Difference between revisions of "Phosphatase Subfamily DSP6"

Revision as of 07:39, 7 March 2015

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

Evolution

Domain

DSP6 subfamily has two domains: rhodanese domain and phosphatase domain. Rhodanese domain mediates interaction with MAP kinases (often ERK). Rhodanese domain of DSP6 also has two conserved Leu-rich nuclear export signals [1] (particular Figure 5 and Figure 11). Binding to MAP kinases induces conformation change in phosphatase domain, which can increase the phosphatase activity [2].

Function

DUSP6 (MKP3/PYST1)

DUSP6 preferentially dephosphorylates ERK [3, 4, 5], which resulted from that DUSP6 binds to ERK but not p38 or JNK. The interaction is mediated by rhodanese domain (or kinase interaction motif embedded in rhodanese domain?) [6]. Later study has shown DUSP6 is ERK1/2-specific, as it does not inactive ERK5 [7].

As a negative regulator of ERK, DUSP6 is proposed to be tumor suppressor. DUSP6 expression was down-regulated through hypermethylation at enhancer in some pancreatic cell lines and pancreatic cancer tissues [8, 9]. But, DUSP6 was up-regulated in endometrial adenocarcinomas [10], thyroid carcinoma [11, 12], and glioblastomas [13]. Meanwhile, DUSP6 upregulation induced by angiotensin II mediates endothelial cell apoptosis [14]. (note: DUSP6 upregulation in cancer may be the response to suppress carcinogenesis?)

Like DUSP2, DUSP4 and DUSP4 of DSP1 subfamily, DUSP6 is phosphorylated by ERK [15]. However, the phosphorylation sites are different. DUSP6 is phosphorylated at serines 159 and 197 [15], which are found in DUSP6 and DUSP7, but not DUSP9 or other DSPs.

Nitric oxide down-regulates MKP-3 mRNA levels [16].

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 [17].

DUSP7 has at least two isoforms. The longer isoform is constitutively highly expressed in myeloid leukemia and other malignant cells [18, 19, 20].

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 [21, 22]. 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 [23].

Decreased expression of DUSP-9 is associated with poor prognosis in clear cell renal cell carcinomas [24].

References

1. 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]
2. 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]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. 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]
22. 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]
23. 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]
24. 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]