scholarly journals Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

2019 ◽  
Author(s):  
Yashwanth Subbannayya ◽  
Sneha M. Pinto ◽  
Korbinian Bösl ◽  
T. S. Keshava Prasad ◽  
Richard K. Kandasamy
Keyword(s):  
Immune Response ◽  
Protein Kinases ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Tlr4 Signaling ◽  
Cyclin Dependent Kinases ◽  
Therapeutic Modalities ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

AbstractDual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focused on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSP-mediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study has the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.

scholarly journals Dynamics of Dual Specificity Phosphatases and Their Interplay with Protein Kinases in Immune Signaling

2019 ◽  
Vol 20 (9) ◽  
pp. 2086 ◽  
Author(s):  
Yashwanth Subbannayya ◽  
Sneha M. Pinto ◽  
Korbinian Bösl ◽  
T. S. Keshava Prasad ◽  
Richard K. Kandasamy
Keyword(s):  
Immune Response ◽  
Protein Kinases ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Tlr4 Signaling ◽  
Cyclin Dependent Kinases ◽  
Therapeutic Modalities ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen-activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focus on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSP-mediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR, and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study have the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.

scholarly journals Regulation of Dual-Specificity Phosphatase (DUSP) Ubiquitination and Protein Stability

2019 ◽  
Vol 20 (11) ◽  
pp. 2668 ◽  
Author(s):  
Hsueh-Fen Chen ◽  
Huai-Chia Chuang ◽  
Tse-Hua Tan
Keyword(s):  
Signal Transduction ◽  
Protein Stability ◽  
Protein Kinases ◽  
Post Translational Modifications ◽  
Mitogen Activated Protein Kinases ◽  
Cell Responses ◽  
Dual Specificity ◽  
Duration Magnitude ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

Mitogen-activated protein kinases (MAPKs) are key regulators of signal transduction and cell responses. Abnormalities in MAPKs are associated with multiple diseases. Dual-specificity phosphatases (DUSPs) dephosphorylate many key signaling molecules, including MAPKs, leading to the regulation of duration, magnitude, or spatiotemporal profiles of MAPK activities. Hence, DUSPs need to be properly controlled. Protein post-translational modifications, such as ubiquitination, phosphorylation, methylation, and acetylation, play important roles in the regulation of protein stability and activity. Ubiquitination is critical for controlling protein degradation, activation, and interaction. For DUSPs, ubiquitination induces degradation of eight DUSPs, namely, DUSP1, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, and DUSP16. In addition, protein stability of DUSP2 and DUSP10 is enhanced by phosphorylation. Methylation-induced ubiquitination of DUSP14 stimulates its phosphatase activity. In this review, we summarize the knowledge of the regulation of DUSP stability and ubiquitination through post-translational modifications.

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 The Dual Specificity Phosphatases M3/6 and MKP-3 Are Highly Selective for Inactivation of Distinct Mitogen-activated Protein Kinases

1996 ◽  
Vol 271 (44) ◽  
pp. 27205-27208 ◽  
Author(s):  
Marco Muda ◽  
Aspasia Theodosiou ◽  
Nanda Rodrigues ◽  
Ursula Boschert ◽  
Montserrat Camps ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Mitogen Activated Protein Kinases ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

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 Phosphatases: From Molecular Mechanisms to Biological Function

2019 ◽  
Vol 20 (18) ◽  
pp. 4372 ◽  
Author(s):  
Rafael Pulido ◽  
Roland Lang
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Biological Function ◽  
Tyrosine Phosphatase ◽  
Heterogeneous Group ◽  
Class I ◽  
Protein Tyrosine ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases

Dual specificity phosphatases (DUSPs) constitute a heterogeneous group of enzymes, relevant in human disease, which belong to the class I Cys-based group of protein tyrosine phosphatase (PTP) gene superfamily [...]

scholarly journals The MKK7 Gene Encodes a Group of c-Jun NH2-Terminal Kinase Kinases

1999 ◽  
Vol 19 (2) ◽  
pp. 1569-1581 ◽  
Author(s):  
Cathy Tournier ◽  
Alan J. Whitmarsh ◽  
Julie Cavanagh ◽  
Tamera Barrett ◽  
Roger J. Davis
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Cultured Cells ◽  
Biochemical Properties ◽  
Mitogen Activated Protein Kinase ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Jnk Activation

ABSTRACT The c-Jun NH2-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) group and is an essential component of a signaling cascade that is activated by exposure of cells to environmental stress. JNK activation is regulated by phosphorylation on both Thr and Tyr residues by a dual-specificity MAPK kinase (MAPKK). Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators. Genetic studies demonstrate that MKK4 and MKK7 serve nonredundant functions as activators of JNK in vivo. We report here the molecular cloning of the gene that encodes MKK7 and demonstrate that six isoforms are created by alternative splicing to generate a group of protein kinases with three different NH2 termini (α, β, and γ isoforms) and two different COOH termini (1 and 2 isoforms). The MKK7α isoforms lack an NH2-terminal extension that is present in the other MKK7 isoforms. This NH2-terminal extension binds directly to the MKK7 substrate JNK. Comparison of the activities of the MKK7 isoforms demonstrates that the MKK7α isoforms exhibit lower activity, but a higher level of inducible fold activation, than the corresponding MKK7β and MKK7γ isoforms. Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells. The presence of MKK7 in the nucleus was not, however, required for JNK activation in vivo. These data establish that theMKK4 and MKK7 genes encode a group of protein kinases with different biochemical properties that mediate activation of JNK in response to extracellular stimuli.

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