Targeting dual-specificity phosphatases: Manipulating MAP kinase signalling and immune responses

Immunology and Inflammation Research Program, The Garvan Institute, Darlinghurst, Sydney, NSW 2010, Australia.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 06/2007; 6(5):391-403. DOI: 10.1038/nrd2289
Source: PubMed


Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine phosphatases, many of which dephosphorylate threonine and tyrosine residues on mitogen-activated protein kinases (MAPKs), and hence are also referred to as MAPK phosphatases (MKPs). The regulated expression and activity of DUSP family members in different cells and tissues controls MAPK intensity and duration to determine the type of physiological response. For immune cells, DUSPs regulate responses in both positive and negative ways, and DUSP-deficient mice have been used to identify individual DUSPs as key regulators of immune responses. From a drug discovery perspective, DUSP family members are promising drug targets for manipulating MAPK-dependent immune responses in a cell-type and disease-context-dependent manner, to either boost or subdue immune responses in cancers, infectious diseases or inflammatory disorders.

Download full-text


Available from: Kate L Jeffrey, Apr 27, 2015
  • Source
    • "The MAPKs are a family of proteins that includes the p38, ERK, and JNK, which activate transcription factors involved in the production of inflammatory cytokines in response to external stresses or cytokine stimulation [27]. To investigate the association between the MAPKs and Asian dust particles-induced macrophage activation, RAW264.7 cells were incubated with ADP1 or ADP2 in the presence or absence of an inhibitor of the JNKs (SP600125) or ERKs (U0126), and the level of TNF-α in the cell culture supernatant was measured. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Asian dust is a springtime meteorological phenomenon that originates in the deserts of China and Mongolia. The dust is carried by prevailing winds across East Asia where it causes serious health problems. Most of the information available on the impact of Asian dust on human health is based on epidemiological investigations, so from a biological standpoint little is known of its effects. To clarify the effects of Asian dust on human health, it is essential to assess inflammatory responses to the dust and to evaluate the involvement of these responses in the pathogenesis or aggravation of disease. Here, we investigated the induction of inflammatory responses by Asian dust particles in macrophages. Treatment with Asian dust particles induced greater production of inflammatory cytokines interleukin-6 and tumor necrosis factor- α (TNF- α ) compared with treatment with soil dust. Furthermore, a soil dust sample containing only particles ≤10 μ m in diameter provoked a greater inflammatory response than soil dust samples containing particles >10 μ m. In addition, Asian dust particles-induced TNF- α production was dependent on endocytosis, the production of reactive oxygen species, and the activation of nuclear factor- κ B and mitogen-activated protein kinases. Together, these results suggest that Asian dust particles induce inflammatory disease through the activation of macrophages.
    Research Journal of Immunology 05/2014; 2014(4464):856154. DOI:10.1155/2014/856154
  • Source
    • "Six genes (DUSP1, DUSP6, FOS, MYC, JUN, and SRF) related to the MAPK signaling pathways were found to be upregulated, and five genes in the proteasome pathways were found to be regulated, among which SUMO1 and SNCA were downregulated and PSMD3, PSMB10, and PSMA7 were upregulated (Table 1). DUSPs regulate the cellular localization and activity of MAPK which functions in the negative feedback loop of ERK regulation [30]. DUSP1 dephosphorylates ERK in the nucleus and allows its trafficking to the cytoplasm [31], while DUSP6 causes the cytoplasmic retention of ERK2 [31]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nonstructural protein 11 (nsp11) of porcine reproductive and respiratory syndrome virus (PRRSV) is a viral endoribonuclease with an unknown function. The regulation of cellular gene expression by nsp11 was examined by RNA microarrays using MARC-nsp11 cells constitutively expressing nsp11. In these cells, the interferon- β , interferon regulatory factor 3, and nuclear factor- κ B activities were suppressed compared to those of parental cells, suggesting that nsp11 might serve as a viral interferon antagonist. Differential cellular transcriptome was examined using Affymetrix exon chips representing 28,536 transcripts, and after statistical analyses 66 cellular genes were shown to be upregulated and 104 genes were downregulated by nsp11. These genes were grouped into 5 major signaling pathways according to their functional relations: histone-related, cell cycle and DNA replication, mitogen activated protein kinase signaling, complement, and ubiquitin-proteasome pathways. Of these, the modulation of cell cycle by nsp11 was further investigated since many of the regulated genes fell in this particular pathway. Flow cytometry showed that nsp11 caused the delay of cell cycle progression at the S phase and the BrdU staining confirmed the cell cycle arrest in nsp11-expressing cells. The study provides insights into the understanding of specific cellular responses to nsp11 during PRRSV infection.
    02/2014; 2014(2):430508. DOI:10.1155/2014/430508
  • Source
    • "DSPs dephosphorylate phosphotyrosine, phosphoserine, and phosphothreonine residues on substrates (Alonso et al. 2004; Tonks 2006). DSPs can be further classified on the basis of the presence (typical) or absence (atypical) of a MAPK-interacting domain, (Huang and Tan 2012; Jeffrey et al. 2007). For example, in Ustilago maydis, the DSP Rok1 is known to regulate mating and virulence by controlling the phosphorylation of Erk MAPKs Kpp2 and Kpp6 (Di Stasio et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein phosphatases are integral components of the cellular signaling machinery in eukaryotes, regulating diverse aspects of growth and development. The genome of the filamentous fungus and model organism Neurospora crassa encodes catalytic subunits for 30 protein phosphatase genes. In this study, we have characterized 24 viable N. crassa phosphatase catalytic subunit knockout mutants for phenotypes during growth, asexual and sexual development. We found that 91% of the mutants had defects in at least one of these traits, while 29% possessed phenotypes in all three. Chemical sensitivity screens were conducted in order to reveal additional phenotypes for the mutants. This resulted in the identification of at least one chemical sensitivity phenotype for 17 phosphatase knockout mutants, including novel chemical sensitivities for two phosphatase mutants lacking a growth or developmental phenotype. Hence, a chemical sensitivity or growth/developmental phenotype was observed for all 24 viable mutants. We investigated p38 mitogen-activated protein kinase (MAPK) phosphorylation profiles in the phosphatase mutants and identified nine potential candidates for regulators of the p38 MAPK. We demonstrated that the PP2C class phosphatase pph-8 (NCU04600) is an important regulator of female sexual development in N. crassa. In addition, we showed that the Δcsp-6 (ΔNCU08380) mutant exhibits a phenotype similar to the previously identified conidial separation mutants, Δcsp-1 and Δcsp-2, that lack transcription factors important for regulation of conidiation and the circadian clock.
    G3-Genes Genomes Genetics 12/2013; 4(2). DOI:10.1534/g3.113.008813 · 3.20 Impact Factor
Show more