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Gene Review

Dusp1  -  dual specificity phosphatase 1

Mus musculus

Synonyms: 3CH134, 3ch134, Dual specificity protein phosphatase 1, MAP kinase phosphatase 1, MKP-1, ...
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Disease relevance of Dusp1


High impact information on Dusp1

  • In serum-stimulated normal fibroblasts, the kinetics of inactivation of p42MAPK coincides with the appearance of newly synthesized 3CH134 protein, and the protein synthesis inhibitor cycloheximide leads to persistent activation of MAP kinase [5].
  • 3CH134 blocks phosphorylation and activation of p42MAPK mediated by serum, oncogenic Ras, or activated Raf, whereas the catalytically inactive mutant of the phosphatase, Cys-258-->Ser, augments MAP kinase phosphorylation under similar conditions [5].
  • MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo [5].
  • Expression of 3CH134 in COS cells leads to selective dephosphorylation of p42MAPK from the spectrum of phosphotyrosyl proteins [5].
  • Disruption of the bacterial erp gene, which encodes the exported repetitive protein, impaired multiplication of M. tuberculosis and M. bovis Bacille Calmette-Guérin in cultured macrophages and mice [6].

Chemical compound and disease context of Dusp1

  • Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge [1].
  • Taken together, these results demonstrate that activation of PKCdelta triggers degradation of MKP-1 through the ubiquitin-proteasome pathway, thereby contributing to persistent activation of ERK1/2 under glutamate-induced oxidative toxicity [7].
  • Significantly, mkp-1(-/-) mice are resistant to diet-induced obesity due to enhanced energy expenditure, but succumb to glucose intolerance on a high fat diet [8].
  • CONCLUSION: These findings suggest that norepinephrine-induced hypertrophy is linked closely with p38 MAP kinase activation, which can be endogenously modulated through estrogen-responsive regulation of MKP-1 expression [9].
  • We have characterized a growth factor-inducible gene, erp, and demonstrated that it encodes a 367-amino-acid nontransmembrane tyrosine phosphatase protein with significant similarity to the vaccinia virus H1 protein [10].

Biological context of Dusp1


Anatomical context of Dusp1


Associations of Dusp1 with chemical compounds

  • These data together demonstrate a specific regulatory role of DUSP1 in controlling a subset of LPS-induced genes that determines the outcome of endotoxin shock [13].
  • We demonstrate that upon LPS challenge, Mkp-1-/- cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-alpha and interleukin (IL)-6 production compared with wild-type cells [1].
  • Coexpression of MKK1 or MKK2 with MKP-1 resulted in 7-10-fold activation of mitogen-activated protein kinase kinase (MKK), which required the presence of regulatory serine phosphorylation sites [14].
  • Inhibition of endogenous calcineurin with cyclosporin A decreased MKP-1 protein levels and increased p38 activation in response to agonist stimulation [3].
  • Protein kinase Cdelta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death [7].

Enzymatic interactions of Dusp1

  • This negative regulatory loop is further enhanced by the capacity of p42/p44 MAPK to phosphorylate MKP1 and 2 [15].
  • Indeed, adenoviral MKP-1 expression increased insulin expression by decreasing a phosphorylation form of JNKs and a resulting phosphorylated form of c-jun in MIN6 cells [16].

Regulatory relationships of Dusp1


Other interactions of Dusp1

  • Intraperitoneal challenge of DUSP1-/- mice with LPS caused increased lethality and overshooting production of interleukin (IL)-6 and tumor necrosis factor alpha [13].
  • In this study, we examined the effect of MKP-1 on signaling components upstream of ERK1 and ERK2 [14].
  • In contrast, the expression of the important mediators of endotoxin lethality, interferon gamma and IL-12, was not significantly altered by the absence of DUSP1 [13].
  • Triptolide, a diterpenoid triepoxide, potently blocked the induction of MKP-1 by peptidoglycan and prolonged the activation of JNK and p38 [11].
  • Raf-1, a direct regulator of MKK1 and MKK2, was activated under these conditions, and a synergistic activation of MKK was observed upon coexpression of Raf-1 and MKP-1 [14].

Analytical, diagnostic and therapeutic context of Dusp1


  1. MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. Zhao, Q., Wang, X., Nelin, L.D., Yao, Y., Matta, R., Manson, M.E., Baliga, R.S., Meng, X., Smith, C.V., Bauer, J.A., Chang, C.H., Liu, Y. J. Exp. Med. (2006) [Pubmed]
  2. Restraint of proinflammatory cytokine biosynthesis by mitogen-activated protein kinase phosphatase-1 in lipopolysaccharide-stimulated macrophages. Chen, P., Li, J., Barnes, J., Kokkonen, G.C., Lee, J.C., Liu, Y. J. Immunol. (2002) [Pubmed]
  3. Calcineurin enhances MAPK phosphatase-1 expression and p38 MAPK inactivation in cardiac myocytes. Lim, H.W., New, L., Han, J., Molkentin, J.D. J. Biol. Chem. (2001) [Pubmed]
  4. Knockout of Mkp-1 enhances the host inflammatory responses to gram-positive bacteria. Wang, X., Meng, X., Kuhlman, J.R., Nelin, L.D., Nicol, K.K., English, B.K., Liu, Y. J. Immunol. (2007) [Pubmed]
  5. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Sun, H., Charles, C.H., Lau, L.F., Tonks, N.K. Cell (1993) [Pubmed]
  6. Attenuation of virulence by disruption of the Mycobacterium tuberculosis erp gene. Berthet, F.X., Lagranderie, M., Gounon, P., Laurent-Winter, C., Ensergueix, D., Chavarot, P., Thouron, F., Maranghi, E., Pelicic, V., Portnoï, D., Marchal, G., Gicquel, B. Science (1998) [Pubmed]
  7. Protein kinase Cdelta-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death. Choi, B.H., Hur, E.M., Lee, J.H., Jun, D.J., Kim, K.T. J. Cell. Sci. (2006) [Pubmed]
  8. Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. Wu, J.J., Roth, R.J., Anderson, E.J., Hong, E.G., Lee, M.K., Choi, C.S., Neufer, P.D., Shulman, G.I., Kim, J.K., Bennett, A.M. Cell metabolism. (2006) [Pubmed]
  9. Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy. Dash, R., Schmidt, A.G., Pathak, A., Gerst, M.J., Biniakiewicz, D., Kadambi, V.J., Hoit, B.D., Abraham, W.T., Kranias, E.G. Cardiovasc. Res. (2003) [Pubmed]
  10. Structure, mapping, and expression of erp, a growth factor-inducible gene encoding a nontransmembrane protein tyrosine phosphatase, and effect of ERP on cell growth. Noguchi, T., Metz, R., Chen, L., Mattéi, M.G., Carrasco, D., Bravo, R. Mol. Cell. Biol. (1993) [Pubmed]
  11. The function of mitogen-activated protein kinase phosphatase-1 in peptidoglycan-stimulated macrophages. Shepherd, E.G., Zhao, Q., Welty, S.E., Hansen, T.N., Smith, C.V., Liu, Y. J. Biol. Chem. (2004) [Pubmed]
  12. The noncatalytic amino terminus of mitogen-activated protein kinase phosphatase 1 directs nuclear targeting and serum response element transcriptional regulation. Wu, J.J., Zhang, L., Bennett, A.M. Mol. Cell. Biol. (2005) [Pubmed]
  13. Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock. Hammer, M., Mages, J., Dietrich, H., Servatius, A., Howells, N., Cato, A.C., Lang, R. J. Exp. Med. (2006) [Pubmed]
  14. Feedback regulation of Raf-1 and mitogen-activated protein kinase (MAP) kinase kinases 1 and 2 by MAP kinase phosphatase-1 (MKP-1). Shapiro, P.S., Ahn, N.G. J. Biol. Chem. (1998) [Pubmed]
  15. Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. Pouysségur, J., Lenormand, P. Eur. J. Biochem. (2003) [Pubmed]
  16. Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic beta-cells. Zhang, B., Hosaka, M., Sawada, Y., Torii, S., Mizutani, S., Ogata, M., Izumi, T., Takeuchi, T. Diabetes (2003) [Pubmed]
  17. Extracellular signal-regulated kinase-2, but not c-Jun NH2-terminal kinase, activation correlates with surface IgM-mediated apoptosis in the WEHI 231 B cell line. Lee, J.R., Koretzky, G.A. J. Immunol. (1998) [Pubmed]
  18. Role of extracellular signal-regulated protein kinase cascade in macrophage killing of Candida albicans. Ibata-Ombetta, S., Jouault, T., Trinel, P.A., Poulain, D. J. Leukoc. Biol. (2001) [Pubmed]
  19. Macrophage colony-stimulating factor induces the expression of mitogen-activated protein kinase phosphatase-1 through a protein kinase C-dependent pathway. Valledor, A.F., Xaus, J., Marquès, L., Celada, A. J. Immunol. (1999) [Pubmed]
  20. Angiotensin II type 2 receptor mediates programmed cell death. Yamada, T., Horiuchi, M., Dzau, V.J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  21. Mitogen-activated protein kinase phosphatase-1 represses c-Jun NH2-terminal kinase-mediated apoptosis via NF-kappaB regulation. Wang, Z., Cao, N., Nantajit, D., Fan, M., Liu, Y., Li, J.J. J. Biol. Chem. (2008) [Pubmed]
  22. Molecular cloning and characterization of a novel dual specificity phosphatase, LMW-DSP2, that lacks the cdc25 homology domain. Aoyama, K., Nagata, M., Oshima, K., Matsuda, T., Aoki, N. J. Biol. Chem. (2001) [Pubmed]
  23. Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathy. Monteiro, F.A., Sousa, M.M., Cardoso, I., do Amaral, J.B., Guimarães, A., Saraiva, M.J. J. Neurochem. (2006) [Pubmed]
  24. Expression of the nontransmembrane tyrosine phosphatase gene erp during mouse organogenesis. Carrasco, D., Bravo, R. Cell Growth Differ. (1993) [Pubmed]
  25. Mitogen-activated protein kinase phosphatase-1 in olfactory neural regeneration. Shinogami, M., Ishibashi, T. Neuroreport (2000) [Pubmed]
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