MKP-2: out of the DUSP-bin and back into the limelight

Lawan, Ahmed; Torrance, Emma; Al-Harthi, Sameer E.; Shweash, Muhannad; Alnasser, Sulaiman Mohammed; Neamatallah, Thikryat; Schroeder, Joanna L.; Plevin, Robin

doi:10.1042/bst20110648

Cited by 19 publications

(9 citation statements)

References 56 publications

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“…The best-studied role for DUSPs is in negative-feedback regulation of mitogen-activated kinase (MAPK) signaling cascades (reviewed by Lawan et al, 2012). MAPK phosphatases (MKPs) simultaneously dephosphorylate threonine and tyrosine residues within the MAPK activation loop to attenuate signaling in a wide variety of physiological contexts, including immune function, embryonic development and metabolic homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Impaired embryonic motility indusp27mutants reveals a developmental defect in myofibril structure

Fero

Bergeron

Horstick

et al. 2013

Disease Models &Amp; Mechanisms

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An essential step in muscle fiber maturation is the assembly of highly ordered myofibrils that are required for contraction. Much remains unknown about the molecular mechanisms governing the formation of the contractile apparatus. We identified an early embryonic motility mutant in zebrafish caused by integration of a transgene into the pseudophosphatase dual specificity phosphatase 27 (dusp27) gene. dusp27 mutants exhibit near complete paralysis at embryonic and larval stages, producing extremely low levels of spontaneous coiling movements and a greatly diminished touch response. Loss of dusp27 does not prevent somitogenesis but results in severe disorganization of the contractile apparatus in muscle fibers. Sarcomeric structures in mutants are almost entirely absent and only rare triads are observed. These findings are the first to implicate a functional role of dusp27 as a gene required for myofiber maturation and provide an animal model for analyzing the mechanisms governing myofibril assembly.

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Section: Discussionmentioning

confidence: 99%

Impaired embryonic motility indusp27mutants reveals a developmental defect in myofibril structure

Fero

Bergeron

Horstick

et al. 2013

Disease Models &Amp; Mechanisms

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“…This suggests MKP-2 deletion may have effects which regulate other components of the ERK cascade including receptor expression and functional coupling to upstream intermediates. A number of studies including our own have also suggested that MKP-2 can regulate cellular function in a way which is not dependent on the normal predicted effects on ERK and JNK 11 33 34. Indeed, recently MKP-2 has been shown to interact and regulate the cell cycle protein VRK-1 independently of phosphatase activity suggesting multiple cellular effects 35.…”

Section: Discussionmentioning

confidence: 90%

“…MKP-2 (DUSP4) is a type 1 nuclear phosphatase10 specific for ERK and JNK in vitro. As a type 1 DUSP, MKP-2 has been viewed as a surrogate to the prototypic MKP-1 and less extensively examined 11. However, more recent studies have identified distinct roles for MKP-2 in different cellular processes and associated pathologies such as tumour development,12 13 cancer resistance,14 cardiac myopathy,15 infection16 and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis

et al. 2019

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ObjectivesWe have previously shown mitogen-activated protein kinase phosphatase 2 (MKP-2) to be a key regulator of proinflammatory cytokines in macrophages. In the study presented here, we investigated the role of MKP-2 in inflammatory arthritis with a particular focus on neutrophils.MethodsTo achieve this, we subjected MKP-2 deficient and wild type mice to collagen antibody induced arthritis, an innate model of arthritis, and determined disease pathology. To further our investigation, we depleted neutrophils in a prophylactic and therapeutic fashion. Last, we used chemotaxis assays to analyse the impact of MKP-2 deletion on neutrophil migration.ResultsMKP-2-/- mice showed a significant increase in disease pathology linked to elevated levels of proarthritic cytokines and chemokines TNF-α, IL-6 and MCP-1 in comparison to wild type controls. This phenotype is prevented or abolished after administration of neutrophil depleting antibody prior or after onset of disease, respectively. While MCP-1 levels were not affected, neutrophil depletion diminished TNF-α and reduced IL-6, thus linking these cytokines to neutrophils. In vivo imaging showed that MKP-2-/- mice had an increased influx of neutrophils into affected joints, which was higher and potentially prolonged than in wild type animals. Furthermore, using chemotaxis assays we revealed that MKP-2 deficient neutrophils migrate faster towards a Leukotriene B4 gradient. This process correlated with a reduced phosphorylation of ERK in MKP-2-/- neutrophils.ConclusionsThis is the first study to show a protective role for MKP-2 in inflammatory arthritis.

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“…These are termed dual-specificity phosphatases (DUSPs), and each member of the DUSP family has a unique set of properties including tissue distribution, subcellular localization, and precise substrate affinity and specificity [96]. For example, MKP-1 targets primarily p38 MAPK contrary to MKP-2 which preferentially dephosphorylates ERK and JNK [97–99]. The strength and duration of p38 MAPK activation are often the critical determinant of cellular responses regulated by the action of these phosphatases [100].…”

Section: Targeting P38 Mapk In Pemphigus: Corticosteroids Versus Mmentioning

confidence: 99%

p38 MAPK Signaling in Pemphigus: Implications for Skin Autoimmunity

Mavropoulos

Orfanidou

Liaskos

et al. 2013

Autoimmune Diseases

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p38 mitogen activated protein kinase (p38 MAPK) signaling plays a major role in the modulation of immune-mediated inflammatory responses and therefore has been linked with several autoimmune diseases. The extent of the involvement of p38 MAPK in the pathogenesis of autoimmune blistering diseases has started to emerge, but whether it pays a critical role is a matter of debate. The activity of p38 MAPK has been studied in great detail during the loss of keratinocyte cell-cell adhesions and the development of pemphigus vulgaris (PV) and pemphigus foliaceus (PF). These diseases are characterised by autoantibodies targeting desmogleins (Dsg). Whether autoantibody-antigen interactions can trigger signaling pathways (such as p38 MAPK) that are tightly linked to the secretion of inflammatory mediators which may perpetuate inflammation and tissue damage in pemphigus remains unclear. Yet, the ability of p38 MAPK inhibitors to block activation of the proapoptotic proteinase caspase-3 suggests that the induction of apoptosis may be a consequence of p38 MAPK activation during acantholysis in PV. This review discusses the current evidence for the role of p38 MAPK in the pathogenesis of pemphigus. We will also present data relating to the targeting of these cascades as a means of therapeutic intervention.

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MKP-2: out of the DUSP-bin and back into the limelight

Cited by 19 publications

References 56 publications

Impaired embryonic motility indusp27mutants reveals a developmental defect in myofibril structure

Impaired embryonic motility indusp27mutants reveals a developmental defect in myofibril structure

Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis

p38 MAPK Signaling in Pemphigus: Implications for Skin Autoimmunity

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