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

2007 ◽  
Vol 6 (5) ◽  
pp. 391-403 ◽  
Author(s):  
Kate L. Jeffrey ◽  
Montserrat Camps ◽  
Christian Rommel ◽  
Charles R. Mackay
Keyword(s):  
Immune Responses ◽  
Map Kinase ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases

MAP kinase tight binding to dual-specificity phosphatases: A mechanism for enzymatic specificity

1999 ◽  
Vol 27 (3) ◽  
pp. A72-A72
Author(s):  
Montserrat Camps ◽  
Nathalie Bot ◽  
Anthony Nichols ◽  
Marco Muda ◽  
Corine Gillieron ◽  
...  
Keyword(s):  
Map Kinase ◽  
Tight Binding ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases

Dual specificity phosphatases: a gene family for control of MAP kinase function

2000 ◽  
Vol 14 (1) ◽  
pp. 6-16 ◽  
Author(s):  
MONTSERRAT CAMPS ◽  
ANTON NICHOLS ◽  
STEVE ARKINSTALL
Keyword(s):  
Gene Family ◽  
Map Kinase ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases

scholarly journals Dual-Specificity Phosphatases in Immunity and Infection: An Update

2019 ◽  
Vol 20 (11) ◽  
pp. 2710 ◽  
Author(s):  
Roland Lang ◽  
Faizal Raffi
Keyword(s):  
Immune Responses ◽  
Immune Cells ◽  
Knockout Mice ◽  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Selective Inhibition ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

Kinase activation and phosphorylation cascades are key to initiate immune cell activation in response to recognition of antigen and sensing of microbial danger. However, for balanced and controlled immune responses, the intensity and duration of phospho-signaling has to be regulated. The dual-specificity phosphatase (DUSP) gene family has many members that are differentially expressed in resting and activated immune cells. Here, we review the progress made in the field of DUSP gene function in regulation of the immune system during the last decade. Studies in knockout mice have confirmed the essential functions of several DUSP-MAPK phosphatases (DUSP-MKP) in controlling inflammatory and anti-microbial immune responses and support the concept that individual DUSP-MKP shape and determine the outcome of innate immune responses due to context-dependent expression and selective inhibition of different mitogen-activated protein kinases (MAPK). In addition to the canonical DUSP-MKP, several small-size atypical DUSP proteins regulate immune cells and are therefore also reviewed here. Unexpected and complex findings in DUSP knockout mice pose new questions regarding cell type-specific and redundant functions. Another emerging question concerns the interaction of DUSP-MKP with non-MAPK binding partners and substrate proteins. Finally, the pharmacological targeting of DUSPs is desirable to modulate immune and inflammatory responses.

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 Dual-Specificity Phosphatase 12 Targets p38 MAP Kinase to Regulate Macrophage Response to Intracellular Bacterial Infection

2017 ◽  
Vol 8 ◽  
Author(s):  
Sharol Su Lei Cho ◽  
Jian Han ◽  
Sharmy J. James ◽  
Chin Wen Png ◽  
Madhushanee Weerasooriya ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Macrophage Response ◽  
Dual Specificity Phosphatase ◽  
Dual Specificity

scholarly journals Histone H3 as a novel substrate for MAP kinase phosphatase-1

2009 ◽  
Vol 296 (2) ◽  
pp. C242-C249 ◽  
Author(s):  
Corttrell M. Kinney ◽  
Unni M. Chandrasekharan ◽  
Lin Yang ◽  
Jianzhong Shen ◽  
Michael Kinter ◽  
...  
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Histone H3 ◽  
Dual Specificity ◽  
Map Kinase Phosphatase ◽  
Mitogen Activated Protein ◽  
And Control ◽  
Interfering Rna ◽  
Endothelial Growth Factor

Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is a nuclear, dual-specificity phosphatase that has been shown to dephosphorylate MAP kinases. We used a “substrate-trap” technique involving a mutation in MKP-1 of the catalytically critical cysteine to a serine residue (“CS” mutant) to capture novel MKP-1 substrates. We transfected the MKP-1 (CS) mutant and control (wild-type, WT) constructs into phorbol 12-myristate 13-acetate (PMA)-activated COS-1 cells. MKP-1-substrate complexes were immunoprecipitated, which yielded four bands of 17, 15, 14, and 10 kDa with the CS MKP-1 mutant but not the WT MKP-1. The bands were identified by mass spectrometry as histones H3, H2B, H2A, and H4, respectively. Histone H3 was phosphorylated, and purified MKP-1 dephosphorylated histone H3 (phospho-Ser-10) in vitro; whereas, histone H3 (phospho-Thr-3) was unaffected. We have previously shown that thrombin and vascular endothelial growth factor (VEGF) upregulated MKP-1 in human endothelial cells (EC). We now show that both thrombin and VEGF caused dephosphorylation of histone H3 (phospho-Ser-10) and histone H3 (phospho-Thr-3) in EC with kinetics consistent with MKP-1 induction. Furthermore, MKP-1-specific small interfering RNA (siRNA) prevented VEGF- and thrombin-induced H3 (phospho-Ser-10) dephosphorylation but had no effect on H3 (phospho-Thr-3 or Thr-11) dephosphorylation. In summary, histone H3 is a novel substrate of MKP-1, and VEGF- and thrombin-induced H3 (phospho-Ser-10) dephosphorylation requires MKP-1. We propose that MKP-1-mediated H3 (phospho-Ser-10) dephosphorylation is a key regulatory step in EC activation by VEGF and thrombin.

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