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DUSP2  -  dual specificity phosphatase 2

Homo sapiens

Synonyms: Dual specificity protein phosphatase 2, Dual specificity protein phosphatase PAC-1, PAC-1, PAC1
 
 
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Disease relevance of DUSP2

  • PAC-1 is similar to a phosphatase induced by mitogens or heat shock in fibroblasts, a yeast gene, and a vaccinia virus-encoded serine-tyrosine phosphatase (VH1) [1].
  • When we expressed this protein in Escherichia coli as a GST-fusion protein, a 45 kDa (19 kDa PAC-1 variant+26 kDa GST protein) protein was obtained [2].
  • These data functionally define a novel genetic locus, designated PAC1, for prostate adenocarcinoma 1, involved in tumor suppression of human prostate carcinoma and furthermore strongly suggest that the cell death pathway can be functionally restored in prostatic adenocarcinoma [3].
  • In patients with vasospasm, the expression of CD62P, CD63 and PAC-1 on the platelet membrane surface increased in coronary sinus blood samples following coronary vasospasm, although the expression in aortic samples did not change [4].
  • CONCLUSIONS: Despite the limited size of this cohort, our results present the first evidence supporting a clinical role for PAC-1 in ovarian carcinoma [5].
 

Psychiatry related information on DUSP2

  • To assess whether platelets are activated in transient global amnesia (TGA) and TIA, blood samples were analyzed by fluorescence-activated cytoscan using antibodies specific for platelet fibrinogen receptor (PAC1) and P-selectin (CD62P) [6].
 

High impact information on DUSP2

 

Chemical compound and disease context of DUSP2

 

Biological context of DUSP2

 

Anatomical context of DUSP2

  • A mitogen-induced gene (PAC-1) has been cloned from human T cells and encodes a 32-kilodalton protein that contains a sequence that defines the enzymatic site of known protein phosphotyrosine phosphatases (PTPases) [1].
  • A comprehensive microarray analysis of human leukocytes identified DUSP2 (encoding the phosphatase PAC-1) as one of the most highly induced transcripts in activated immune cells [16].
  • Characterization of a variant of PAC-1 in large granular lymphocyte leukemia [2].
  • Like platelets from the patient, GPIIb-Arg560IIIa-transfected CHO cells constitutively bound LIBS antibodies and PAC-1 [17].
  • Differential regulation of the dual-specificity protein-tyrosine phosphatases CL100, B23, and PAC1 in mesangial cells [18].
 

Associations of DUSP2 with chemical compounds

  • AS or SNP did not modify the expression of platelet glycoproteins (Ib, IIb-IIIa, la-IIa, IV), whereas they substantially decreased the levels of CD62P, CD63 and of PAC-1 (a platelet activated glycoprotein IIb/IIIa epitope) after the stimulation with ADP [19].
  • Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1 [8].
  • Constitutive expression of PAC1 in vivo leads to inhibition of MAP kinase activity normally stimulated by epidermal growth factor, phorbol myristyl acetate, or T-cell receptor crosslinking [8].
  • Thrombasthenic platelets behaved like normal platelets after activation of complement except for lack of PAC-1 binding (also with regard to the effect of PGE1 and microvesicle formation) [20].
  • Activation of GPIIb-IIIa, monitored with mAb PAC-1, was markedly decreased (< 20% of normal) in response to ADP, thrombin and platelet-activating factor (PAF); expression of ligand-induced binding sites (LIBS) was < or = 30% of normal [21].
 

Other interactions of DUSP2

  • Genomic organization and chromosomal localization of the DUSP2 gene, encoding a MAP kinase phosphatase, to human 2p11.2-q11 [14].
  • Relationship between the expression levels of CD61, CD63, and PAC-1 on platelet surface in peripheral blood and the transplanted kidney function [22].
  • We generated Dusp2(-/-) mice and found considerably reduced inflammatory responses in the 'K/BxN' model of rheumatoid arthritis [16].
  • The platelet-specific monoclonal antibodies used in this study were anti-CD61, PAC-1 (which recognizes only the conformationally activated GPIIb/IIIa) and anti-CD62P [23].
  • PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression [7].
 

Analytical, diagnostic and therapeutic context of DUSP2

  • Furthermore, flow cytometry showed that the platelets failed to bind the activation-dependent monoclonal antibody, PAC-1, after stimulation [24].
  • RESULTS: Changes in the percentage of PAC-1-positive platelets were significantly greater during hemodialysis with RC than with PS [23].
  • Platelets in coronary sinus blood showed significant binding of mAbs that specifically detect activation epitopes associated with the GPIIb-IIIa complex (PAC1, anti-LIBS1, and 9F9) during and for 30 minutes after angioplasty in four of the five patients [25].
  • The relative proportion of platelets positive for PAC1 and anti-LIBS1 increased from baseline values of 2.0 +/- 0.3% (mean +/- SD) and 2.0 +/- 0.5% to 18 +/- 14% and 28 +/- 14%, respectively, during PTCA or 30 minutes after PTCA (p < 0.01 in both cases) [25].
  • First, PAC-1 binds specifically to the IIb.IIIa complex on Western blots [26].

References

  1. PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase. Rohan, P.J., Davis, P., Moskaluk, C.A., Kearns, M., Krutzsch, H., Siebenlist, U., Kelly, K. Science (1993) [Pubmed]
  2. Characterization of a variant of PAC-1 in large granular lymphocyte leukemia. Kothapalli, R., Yoder, S.J., Kusmartseva, I., Loughran, T.P. Protein Expr. Purif. (2003) [Pubmed]
  3. Tumor suppression and apoptosis of human prostate carcinoma mediated by a genetic locus within human chromosome 10pter-q11. Sanchez, Y., Lovell, M., Marin, M.C., Wong, P.E., Wolf-Ledbetter, M.E., McDonnell, T.J., Killary, A.M. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  4. Detection of platelets activated during acetylcholine-induced coronary vasospasm. Inoue, T., Fujito, T., Hoshi, K., Sakai, Y., Morooka, S., Sohma, R. Thromb. Haemost. (1998) [Pubmed]
  5. The PAC-1 dual specificity phosphatase predicts poor outcome in serous ovarian carcinoma. Givant-Horwitz, V., Davidson, B., Goderstad, J.M., Nesland, J.M., Tropé, C.G., Reich, R. Gynecol. Oncol. (2004) [Pubmed]
  6. Activated platelets in transient global amnesia and TIA. Hirabayashi, H., Shimizu, M., Kohara, S., Shinohara, Y. Neurology (2004) [Pubmed]
  7. PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. Yin, Y., Liu, Y.X., Jin, Y.J., Hall, E.J., Barrett, J.C. Nature (2003) [Pubmed]
  8. Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1. Ward, Y., Gupta, S., Jensen, P., Wartmann, M., Davis, R.J., Kelly, K. Nature (1994) [Pubmed]
  9. Ketoconazole activates Cl- conductance and blocks Cl- and fluid absorption by cultured cystic fibrosis (CFPAC-1) cells. Kersting, U., Kersting, D., Spring, K.R. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  10. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Xiao, Z., Théroux, P. Circulation (1998) [Pubmed]
  11. Analysis of platelet aggregation disorders based on flow cytometric analysis of membrane glycoprotein IIb-IIIa with conformation-specific monoclonal antibodies. Ginsberg, M.H., Frelinger, A.L., Lam, S.C., Forsyth, J., McMillan, R., Plow, E.F., Shattil, S.J. Blood (1990) [Pubmed]
  12. The high affinity alphaIIb beta3 integrin is involved in invasion of human melanoma cells. Trikha, M., Timar, J., Lundy, S.K., Szekeres, K., Cai, Y., Porter, A.T., Honn, K.V. Cancer Res. (1997) [Pubmed]
  13. Induction of the fibrinogen receptor on human platelets by intracellular mediators. Shattil, S.J., Brass, L.F. J. Biol. Chem. (1987) [Pubmed]
  14. Genomic organization and chromosomal localization of the DUSP2 gene, encoding a MAP kinase phosphatase, to human 2p11.2-q11. Yi, H., Morton, C.C., Weremowicz, S., McBride, O.W., Kelly, K. Genomics (1995) [Pubmed]
  15. Conditional expression of mitogen-activated protein kinase phosphatase-1, MKP-1, is cytoprotective against UV-induced apoptosis. Franklin, C.C., Srikanth, S., Kraft, A.S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  16. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Jeffrey, K.L., Brummer, T., Rolph, M.S., Liu, S.M., Callejas, N.A., Grumont, R.J., Gillieron, C., Mackay, F., Grey, S., Camps, M., Rommel, C., Gerondakis, S.D., Mackay, C.R. Nat. Immunol. (2006) [Pubmed]
  17. A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (alphaIIbbeta3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype. Ruiz, C., Liu, C.Y., Sun, Q.H., Sigaud-Fiks, M., Fressinaud, E., Muller, J.Y., Nurden, P., Nurden, A.T., Newman, P.J., Valentin, N. Blood (2001) [Pubmed]
  18. Differential regulation of the dual-specificity protein-tyrosine phosphatases CL100, B23, and PAC1 in mesangial cells. Bokemeyer, D., Sorokin, A., Dunn, M.J. J. Am. Soc. Nephrol. (1997) [Pubmed]
  19. Effect of nitroxyl on human platelets function. Bermejo, E., Sáenz, D.A., Alberto, F., Rosenstein, R.E., Bari, S.E., Lazzari, M.A. Thromb. Haemost. (2005) [Pubmed]
  20. Stimulated Glanzmann's thrombasthenia platelets produced microvesicles. Microvesiculation correlates better to exposure of procoagulant surface than to activation of GPIIb-IIIa. Holme, P.A., Solum, N.O., Brosstad, F., Egberg, N., Lindahl, T.L. Thromb. Haemost. (1995) [Pubmed]
  21. Combined defect in membrane expression and activation of platelet GPIIb--IIIa complex without primary sequence abnormalities in myeloproliferative disease. Kaplan, R., Gabbeta, J., Sun, L., Mao, G.F., Rao, A.K. Br. J. Haematol. (2000) [Pubmed]
  22. Relationship between the expression levels of CD61, CD63, and PAC-1 on platelet surface in peripheral blood and the transplanted kidney function. Zhang, Y., Guan, D.L., Xia, C.Q., Han, Z.Y., Xu, J.J., Gao, J.Z., Wu, K.R., Zhang, Y.G., Guan, D. Transplant. Proc. (2003) [Pubmed]
  23. Platelet GPIIb/IIIa is activated and platelet-leukocyte coaggregates formed in vivo during hemodialysis. Kawabata, K., Nakai, S., Miwa, M., Sugiura, T., Otsuka, Y., Shinzato, T., Hiki, Y., Tomimatsu, I., Ushida, Y., Hosono, F., Maeda, K. Nephron (2002) [Pubmed]
  24. A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation. Lanza, F., Stierlé, A., Fournier, D., Morales, M., André, G., Nurden, A.T., Cazenave, J.P. J. Clin. Invest. (1992) [Pubmed]
  25. Activation of platelets in blood perfusing angioplasty-damaged coronary arteries. Flow cytometric detection. Scharf, R.E., Tomer, A., Marzec, U.M., Teirstein, P.S., Ruggeri, Z.M., Harker, L.A. Arterioscler. Thromb. (1992) [Pubmed]
  26. Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation. Shattil, S.J., Hoxie, J.A., Cunningham, M., Brass, L.F. J. Biol. Chem. (1985) [Pubmed]
 
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