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Gene Review

DUSP6  -  dual specificity phosphatase 6

Homo sapiens

Synonyms: Dual specificity protein phosphatase 6, Dual specificity protein phosphatase PYST1, HH19, MAP kinase phosphatase 3, MKP-3, ...
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Disease relevance of DUSP6


Psychiatry related information on DUSP6


High impact information on DUSP6


Chemical compound and disease context of DUSP6


Biological context of DUSP6


Anatomical context of DUSP6

  • First, we checked intrinsic transcriptional expression levels of DUSP6 by a quantitative real time PCR assay in 16 cultured pancreatic cancer cell lines and found that the cells could be classified into four groups: very-low-level expression, low-level expression, high-level expression, and very-high-level expression [3].
  • Pyst1 is expressed constitutively in human skin fibroblasts and, in contrast to other members of this family of enzymes, its mRNA is not inducible by either stress or mitogens [9].
  • We found that 308 keratinocytes highly express mitogen-activated protein kinase phosphatase-3 (MKP-3), which selectively inactivates ERK [13].
  • MKP-1, but not MKP-3, mRNA expression was 10-fold up-regulated in both mouse and human osteoblast cell lines within 30 min of Dex treatment and remained elevated for 24 h [14].
  • Angiotensin II-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis [15].

Associations of DUSP6 with chemical compounds

  • Using a sodium-bisulfite-modification assay, we found that CpG sequences in intron 1 of DUSP6 were heavily methylated in MIA PaCa-2 and PAN07JCK, both showing the very low level of intrinsic expression of the gene [3].
  • We observed restored expression of DUSP6 after treatment with 5-azacytidine and trichostatin A, a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, respectively, in cells with intrinsically very-low-level and low-level expression of DUSP6 [3].
  • Accumulation of reactive oxygen species was observed with tamoxifen treatment of MKP3-overexpressing cells, and antioxidant treatment increased MKP3 phosphatase activity, thereby blocking resistance [4].
  • Furthermore, the nuclear translocation of MKP-3 seen in the presence of leptomycin B is mediated by an active process, indicating that MKP-3 shuttles between the nucleus and cytoplasm [16].
  • The amino-terminal noncatalytic domain of MKP-3 is both necessary and sufficient for nuclear export of the phosphatase and contains a single functional leucine-rich nuclear export signal (NES) [16].

Physical interactions of DUSP6

  • A third ERK2 binding site is localized in the C terminus of MKP3 (residues 348--381) [17].

Enzymatic interactions of DUSP6


Regulatory relationships of DUSP6


Other interactions of DUSP6

  • This reinforces the conclusion that Pyst1 and Pyst2 are members of a distinct and structurally homologous subfamily of dual-specificity (Thr/Tyr) MAP kinase phosphatases [19].
  • Most of the intraductal adenoma/borderline lesions with abrogation of DUSP6 harbored mutations of KRAS2 [2].
  • Gene expression profiling was used to identify mitogen-activated protein kinase (MAPK) phosphatase 3 (MKP3) whose expression was correlated with response to the antiestrogen tamoxifen in both patients and in vitro-derived cell line models [4].
  • MKP3 represents a novel mechanism of resistance, which may be a potential biomarker for the use of ERK1/2 and/or JNK inhibitors in combination with tamoxifen treatment [4].
  • Overexpression of MKP3 rendered ER-alpha-positive breast cancer cells resistant to the growth-inhibitory effects of tamoxifen and enhanced tamoxifen agonist activity in endometrial cells [4].

Analytical, diagnostic and therapeutic context of DUSP6


  1. 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) [Pubmed]
  2. Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas. Furukawa, T., Fujisaki, R., Yoshida, Y., Kanai, N., Sunamura, M., Abe, T., Takeda, K., Matsuno, S., Horii, A. Mod. Pathol. (2005) [Pubmed]
  3. Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. Xu, S., Furukawa, T., Kanai, N., Sunamura, M., Horii, A. J. Hum. Genet. (2005) [Pubmed]
  4. Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance. Cui, Y., Parra, I., Zhang, M., Hilsenbeck, S.G., Tsimelzon, A., Furukawa, T., Horii, A., Zhang, Z.Y., Nicholson, R.I., Fuqua, S.A. Cancer Res. (2006) [Pubmed]
  5. Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler. Toyota, T., Watanabe, A., Shibuya, H., Nankai, M., Hattori, E., Yamada, K., Kurumaji, A., Karkera, J.D., Detera-Wadleigh, S.D., Yoshikawa, T. Mol. Psychiatry (2000) [Pubmed]
  6. The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder. Lee, K.Y., Ahn, Y.M., Joo, E.J., Chang, J.S., Kim, Y.S. Mol. Psychiatry (2006) [Pubmed]
  7. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Camps, M., Nichols, A., Gillieron, C., Antonsson, B., Muda, M., Chabert, C., Boschert, U., Arkinstall, S. Science (1998) [Pubmed]
  8. 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, M.M. Mol. Cell (2001) [Pubmed]
  9. Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. Groom, L.A., Sneddon, A.A., Alessi, D.R., Dowd, S., Keyse, S.M. EMBO J. (1996) [Pubmed]
  10. Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. Furukawa, T., Yatsuoka, T., Youssef, E.M., Abe, T., Yokoyama, T., Fukushige, S., Soeda, E., Hoshi, M., Hayashi, Y., Sunamura, M., Kobari, M., Horii, A. Cytogenet. Cell Genet. (1998) [Pubmed]
  11. Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade. Ogawa, K., Sun, C., Horii, A. Oncol. Rep. (2005) [Pubmed]
  12. Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation. Marchetti, S., Gimond, C., Chambard, J.C., Touboul, T., Roux, D., Pouysségur, J., Pagès, G. Mol. Cell. Biol. (2005) [Pubmed]
  13. Mitogen-activated protein kinase phosphatase-3 is a tumor promoter target in initiated cells that express oncogenic Ras. Warmka, J.K., Mauro, L.J., Wattenberg, E.V. J. Biol. Chem. (2004) [Pubmed]
  14. Glucocorticoids induce rapid up-regulation of mitogen-activated protein kinase phosphatase-1 and dephosphorylation of extracellular signal-regulated kinase and impair proliferation in human and mouse osteoblast cell lines. Engelbrecht, Y., de Wet, H., Horsch, K., Langeveldt, C.R., Hough, F.S., Hulley, P.A. Endocrinology (2003) [Pubmed]
  15. Angiotensin II-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis. Rössig, L., Hermann, C., Haendeler, J., Assmus, B., Zeiher, A.M., Dimmeler, S. Basic Res. Cardiol. (2002) [Pubmed]
  16. 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, R.J., Mandl, M., Keyse, S.M. J. Biol. Chem. (2004) [Pubmed]
  17. Multiple regions of MAP kinase phosphatase 3 are involved in its recognition and activation by ERK2. Zhou, B., Wu, L., Shen, K., Zhang, J., Lawrence, D.S., Zhang, Z.Y. J. Biol. Chem. (2001) [Pubmed]
  18. ERK1/2-driven and MKP-mediated inhibition of EGF-induced ERK5 signaling in human proximal tubular cells. Sarközi, R., Miller, B., Pollack, V., Feifel, E., Mayer, G., Sorokin, A., Schramek, H. J. Cell. Physiol. (2007) [Pubmed]
  19. 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, A.A., Keyse, S.M. J. Cell. Sci. (1998) [Pubmed]
  20. MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. Muda, M., Boschert, U., Dickinson, R., Martinou, J.C., Martinou, I., Camps, M., Schlegel, W., Arkinstall, S. J. Biol. Chem. (1996) [Pubmed]
  21. Calcium-mediated inactivation of the MAP kinase pathway in sea urchin eggs at fertilization. Kumano, M., Carroll, D.J., Denu, J.M., Foltz, K.R. Dev. Biol. (2001) [Pubmed]
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