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

• PAC1 (phosphatase of activated cells 1; also known as dual specificity phosphatase 2, DUSP2) is a dual threonine/tyrosine phosphatase that specifically dephosphorylates and inactivates mitogen-activated protein (MAP) kinases [7].
• Here we show that during apoptosis, p53 activates transcription of PAC1 by binding to a palindromic site in the PAC1 promoter [7].
• Reduction of PAC1 transcription using small interfering RNA inhibits p53-mediated apoptosis, whereas overexpression of PAC1 increases susceptibility to apoptosis and suppresses tumour formation [7].
• Here we present several lines of evidence indicating that PAC1 is a physiologically relevant MAP kinase phosphatase [8].
• We have previously identified PAC1 as an immediate-early mitogen-inducible tyrosine phosphatase in nuclei of T cells [8].

Chemical compound and disease context of DUSP2

• The role of arachidonic acid metabolites in the regulation of apical cell membrane Cl- conductance and transepithelial transport of fluid and Cl- by cultured pancreatic cells from cystic fibrosis (CFPAC-1) and corrected (PAC-1) cell lines was evaluated by the use of inhibitors [9].
• METHODS AND RESULTS: Platelet P-selectin (CD62) and activated GP IIb/IIIa (PAC-1) expression on platelet membrane was quantified in whole blood as well as platelet aggregation in platelet-rich plasma in 43 patients with unstable angina before and during treatment with UFH or enoxaparin [10].
• In another patient with myelofibrosis and defective aggregation, PAC1 failed to bind to adenosine diphosphate-stimulated platelets, but did bind when protein kinase C was directly activated with phorbol myristate acetate [11].
• Phorbol 12-myristate 13-acetate and 12(S)-hydroxyeicosatetraenoic acid, two activators of protein kinase C, stimulated adhesion of melanoma cells to immobilized fibronectin and PAC-1, a mAb to alphaIIb beta3 [12].
• Thrombin-induced PAC1 binding and phosphoinositide hydrolysis were also inhibited by GDP beta S and by pertussis toxin [13].

Biological context of DUSP2

• DUSP2 downregulates intracellular signal transduction through the dephosphorylation/inactivation of MAP kinases [14].
• The mitogen-induced gene, DUSP2, encodes a nuclear protein, PAC1, that acts as a dual-specific protein phosphatase with stringent substrate specificity for MAP kinase [14].
• DUSP2 has been localized to the pericentromeric region of human chromosome 2 (2p11.2-q11) by analysis of somatic cell hybrids, in situ chromosome hybridization, and genetic linkage analysis using a single-strand conformational polymorphism (SSCP) that has been identified in the 3' UTR of the gene [14].
• The dual-specificity phosphatase, PAC1, which does not inhibit UV-induced activation of SAPK, did not provide a similar cytoprotection against UV-induced apoptosis [15].
• The deduced amino acid sequence of the predicted protein contains 170 amino acids and is 144 amino acids shorter than PAC-1 [2].

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