Written | 2011-09 | Zhenfeng Zhang, Balazs Halmos |
Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, New York Presbyterian Hospital-Columbia University Medical Center, New York, NY, USA |
Identity |
Alias (NCBI) | MKP-3 | MKP3 | PYST1 | rVH6 |
HGNC (Hugo) | DUSP6 |
HGNC Alias symb | MKP-3 | PYST1 |
LocusID (NCBI) | 1848 |
Atlas_Id | 46105 |
Location | 12q21.33 [Link to chromosome band 12q21] |
Location_base_pair | Starts at 89347237 and ends at 89352501 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping DUSP6.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
HARS (5q31.3) / DUSP6 (12q21.33) |
DNA/RNA |
![]() | |
The diagram depicts the structure of the DUSP6 gene (bottom) roughly aligned with its corresponding functional protein domains (middle and top). DUSP6 comprises a C-terminal catalytic domain and an N-terminal non-catalytic domain (middle). The 3 exons of DUSP6 (rectangles) are connected with lines representing introns. | |
Description | The human DUSP6 gene is located on chromosome 12q21.33 and consists of 3 exons. The full-length coding sequence of DUSP6 contains 1146 nucleotides. The functional phosphatase domain of DUSP6 is encoded by half of exon 2 and almost the entire sequence of exon 3. |
Transcription | DUSP6 gene transcription can start from either the first ATG or alternatively the second ATG (Met14), and therefore two protein products are generated which usually demonstrate a double-band appearance in regular immunoblotting assays (Dowd et al., 1998; Zhang et al., 2010). |
Protein |
![]() | |
The diagram depicts the structural features of DUSP6. The highly conserved C-terminal domain of DUSP6 contains the canonical tyrosine/threonine-specific phosphatase signature sequence HCXXXXXR at the active site, where the cysteine acts as the essential enzymatic nucleophile and arginine interacts directly with the phosphate group on phosphotyrosine or phosphothreonine (Farooq et al., 2001). The amino-terminal domain of DUSP6 contains a specific arginine-rich kinase interaction motif (KIM) (Tárrega et al., 2005) and a leucine-rich nuclear export signal (NES) necessary and sufficient for nuclear export of the phosphatase (Karlsson et al., 2004). | |
Description | The full-length DUSP6 protein contains 381 amino acids and has a molecular weight of 44 kDa. DUSPs are characterized by a common structure comprising a C-terminal phosphatase domain that are defined by the active-site signature motif HCXXXXXR. The structure of DUSP proteins confers phosphatase activity for both phosphoserine/threonine and phosphotyrosine residues. An enzyme-dead DUSP6 expression construct can be generated via a 293 Cysteine to Serine/Glycine (C293S/G) point mutation (Wishart et al., 1995; Zhang et al., 2010; Zhou et al., 2006). |
Expression | DUSP6 is expressed usually at low level in resting, nonstimulated cells in a variety of tissues and is induced as an early response gene after activation of the ERK-MAPK signaling pathway. |
Localisation | DUSP6 is a cytoplasmic dual specificity protein phosphatase. |
Function | Mitogen-activated protein kinases (MAPK) constitute a highly conserved family of kinases that relay information from extracellular signals to downstream effectors that control diverse cellular processes such as proliferation, differentiation, migration, survival and apoptosis (Wada and Penninger, 2004). A balance between the activities of upstream activators and various negative regulatory mechanisms of MAPK signaling, which terminate its activation, determines its biological outcomes. DUSP6 is a prototypical member of a subfamily of cytoplasmic MKPs, which includes DUSP7 and DUSP9 as well. These enzymes all display a high degree of substrate selectivity for ERK1 and ERK2 (Keyse, 2008). DUSP6 has been shown to act as a central feedback regulator attenuating ERK levels in developmental programs (Echevarria et al., 2005; Li et al., 2007). The cytoplasmic localization of DUSP6 is mediated by a chromosome region maintenance-1-dependent nuclear export pathway. DUSP6 appears to play a role in determining the subcellular localization of ERK by serving as a cytoplasmic anchor for ERK, thereby mediating a spatio-temporal mechanism of ERK signaling regulation. Cytoplasmic retention of ERK requires both a functional kinase interaction motif and nuclear export site. Defects of these feedback regulation steps are thought to contribute to ERK-MAPK related oncogenesis. An in vivo study has identified DUSP6 as a negative feedback regulator of fibroblast growth factor-stimulated ERK signaling during murine development (Li et al., 2007). Several in vitro studies have demonstrated that DUSP6 acts as a negative regulator of fibroblast growth factor receptor signaling and endothelial cell platelet-derived growth factor receptor signaling via termination of ERK activation (Ekerot et al., 2008; Jurek et al., 2009). |
Homology | DUSP6 belongs to a subfamily of ten more closely related dual-specificity MAPK phosphatases (MKPs) within the larger cysteine-dependent dual specificity phosphatase (DUSP) family (Keyse, 2008). While DUSP1 (MKP-1), DUSP4 (MKP-2), and DUSP9 (MKP4) dephosphorylate both ERKs, p38 and JNK, the phosphatases DUSP5 (Hvh-3), DUSP6 (MKP-3), and DUSP7 (MKP-X) exclusively target ERK1/2 MAPKs (Keyse, 2008). The N-terminal domain of all DUSPs has two regions of homology with the Cdc25 cell cycle regulatory phosphatase. The more conserved catalytic domain within DUSPs contains an active site sequence related to the prototypic VH-1 phosphatase encoded by the vaccinia virus. Specificity of MKPs toward MAPKs relies on the KIM domain. Although each MKP targets different subsets of MAPKs, there is an overlap between their specificities (Bermudez et al., 2010). |
Mutations |
Note | Although DUSP6 has been implicated as a candidate tumor suppressor in several cancer setting, no mutations in the gene have been identified so far. |
Implicated in |
Note | |
Entity | Various cancers |
Note | DUSP6 null mice demonstrate enhanced ERK1/2 phosphorylation leading to increased myocyte proliferation and cardiac hypercellularity (Maillet et al., 2008). DUSP6 has been identified as a potential novel tumor suppressor gene in pancreatic cancer since loss of DUSP6 expression might synergize with activating-mutated k-Ras resulting in increased activation of ERK1/2 MAP kinase and thus contribute to the development of the malignant and invasive phenotype in pancreatic cancer (Furukawa et al., 2003). Loss of DUSP6 expression caused by oxidative stress-mediated degradation was also noted in ovarian cancer and correlated with high ERK1/2 activity (Chan et al., 2008). DUSP6 has also been identified as one of only three genes which are uniquely expressed in myeloma cells harboring a constitutively active mutant N-ras gene and is also overexpressed in human melanoma cell lines with potent activating mutations in B-raf and in breast epithelial cells stably expressing H-Ras (Bloethner et al., 2005; Croonquist et al., 2003; Warmka et al., 2004), suggesting that the over-expression of DUSP6 seen in response to activating-mutated Ras or Raf might represent a compensatory increase in the negative feedback control of the ERK1/2 MAPK pathway, which lies downstream of these activated oncogenes. In support of this, the tetracycline-induced expression of a functional fusion protein between DUSP6 and green fluorescent protein in H-ras transformed fibroblasts following injection into nude mice resulted in a large delay in tumor emergence and growth as compared to the untreated control group (Marchetti et al., 2004 ). DUSP6 has been reported to be one of the most highly regulated genes in chronic myeloid leukemia cells upon imatinib treatment (Hakansson et al., 2008) and similarly DUSP6 is overexpressed upon inducible expression of the EGFRvIII oncogene in glioblastoma cells (Ramnarain et al., 2006). DUSP6 has also been demonstrated to be positively correlated with the activity of the oncogenic ERK pathway in non-small cell lung cancer tissue and is an ETS-regulated negative feedback mediator of ERK signaling in lung cancer cells (Zhang et al., 2010). |
Prognosis | Elevated DUSP6 RNA expression was reported to be a major negative predictor of survival in patients with resected non-small cell lung cancer as part of a five-gene signature model (Chen et al., 2007). |
Bibliography |
Protein tyrosine phosphatases in the human genome. |
Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T. |
Cell. 2004 Jun 11;117(6):699-711. (REVIEW) |
PMID 15186772 |
The dual-specificity MAP kinase phosphatases: critical roles in development and cancer. |
Bermudez O, Pages G, Gimond C. |
Am J Physiol Cell Physiol. 2010 Aug;299(2):C189-202. Epub 2010 May 12. (REVIEW) |
PMID 20463170 |
Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. |
Bloethner S, Chen B, Hemminki K, Muller-Berghaus J, Ugurel S, Schadendorf D, Kumar R. |
Carcinogenesis. 2005 Jul;26(7):1224-32. Epub 2005 Mar 10. |
PMID 15760917 |
Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells. |
Chan DW, Liu VW, Tsao GS, Yao KM, Furukawa T, Chan KK, Ngan HY. |
Carcinogenesis. 2008 Sep;29(9):1742-50. Epub 2008 Jul 16. |
PMID 18632752 |
A five-gene signature and clinical outcome in non-small-cell lung cancer. |
Chen HY, Yu SL, Chen CH, Chang GC, Chen CY, Yuan A, Cheng CL, Wang CH, Terng HJ, Kao SF, Chan WK, Li HN, Liu CC, Singh S, Chen WJ, Chen JJ, Yang PC. |
N Engl J Med. 2007 Jan 4;356(1):11-20. |
PMID 17202451 |
Gene profiling of a myeloma cell line reveals similarities and unique signatures among IL-6 response, N-ras-activating mutations, and coculture with bone marrow stromal cells. |
Croonquist PA, Linden MA, Zhao F, Van Ness BG. |
Blood. 2003 Oct 1;102(7):2581-92. Epub 2003 Jun 5. |
PMID 12791645 |
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. |
Dowd S, Sneddon AA, Keyse SM. |
J Cell Sci. 1998 Nov;111 ( Pt 22):3389-99. |
PMID 9788880 |
Mkp3 is a negative feedback modulator of Fgf8 signaling in the mammalian isthmic organizer. |
Echevarria D, Martinez S, Marques S, Lucas-Teixeira V, Belo JA. |
Dev Biol. 2005 Jan 1;277(1):114-28. |
PMID 15572144 |
Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. |
Ekerot M, Stavridis MP, Delavaine L, Mitchell MP, Staples C, Owens DM, Keenan ID, Dickinson RJ, Storey KG, Keyse SM. |
Biochem J. 2008 Jun 1;412(2):287-98. |
PMID 18321244 |
Solution structure of ERK2 binding domain of MAPK phosphatase MKP-3: structural insights into MKP-3 activation by ERK2. |
Farooq A, Chaturvedi G, Mujtaba S, Plotnikova O, Zeng L, Dhalluin C, Ashton R, Zhou MM. |
Mol Cell. 2001 Feb;7(2):387-99. |
PMID 11239467 |
Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. |
Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A. |
Am J Pathol. 2003 Jun;162(6):1807-15. |
PMID 12759238 |
Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation. |
Hakansson P, Nilsson B, Andersson A, Lassen C, Gullberg U, Fioretos T. |
Genes Chromosomes Cancer. 2008 Apr;47(4):267-75. |
PMID 18181176 |
Negative and positive regulation of MAPK phosphatase 3 controls platelet-derived growth factor-induced Erk activation. |
Jurek A, Amagasaki K, Gembarska A, Heldin CH, Lennartsson J. |
J Biol Chem. 2009 Feb 13;284(7):4626-34. Epub 2008 Dec 23. |
PMID 19106095 |
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. |
Karlsson M, Mathers J, Dickinson RJ, Mandl M, Keyse SM. |
J Biol Chem. 2004 Oct 1;279(40):41882-91. Epub 2004 Jul 21. |
PMID 15269220 |
Dual-specificity MAP kinase phosphatases (MKPs) and cancer. |
Keyse SM. |
Cancer Metastasis Rev. 2008 Jun;27(2):253-61. (REVIEW) |
PMID 18330678 |
Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. |
Li C, Scott DA, Hatch E, Tian X, Mansour SL. |
Development. 2007 Jan;134(1):167-76. |
PMID 17164422 |
DUSP6 (MKP3) null mice show enhanced ERK1/2 phosphorylation at baseline and increased myocyte proliferation in the heart affecting disease susceptibility. |
Maillet M, Purcell NH, Sargent MA, York AJ, Bueno OF, Molkentin JD. |
J Biol Chem. 2008 Nov 7;283(45):31246-55. Epub 2008 Aug 27. |
PMID 18753132 |
Inducible expression of a MAP kinase phosphatase-3-GFP chimera specifically blunts fibroblast growth and ras-dependent tumor formation in nude mice. |
Marchetti S, Gimond C, Roux D, Gothie E, Pouyssegur J, Pages G. |
J Cell Physiol. 2004 Jun;199(3):441-50. |
PMID 15095291 |
Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells. |
Ramnarain DB, Park S, Lee DY, Hatanpaa KJ, Scoggin SO, Otu H, Libermann TA, Raisanen JM, Ashfaq R, Wong ET, Wu J, Elliott R, Habib AA. |
Cancer Res. 2006 Jan 15;66(2):867-74. |
PMID 16424019 |
ERK2 shows a restrictive and locally selective mechanism of recognition by its tyrosine phosphatase inactivators not shared by its activator MEK1. |
Tarrega C, Rios P, Cejudo-Marin R, Blanco-Aparicio C, van den Berk L, Schepens J, Hendriks W, Tabernero L, Pulido R. |
J Biol Chem. 2005 Nov 11;280(45):37885-94. Epub 2005 Sep 7. |
PMID 16148006 |
Mitogen-activated protein kinases in apoptosis regulation. |
Wada T, Penninger JM. |
Oncogene. 2004 Apr 12;23(16):2838-49. (REVIEW) |
PMID 15077147 |
Mitogen-activated protein kinase phosphatase-3 is a tumor promoter target in initiated cells that express oncogenic Ras. |
Warmka JK, Mauro LJ, Wattenberg EV. |
J Biol Chem. 2004 Aug 6;279(32):33085-92. Epub 2004 May 24. |
PMID 15159408 |
A single mutation converts a novel phosphotyrosine binding domain into a dual-specificity phosphatase. |
Wishart MJ, Denu JM, Williams JA, Dixon JE. |
J Biol Chem. 1995 Nov 10;270(45):26782-5. |
PMID 7592916 |
Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. |
Zhang Z, Kobayashi S, Borczuk AC, Leidner RS, Laframboise T, Levine AD, Halmos B. |
Carcinogenesis. 2010 Apr;31(4):577-86. Epub 2010 Jan 22. |
PMID 20097731 |
Mapping ERK2-MKP3 binding interfaces by hydrogen/deuterium exchange mass spectrometry. |
Zhou B, Zhang J, Liu S, Reddy S, Wang F, Zhang ZY. |
J Biol Chem. 2006 Dec 15;281(50):38834-44. Epub 2006 Oct 17. |
PMID 17046812 |
Citation |
This paper should be referenced as such : |
Zhang, Z ; Halmos, B |
DUSP6 (dual specificity phosphatase 6) |
Atlas Genet Cytogenet Oncol Haematol. 2012;16(2):119-122. |
Free journal version : [ pdf ] [ DOI ] |
External links |
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
© Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Thu Mar 25 19:58:58 CET 2021 |
For comments and suggestions or contributions, please contact us