q, Muller M, Chen CH, Zeng L, Farooq A, and Zhou MM. New insights into the catalytic activation of the MAPK phosphatase PAC-1 induced by its substrate MAPK ERK2 binding. J Mol Biol. 2005 Dec 9;354(4):777-88. DOI:10.1016/j.jmb.2005.10.006 |
4. Kucharska A, Rushworth LK, Staples C, Morrice NA, and Keyse SM. Regulation of the inducible nuclear dual-specificity phosphatase DUSP5 by ERK MAPK. Cell Signal. 2009 Dec;21(12):1794-805. DOI:10.1016/j.cellsig.2009.07.015 |
5. Patterson KI, Brummer T, O'Brien PM, and Daly RJ. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J. 2009 Mar 15;418(3):475-89. DOI:10.1042/bj20082234 |
6. Kwak SP and Dixon JE. Multiple dual specificity protein tyrosine phosphatases are expressed and regulated differentially in liver cell lines. J Biol Chem. 1995 Jan 20;270(3):1156-60. DOI:10.1074/jbc.270.3.1156 |
7. Smallie T, Ross EA, Ammit AJ, Cunliffe HE, Tang T, Rosner DR, Ridley ML, Buckley CD, Saklatvala J, Dean JL, and Clark AR. Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide. J Immunol. 2015 Jul 1;195(1):277-88. DOI:10.4049/jimmunol.1402830 |
8. Golebski K, van Egmond D, de Groot EJ, Roschmann KI, Fokkens WJ, and van Drunen CM. EGR-1 and DUSP-1 are important negative regulators of pro-allergic responses in airway epithelium. Mol Immunol. 2015 May;65(1):43-50. DOI:10.1016/j.molimm.2014.12.011 |
9. Sharma AK, Khan SA, Sharda A, Reddy DV, and Gupta S. MKP1 phosphatase mediates G1-specific dephosphorylation of H3Serine10P in response to DNA damage. Mutat Res. 2015 Aug;778:71-9. DOI:10.1016/j.mrfmmm.2015.06.001 |
10. Yin Y, Liu YX, Jin YJ, Hall EJ, and Barrett JC. PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. Nature. 2003 Apr 3;422(6931):527-31. DOI:10.1038/nature01519 |
11. Lin SC, Chien CW, Lee JC, Yeh YC, Hsu KF, Lai YY, Lin SC, and Tsai SJ. Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells. J Clin Invest. 2011 May;121(5):1905-16. DOI:10.1172/JCI44362 |
12. Wu MH, Lin SC, Hsiao KY, and Tsai SJ. Hypoxia-inhibited dual-specificity phosphatase-2 expression in endometriotic cells regulates cyclooxygenase-2 expression. J Pathol. 2011 Nov;225(3):390-400. DOI:10.1002/path.2963 |
13. Guan KL and Butch E. Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase. J Biol Chem. 1995 Mar 31;270(13):7197-203. DOI:10.1074/jbc.270.13.7197 |
14. King AG, Ozanne BW, Smythe C, and Ashworth A. Isolation and characterisation of a uniquely regulated threonine, tyrosine phosphatase (TYP 1) which inactivates ERK2 and p54jnk. Oncogene. 1995 Dec 21;11(12):2553-63.
15. Chu Y, Solski PA, Khosravi-Far R, Der CJ, and Kelly K. The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J Biol Chem. 1996 Mar 15;271(11):6497-501. DOI:10.1074/jbc.271.11.6497 |
16. Chen P, Hutter D, Yang X, Gorospe M, Davis RJ, and Liu Y. Discordance between the binding affinity of mitogen-activated protein kinase subfamily members for MAP kinase phosphatase-2 and their ability to activate the phosphatase catalytically. J Biol Chem. 2001 Aug 3;276(31):29440-9. DOI:10.1074/jbc.M103463200 |
17. Cadalbert L, Sloss CM, Cameron P, and Plevin R. Conditional expression of MAP kinase phosphatase-2 protects against genotoxic stress-induced apoptosis by binding and selective dephosphorylation of nuclear activated c-jun N-terminal kinase. Cell Signal. 2005 Oct;17(10):1254-64. DOI:10.1016/j.cellsig.2005.01.003 |
18. Cadalbert LC, Sloss CM, Cunningham MR, Al-Mutairi M, McIntire A, Shipley J, and Plevin R. Differential regulation of MAP kinase activation by a novel splice variant of human MAP kinase phosphatase-2. Cell Signal. 2010 Mar;22(3):357-65. DOI:10.1016/j.cellsig.2009.10.002 |
19. Peng DJ, Zhou JY, and Wu GS. Post-translational regulation of mitogen-activated protein kinase phosphatase-2 (MKP-2) by ERK. Cell Cycle. 2010 Dec 1;9(23):4650-5. DOI:10.4161/cc.9.23.13957 |
20. Waha A, Felsberg J, Hartmann W, von dem Knesebeck A, Mikeska T, Joos S, Wolter M, Koch A, Yan PS, Endl E, Wiestler OD, Reifenberger G, Pietsch T, and Waha A. Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP-2 relieves its growth suppressive activity in glioma cells. Cancer Res. 2010 Feb 15;70(4):1689-99. DOI:10.1158/0008-5472.CAN-09-3218 |
21. Kim H, Jang SM, Ahn H, Sim J, Yi K, Chung Y, Han H, Rehman A, Chung MS, Jang K, and Paik SS. Clinicopathological significance of dual-specificity protein phosphatase 4 expression in invasive ductal carcinoma of the breast. J Breast Cancer. 2015 Mar;18(1):1-7. DOI:10.4048/jbc.2015.18.1.1 |
22. Jiao H, Tang P, and Zhang Y. MAP kinase phosphatase 2 regulates macrophage-adipocyte interaction. PLoS One. 2015;10(3):e0120755. DOI:10.1371/journal.pone.0120755 |
23. Tanoue T, Adachi M, Moriguchi T, and Nishida E. A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol. 2000 Feb;2(2):110-6. DOI:10.1038/35000065 |
24. Ishibashi T, Bottaro DP, Michieli P, Kelley CA, and Aaronson SA. A novel dual specificity phosphatase induced by serum stimulation and heat shock. J Biol Chem. 1994 Nov 25;269(47):29897-902.
25. Kovanen PE, Bernard J, Al-Shami A, Liu C, Bollenbacher-Reilley J, Young L, Pise-Masison C, Spolski R, and Leonard WJ. T-cell development and function are modulated by dual specificity phosphatase DUSP5. J Biol Chem. 2008 Jun 20;283(25):17362-9. DOI:10.1074/jbc.M709887200 |
26. Wang Z, Reinach PS, Zhang F, Vellonen KS, Urtti A, Turner H, and Wolosin JM. DUSP5 and DUSP6 modulate corneal epithelial cell proliferation. Mol Vis. 2010 Aug 22;16:1696-704.
27. Echavarria R and Hussain SN. Regulation of angiopoietin-1/Tie-2 receptor signaling in endothelial cells by dual-specificity phosphatases 1, 4, and 5. J Am Heart Assoc. 2013 Dec 5;2(6):e000571. DOI:10.1161/JAHA.113.000571 |
28. Grasset MF, Gobert-Gosse S, Mouchiroud G, and Bourette RP. Macrophage differentiation of myeloid progenitor cells in response to M-CSF is regulated by the dual-specificity phosphatase DUSP5. J Leukoc Biol. 2010 Jan;87(1):127-35. DOI:10.1189/jlb.0309151 |
29. Shin SH, Park SY, and Kang GH. Down-regulation of dual-specificity phosphatase 5 in gastric cancer by promoter CpG island hypermethylation and its potential role in carcinogenesis. Am J Pathol. 2013 Apr;182(4):1275-85. DOI:10.1016/j.ajpath.2013.01.004 |
30. Nunes-Xavier CE, Tárrega C, Cejudo-Marín R, Frijhoff J, Sandin A, Ostman A, and Pulido R. Differential up-regulation of MAP kinase phosphatases MKP3/DUSP6 and DUSP5 by Ets2 and c-Jun converge in the control of the growth arrest versus proliferation response of MCF-7 breast cancer cells to phorbol ester. J Biol Chem. 2010 Aug 20;285(34):26417-30. DOI:10.1074/jbc.M110.121830 |
31. Cai C, Chen JY, Han ZD, He HC, Chen JH, Chen YR, Yang SB, Wu YD, Zeng YR, Zou J, Liang YX, Dai QS, Jiang FN, and Zhong WD. Down-regulation of dual-specificity phosphatase 5 predicts poor prognosis of patients with prostate cancer. Int J Clin Exp Med. 2015;8(3):4186-94.
32. Ueda K, Arakawa H, and Nakamura Y. Dual-specificity phosphatase 5 (DUSP5) as a direct transcriptional target of tumor suppressor p53. Oncogene. 2003 Aug 28;22(36):5586-91. DOI:10.1038/sj.onc.1206845 |