scholarly journals Structure of human dual-specificity phosphatase 7, a potential cancer drug target

2015 ◽  
Vol 71 (6) ◽  
pp. 650-656 ◽  
Author(s):  
George T. Lountos ◽  
Brian P. Austin ◽  
Joseph E. Tropea ◽  
David S. Waugh
Keyword(s):  
Catalytic Domain ◽  
Three Dimensional ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Drug ◽  
Dual Specificity Phosphatase ◽  
Dual Specificity ◽  
Starting Point ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

Human dual-specificity phosphatase 7 (DUSP7/Pyst2) is a 320-residue protein that belongs to the mitogen-activated protein kinase phosphatase (MKP) subfamily of dual-specificity phosphatases. Although its precise biological function is still not fully understood, previous reports have demonstrated that DUSP7 is overexpressed in myeloid leukemia and other malignancies. Therefore, there is interest in developing DUSP7 inhibitors as potential therapeutic agents, especially for cancer. Here, the purification, crystallization and structure determination of the catalytic domain of DUSP7 (Ser141–Ser289/C232S) at 1.67 Å resolution are reported. The structure described here provides a starting point for structure-assisted inhibitor-design efforts and adds to the growing knowledge base of three-dimensional structures of the dual-specificity phosphatase family.

scholarly journals Mitogen-Activated Protein Kinase Phosphatases (MKPs) in Fungal Signaling: Conservation, Function, and Regulation

2019 ◽  
Vol 20 (7) ◽  
pp. 1709 ◽  
Author(s):  
Gema González-Rubio ◽  
Teresa Fernández-Acero ◽  
Humberto Martín ◽  
María Molina
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Specific Interaction ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cell Physiology ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Activation Mechanisms ◽  
Dual Specificity Phosphatases

Mitogen-activated protein kinases (MAPKs) are key mediators of signaling in fungi, participating in the response to diverse stresses and in developmental processes. Since the precise regulation of MAPKs is fundamental for cell physiology, fungi bear dual specificity phosphatases (DUSPs) that act as MAP kinase phosphatases (MKPs). Whereas fungal MKPs share characteristic domains of this phosphatase subfamily, they also have specific interaction motifs and particular activation mechanisms, which, for example, allow some yeast MKPs, such as Saccharomyces cerevisiae Sdp1, to couple oxidative stress with substrate recognition. Model yeasts show that MKPs play a key role in the modulation of MAPK signaling flow. Mutants affected in S. cerevisiae Msg5 or in Schizosaccharomyces pombe Pmp1 display MAPK hyperactivation and specific phenotypes. MKPs from virulent fungi, such as Candida albicans Cpp1, Fusarium graminearum Msg5, and Pyricularia oryzae Pmp1, are relevant for pathogenicity. Apart from transcriptional regulation, MKPs can be post-transcriptionally regulated by RNA-binding proteins such as Rnc1, which stabilizes the S. pombe PMP1 mRNA. P. oryzae Pmp1 activity and S. cerevisiae Msg5 stability are regulated by phosphorylation and ubiquitination, respectively. Therefore, fungi offer a platform to gain insight into the regulatory mechanisms that control MKPs.

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

2012 ◽  
Vol 40 (1) ◽  
pp. 235-239 ◽  
Author(s):  
Ahmed Lawan ◽  
Emma Torrance ◽  
Sameer Al-Harthi ◽  
Muhannad Shweash ◽  
Sulaiman Alnasser ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Metabolic Disorders ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Progression ◽  
Extracellular Signal Regulated Kinase ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

The MKPs (mitogen-activated protein kinase phosphatases) are a family of at least ten DUSPs (dual-specificity phosphatases) which function to terminate the activity of the MAPKs (mitogen-activated protein kinases). Several members have already been demonstrated to have distinct roles in immune function, cancer, fetal development and metabolic disorders. One DUSP of renewed interest is the inducible nuclear phosphatase MKP-2, which dephosphorylates both ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase) in vitro. Recently, the understanding of MKP-2 function has been advanced due to the development of mouse knockout models, which has resulted in the discovery of novel roles for MKP-2 in the regulation of sepsis, infection and cell-cycle progression that are distinct from those of other DUSPs. However, many functions for MKP-2 still await to be characterized.

Dual-specificity phosphatases: critical regulators with diverse cellular targets

2009 ◽  
Vol 418 (3) ◽  
pp. 475-489 ◽  
Author(s):  
Kate I. Patterson ◽  
Tilman Brummer ◽  
Philippa M. O'brien ◽  
Roger J. Daly
Keyword(s):  
Protein Kinase ◽  
Sequence Similarity ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Targets ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases ◽  
The One ◽  
And Function

DUSPs (dual-specificity phosphatases) are a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within the one substrate. DUSPs have been implicated as major modulators of critical signalling pathways that are dysregulated in various diseases. DUSPs can be divided into six subgroups on the basis of sequence similarity that include slingshots, PRLs (phosphatases of regenerating liver), Cdc14 phosphatases (Cdc is cell division cycle), PTENs (phosphatase and tensin homologues deleted on chromosome 10), myotubularins, MKPs (mitogen-activated protein kinase phosphatases) and atypical DUSPs. Of these subgroups, a great deal of research has focused on the characterization of the MKPs. As their name suggests, MKPs dephosphorylate MAPK (mitogen-activated protein kinase) proteins ERK (extracellular-signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 with specificity distinct from that of individual MKP proteins. Atypical DUSPs are mostly of low-molecular-mass and lack the N-terminal CH2 (Cdc25 homology 2) domain common to MKPs. The discovery of most atypical DUSPs has occurred in the last 6 years, which has initiated a large amount of interest in their role and regulation. In the past, atypical DUSPs have generally been grouped together with the MKPs and characterized for their role in MAPK signalling cascades. Indeed, some have been shown to dephosphorylate MAPKs. The current literature hints at the potential of the atypical DUSPs as important signalling regulators, but is crowded with conflicting reports. The present review provides an overview of the DUSP family before focusing on atypical DUSPs, emerging as a group of proteins with vastly diverse substrate specificity and function.

scholarly journals Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock

2005 ◽  
Vol 203 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Michael Hammer ◽  
Jörg Mages ◽  
Harald Dietrich ◽  
Angela Servatius ◽  
Norma Howells ◽  
...  
Keyword(s):  
Transcriptional Profiling ◽  
Interferon Γ ◽  
Endotoxin Shock ◽  
Mitogen Activated Protein Kinase ◽  
Cytokine Gene Expression ◽  
Dual Specificity Phosphatase ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Induced Genes ◽  
Factor Α

Activation of the mitogen-activated protein kinase (MAPK) cascade after Toll-like receptor stimulation enables innate immune cells to rapidly activate cytokine gene expression. A balanced response to signals of infectious danger requires that cellular activation is transient. Here, we identify the MAPK phosphatase dual specificity phosphatase 1 (DUSP1) as an essential endogenous regulator of the inflammatory response to lipopolysaccharide (LPS). DUSP1-deficient (DUSP1−/−) bone marrow–derived macrophages showed selectively prolonged activation of p38 MAPK and increased cytokine production. Intraperitoneal challenge of DUSP1−/− mice with LPS caused increased lethality and overshooting production of interleukin (IL)-6 and tumor necrosis factor α. Transcriptional profiling revealed that DUSP1 controls a significant fraction of LPS-induced genes, which includes IL-6 and IL-10 as well as the chemokines CCL3, CCL4, and CXCL2. In contrast, the expression of the important mediators of endotoxin lethality, interferon γ and IL-12, was not significantly altered by the absence of DUSP1. 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.

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