Difference between revisions of "Phosphatase Subfamily DSP6"

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[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]:  [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_DSP6|Subfamily DSP6]]
 
[[Phosphatase classification|Phosphatase Classification]]: [[Phosphatase_Fold_CC1|Fold CC1]]:  [[Phosphatase_Superfamily_CC1|Superfamily CC1]]: [[Phosphatase_Family_DSP|Family DSP]]: [[Phosphatase_Subfamily_DSP6|Subfamily DSP6]]
  

Latest revision as of 19:02, 20 February 2018

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily DSP6

DSP6 is a metazoan cytoplasmic MKP subfamily that selectively dephosphorylates ERK.

Evolution

DSP6 is found throughout metazoa. It duplicated in vertebrates. The three human members are DUSP6 (MKP3), DUSP7 (MKPX) and DUSP9 (MKP4).

Domain

DSP6 has two domains: rhodanese domain and phosphatase domain.

The rhodanese domain inhibit phosphatase domain activity in DUSP6 [1], which is achieved by the binding of rhodanese domain and phosphatase domain. The binding stabilizes the inactive conformation of the phosphatase catalytic site [2]. The rhodanese domain also mediates interaction with MAP kinases (often ERK) (via kinase interaction motif?). Its binding to MAP kinases induces conformation change in phosphatase domain, which can increase the phosphatase activity [3].

Rhodanese domain of DSP6 also has two conserved Leu-rich nuclear export signals [4] (particular Figure 5 and Figure 11).

The rhodanese domain was lost in many nematodes (see technical notes).

Function

DUSP6 (MKP3/PYST1)

DUSP6 preferentially dephosphorylates ERK [5, 6, 7], due to ability of DUSP6 to bind ERK but not p38 or JNK. The interaction is mediated by rhodanese domain (or kinase interaction motif embedded in rhodanese domain?) [8]. Later study has shown DUSP6 is ERK1/2-specific, as it does not inactive ERK5 [9].

Furthermore, DUSP6, ERK2, and phosphorylated p38alpha can form a stable ternary complex in solution, and the phosphatase activity of DUSP6 toward p38alpha substrate is allosterically regulated by ERK2-DUSP6 interaction. This suggests that DUSP6 may mediate cross-talk between ERK and p38 pathways [10]. (note: this is perhaps the mechanism behind DUSP6 modules DNA damage response [11].)

As a negative regulator of ERK [1, 5, 12, 13], DUSP6 is proposed to be tumor suppressor via feedback mechanisms [14]:

  • Significant loss of DUSP6 was observed in 100% of 11 esophageal squamous cell carcinoma cell lines and 71% of seven nasopharyngeal carcinoma cell lines [15].
  • DUSP6 plays tumor suppressive role in non-small-cell lung cancers [13].
  • DUSP6 expression was correlated with lower histological grade and lower Ki-67 index in the lung adenocarcinomas [16].
  • DUSP6 expression was down-regulated through hypermethylation at enhancer in some pancreatic cell lines and pancreatic cancer tissues [17, 18].
  • Degradation of DUSP6 caused by reactive oxygen species (ROS) leads to aberrant ERK1/2 activation and contributes to tumorigenicity and chemoresistance of human ovarian cancer cells [19].
  • DUSP6 upregulation induced by angiotensin II mediates endothelial cell apoptosis [20].

But, DUSP6 is up-regulated or not associated with cancers in some cases:

  • DUSP6 was up-regulated in endometrial adenocarcinomas [21], thyroid carcinoma [22, 23], and glioblastomas [24], MCF-7 breast cancer cells [25].
  • DUSP6 methylation is a rare event in endometrial cancer. Thus, silencing of the DUSP6 phosphatase is unlikely to contribute to constitutive activation of the ERK kinase cascade in endometrial cancer [26].
  • DUSP6 expression was not correlated with Ki-67 index lung squamous cell carcinomas [16].

(note: DUSP6 upregulation in cancer could be explained by feedback mechanisms?)

DUSP6 (MKP3) inhibits brown adipocyte differentiation perhaps via regulation of Erk phosphorylation [27].

Like DUSP2, DUSP4 and DUSP4 of DSP1 subfamily, DUSP6 is phosphorylated by ERK [28]. However, the phosphorylation sites are different. DUSP6 is phosphorylated at serines 159 and 197 [28], which are found in DUSP6 and DUSP7, but not DUSP9 or other DSPs.

DUSP6 expression is regulated by:

  • p53. There are two p53 binding sites in DUSP6 promoter [29]. p53 binds to promoter of DUSP2 and DUSP5 of DSP1 subfamily.
  • ETS1, a transcription factor that can be activated by Erk2 and Ras at Thr38 [13] (note: a feedback of ERK2, DUSP6, ETS1).
  • Wilms tumor protein (WT1), a transcription factor as tumor suppressor, up-regulates DUSP6 expression [30].
  • Nitric oxide down-regulates DUSP6 mRNA levels [31] (note: which pathway?). Read here for NO's biological function.
DUSP7 (MKPX/PYST2)

DUSP7 is constitutively expressed in a wide variety of human cell lines. DUSP7 is predominantly cytosolic when expressed in COS-1 cells. In common with other members of DSP6 subfamily, DUSP7 shows substrate selectivity ERK > p38 = JNK. DUSP7 binds ERK in vivo. Both ERK and JNK activate DUSP7 phosphatase activity in vitro [32].

DUSP7 has at least two isoforms. The longer isoform is constitutively highly expressed in myeloid leukemia and other malignant cells [33, 34, 35].

DUSP9 (MKP4)

DUSP6 blocks activation of MAP kinases with the selectivity ERK > p38 = JNK. Same as other members in the subfamily, it locates in cytosol [36, 37]. DUSP9 is unique among these cytoplasmic MKPs in containing a conserved PKA consensus phosphorylation site (55)RRXSer-58 immediately adjacent to the kinase interaction motif. DUSP9 is phosphorylated on Ser-58 by PKA in vitro, and phosphorylation abrogates the binding of DUSP9 to both ERK2 and p38alpha MAP kinases [38].

Decreased expression of DUSP-9 is associated with poor prognosis in clear cell renal cell carcinomas [39].

Technical notes

Nematodes lost rhodanese domain

We observed the absence of rhodanese domain in C. elegans. We then asked whether the loss is conserved, which can be use to measure the reliability of the loss. We obtained DSP6s from our internal orthology database, which has 203 eukaryotic genomes and 9 nematode genomes. We then searched Pfam domain in the DSP6s using Pfam web server (E-value cutoff 1.0). We found none of the 10 nematode DSPs from 7 nematode genomes has rhodanese domain. The DSP6 subfamily is not found in another 2 nematode genomes: Pristionchus pacificus and Loa loa.

We also BLASTed human DUSP6 against nematode NR protein data set. We found rhodanese-containing DSP6 in most Trichocephalida, which suggest the lost in happened posterior to Trichocephalida diverged from other nematodes.

References

  1. Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, Boschert U, and Arkinstall S. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science. 1998 May 22;280(5367):1262-5. DOI:10.1126/science.280.5367.1262 | PubMed ID:9596579 | HubMed [Camps98]
  2. Mark JK, Aubin RA, Smith S, and Hefford MA. Inhibition of mitogen-activated protein kinase phosphatase 3 activity by interdomain binding. J Biol Chem. 2008 Oct 17;283(42):28574-83. DOI:10.1074/jbc.M801747200 | PubMed ID:18694935 | HubMed [Mark08]
  3. Stewart AE, Dowd S, Keyse SM, and McDonald NQ. Crystal structure of the MAPK phosphatase Pyst1 catalytic domain and implications for regulated activation. Nat Struct Biol. 1999 Feb;6(2):174-81. DOI:10.1038/5861 | PubMed ID:10048930 | HubMed [Stewart99]
  4. Karlsson M, Mathers J, Dickinson RJ, Mandl M, and Keyse SM. Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal. J Biol Chem. 2004 Oct 1;279(40):41882-91. DOI:10.1074/jbc.M406720200 | PubMed ID:15269220 | HubMed [Karlsson04]
  5. Muda M, Boschert U, Dickinson R, Martinou JC, Martinou I, Camps M, Schlegel W, and Arkinstall S. MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. J Biol Chem. 1996 Feb 23;271(8):4319-26. DOI:10.1074/jbc.271.8.4319 | PubMed ID:8626780 | HubMed [Muda96]
  6. Groom LA, Sneddon AA, Alessi DR, Dowd S, and Keyse SM. Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO J. 1996 Jul 15;15(14):3621-32. PubMed ID:8670865 | HubMed [Groom96]
  7. Kim Y, Rice AE, and Denu JM. Intramolecular dephosphorylation of ERK by MKP3. Biochemistry. 2003 Dec 30;42(51):15197-207. DOI:10.1021/bi035346b | PubMed ID:14690430 | HubMed [Kim03]
  8. Muda M, Theodosiou A, Gillieron C, Smith A, Chabert C, Camps M, Boschert U, Rodrigues N, Davies K, Ashworth A, and Arkinstall S. The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity. J Biol Chem. 1998 Apr 10;273(15):9323-9. DOI:10.1074/jbc.273.15.9323 | PubMed ID:9535927 | HubMed [Muda98]
  9. Arkell RS, Dickinson RJ, Squires M, Hayat S, Keyse SM, and Cook SJ. DUSP6/MKP-3 inactivates ERK1/2 but fails to bind and inactivate ERK5. Cell Signal. 2008 May;20(5):836-43. DOI:10.1016/j.cellsig.2007.12.014 | PubMed ID:18280112 | HubMed [Arkell08]
  10. Zhang YY, Wu JW, and Wang ZX. Mitogen-activated protein kinase (MAPK) phosphatase 3-mediated cross-talk between MAPKs ERK2 and p38alpha. J Biol Chem. 2011 May 6;286(18):16150-62. DOI:10.1074/jbc.M110.203786 | PubMed ID:21454500 | HubMed [Zhang11]
  11. Bagnyukova TV, Restifo D, Beeharry N, Gabitova L, Li T, Serebriiskii IG, Golemis EA, and Astsaturov I. DUSP6 regulates drug sensitivity by modulating DNA damage response. Br J Cancer. 2013 Aug 20;109(4):1063-71. DOI:10.1038/bjc.2013.353 | PubMed ID:23839489 | HubMed [Bagnyukova13]
  12. Jurek A, Amagasaki K, Gembarska A, Heldin CH, and Lennartsson J. Negative and positive regulation of MAPK phosphatase 3 controls platelet-derived growth factor-induced Erk activation. J Biol Chem. 2009 Feb 13;284(7):4626-34. DOI:10.1074/jbc.M808490200 | PubMed ID:19106095 | HubMed [Jurek09]
  13. Zhang Z, Kobayashi S, Borczuk AC, Leidner RS, Laframboise T, Levine AD, and Halmos B. Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis. 2010 Apr;31(4):577-86. DOI:10.1093/carcin/bgq020 | PubMed ID:20097731 | HubMed [Zhang10]
  14. Zeliadt NA, Mauro LJ, and Wattenberg EV. Reciprocal regulation of extracellular signal regulated kinase 1/2 and mitogen activated protein kinase phosphatase-3. Toxicol Appl Pharmacol. 2008 Nov 1;232(3):408-17. DOI:10.1016/j.taap.2008.08.007 | PubMed ID:18771677 | HubMed [Zeliadt08]
  15. Wong VC, Chen H, Ko JM, Chan KW, Chan YP, Law S, Chua D, Kwong DL, Lung HL, Srivastava G, Tang JC, Tsao SW, Zabarovsky ER, Stanbridge EJ, and Lung ML. Tumor suppressor dual-specificity phosphatase 6 (DUSP6) impairs cell invasion and epithelial-mesenchymal transition (EMT)-associated phenotype. Int J Cancer. 2012 Jan 1;130(1):83-95. DOI:10.1002/ijc.25970 | PubMed ID:21387288 | HubMed [Wong12]
  16. Lee H, Kim JM, Huang SM, Park SK, Kim DH, Kim DH, Lee CS, Suh KS, Yi ES, and Kim KH. Differential expression of DUSP6 with expression of ERK and Ki-67 in non-small cell lung carcinoma. Pathol Res Pract. 2011 Jul 15;207(7):428-32. DOI:10.1016/j.prp.2011.05.004 | PubMed ID:21680106 | HubMed [Lee11]
  17. Furukawa T, Yatsuoka T, Youssef EM, Abe T, Yokoyama T, Fukushige S, Soeda E, Hoshi M, Hayashi Y, Sunamura M, Kobari M, and Horii A. Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Cytogenet Cell Genet. 1998;82(3-4):156-9. DOI:10.1159/000015091 | PubMed ID:9858808 | HubMed [Furukawa98]
  18. Xu S, Furukawa T, Kanai N, Sunamura M, and Horii A. Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. J Hum Genet. 2005;50(4):159-167. DOI:10.1007/s10038-005-0235-y | PubMed ID:15824892 | HubMed [Xu05]
  19. Chan DW, Liu VW, Tsao GS, Yao KM, Furukawa T, Chan KK, and Ngan HY. Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells. Carcinogenesis. 2008 Sep;29(9):1742-50. DOI:10.1093/carcin/bgn167 | PubMed ID:18632752 | HubMed [Chan08]
  20. Rössig L, Hermann C, Haendeler J, Assmus B, Zeiher AM, and Dimmeler S. Angiotensin II-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis. Basic Res Cardiol. 2002 Jan;97(1):1-8. DOI:10.1007/s395-002-8381-2 | PubMed ID:11998972 | HubMed [Rossig02]
  21. Zhang H, Guo Q, Wang C, Yan L, Fu Y, Fan M, Zhao X, and Li M. Dual-specificity phosphatase 6 (Dusp6), a negative regulator of FGF2/ERK1/2 signaling, enhances 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell. Mol Cell Endocrinol. 2013 Aug 25;376(1-2):60-9. DOI:10.1016/j.mce.2013.02.007 | PubMed ID:23419500 | HubMed [Zhang13]
  22. Lee JU, Huang S, Lee MH, Lee SE, Ryu MJ, Kim SJ, Kim YK, Kim SY, Joung KH, Kim JM, Shong M, and Jo YS. Dual specificity phosphatase 6 as a predictor of invasiveness in papillary thyroid cancer. Eur J Endocrinol. 2012 Jul;167(1):93-101. DOI:10.1530/EJE-12-0010 | PubMed ID:22535643 | HubMed [Lee12]
  23. Degl'Innocenti D, Romeo P, Tarantino E, Sensi M, Cassinelli G, Catalano V, Lanzi C, Perrone F, Pilotti S, Seregni E, Pierotti MA, Greco A, and Borrello MG. DUSP6/MKP3 is overexpressed in papillary and poorly differentiated thyroid carcinoma and contributes to neoplastic properties of thyroid cancer cells. Endocr Relat Cancer. 2013 Feb;20(1):23-37. DOI:10.1530/ERC-12-0078 | PubMed ID:23132790 | HubMed [DeglInnocenti13]
  24. Messina S, Frati L, Leonetti C, Zuchegna C, Di Zazzo E, Calogero A, and Porcellini A. Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas. Oncogene. 2011 Sep 1;30(35):3813-20. DOI:10.1038/onc.2011.99 | PubMed ID:21499306 | HubMed [Messina11]
  25. 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 | PubMed ID:20554528 | HubMed [Nunes-Xavier10]
  26. Chiappinelli KB, Rimel BJ, Massad LS, and Goodfellow PJ. Infrequent methylation of the DUSP6 phosphatase in endometrial cancer. Gynecol Oncol. 2010 Oct;119(1):146-50. DOI:10.1016/j.ygyno.2010.06.015 | PubMed ID:20638106 | HubMed [Chiappinelli10]
  27. Kim WK, Oh KJ, Choi HR, Park A, Han BS, Chi SW, Kim SJ, Bae KH, and Lee SC. MAP kinase phosphatase 3 inhibits brown adipocyte differentiation via regulation of Erk phosphorylation. Mol Cell Endocrinol. 2015 Nov 15;416:70-6. DOI:10.1016/j.mce.2015.08.023 | PubMed ID:26325440 | HubMed [Kim15]
  28. Marchetti S, Gimond C, Chambard JC, Touboul T, Roux D, Pouysségur J, and Pagès G. Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation. Mol Cell Biol. 2005 Jan;25(2):854-64. DOI:10.1128/MCB.25.2.854-864.2005 | PubMed ID:15632084 | HubMed [Marchetti05]
  29. Piya S, Kim JY, Bae J, Seol DW, Moon AR, and Kim TH. DUSP6 is a novel transcriptional target of p53 and regulates p53-mediated apoptosis by modulating expression levels of Bcl-2 family proteins. FEBS Lett. 2012 Nov 30;586(23):4233-40. DOI:10.1016/j.febslet.2012.10.031 | PubMed ID:23108049 | HubMed [Piya12]
  30. Morrison DJ, Kim MK, Berkofsky-Fessler W, and Licht JD. WT1 induction of mitogen-activated protein kinase phosphatase 3 represents a novel mechanism of growth suppression. Mol Cancer Res. 2008 Jul;6(7):1225-31. DOI:10.1158/1541-7786.MCR-08-0078 | PubMed ID:18644985 | HubMed [Morrison08]
  31. Rössig L, Haendeler J, Hermann C, Malchow P, Urbich C, Zeiher AM, and Dimmeler S. Nitric oxide down-regulates MKP-3 mRNA levels: involvement in endothelial cell protection from apoptosis. J Biol Chem. 2000 Aug 18;275(33):25502-7. DOI:10.1074/jbc.M002283200 | PubMed ID:10846176 | HubMed [Rossig00]
  32. Dowd S, Sneddon AA, and Keyse SM. Isolation of the human genes encoding the pyst1 and Pyst2 phosphatases: characterisation of Pyst2 as a cytosolic dual-specificity MAP kinase phosphatase and its catalytic activation by both MAP and SAP kinases. J Cell Sci. 1998 Nov;111 ( Pt 22):3389-99. DOI:10.1242/jcs.111.22.3389 | PubMed ID:9788880 | HubMed [Dowd98]
  33. Levy-Nissenbaum O, Sagi-Assif O, Kapon D, Hantisteanu S, Burg T, Raanani P, Avigdor A, Ben-Bassat I, and Witz IP. Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells. Oncogene. 2003 Oct 23;22(48):7649-60. DOI:10.1038/sj.onc.1206971 | PubMed ID:14576828 | HubMed [Levy-Nissenbaum03a]
  34. Levy-Nissenbaum O, Sagi-Assif O, Raanani P, Avigdor A, Ben-Bassat I, and Witz IP. cDNA microarray analysis reveals an overexpression of the dual-specificity MAPK phosphatase PYST2 in acute leukemia. Methods Enzymol. 2003;366:103-13. DOI:10.1016/s0076-6879(03)66009-x | PubMed ID:14674243 | HubMed [Levy-Nissenbaum03b]
  35. Levy-Nissenbaum O, Sagi-Assif O, and Witz IP. Characterization of the dual-specificity phosphatase PYST2 and its transcripts. Genes Chromosomes Cancer. 2004 Jan;39(1):37-47. DOI:10.1002/gcc.10295 | PubMed ID:14603440 | HubMed [Levy-Nissenbaum04]
  36. Muda M, Boschert U, Smith A, Antonsson B, Gillieron C, Chabert C, Camps M, Martinou I, Ashworth A, and Arkinstall S. Molecular cloning and functional characterization of a novel mitogen-activated protein kinase phosphatase, MKP-4. J Biol Chem. 1997 Feb 21;272(8):5141-51. DOI:10.1074/jbc.272.8.5141 | PubMed ID:9030581 | HubMed [Muda97]
  37. Liu Y, Lagowski J, Sundholm A, Sundberg A, and Kulesz-Martin M. Microtubule disruption and tumor suppression by mitogen-activated protein kinase phosphatase 4. Cancer Res. 2007 Nov 15;67(22):10711-9. DOI:10.1158/0008-5472.CAN-07-1968 | PubMed ID:18006813 | HubMed [Liu07]
  38. Dickinson RJ, Delavaine L, Cejudo-Marín R, Stewart G, Staples CJ, Didmon MP, Trinidad AG, Alonso A, Pulido R, and Keyse SM. Phosphorylation of the kinase interaction motif in mitogen-activated protein (MAP) kinase phosphatase-4 mediates cross-talk between protein kinase A and MAP kinase signaling pathways. J Biol Chem. 2011 Nov 4;286(44):38018-38026. DOI:10.1074/jbc.M111.255844 | PubMed ID:21908610 | HubMed [Dickinson11]
  39. Wu S, Wang Y, Sun L, Zhang Z, Jiang Z, Qin Z, Han H, Liu Z, Li X, Tang A, Gui Y, Cai Z, and Zhou F. Decreased expression of dual-specificity phosphatase 9 is associated with poor prognosis in clear cell renal cell carcinoma. BMC Cancer. 2011 Sep 26;11:413. DOI:10.1186/1471-2407-11-413 | PubMed ID:21943117 | HubMed [Wu11]
All Medline abstracts: PubMed | HubMed