Abstract
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.
Highlights
Reversible phosphorylation and dephosphorylation events serve as regulatory switches that control the structure, activity as well as the localization of the proteins in subcellular space thereby influencing vital biological processes [1,2]
We aimed to determine the evolutionary conservation of dual specificity phosphatases across eukaryotic species by calculating the number of orthologs for all human Dual specificity phosphatases (DUSPs) obtained from Homologene database [39]
Our analysis revealed the distribution of DUSPs ranging from a minimum, of six orthologs for DUSP2 to 20 for DUSP12 (Figure 1c)
Summary
Reversible phosphorylation and dephosphorylation events serve as regulatory switches that control the structure, activity as well as the localization of the proteins in subcellular space thereby influencing vital biological processes [1,2]. A coordinated interplay between protein kinases (PKs) and protein phosphatases is crucial to regulate these intracellular signaling events as perturbation events in the basal phosphorylation levels of proteins can lead to undesirable consequences including the development of diseases such as cancers [3]. A unique feature that distinguishes DUSPs from other protein phosphatases is their ability to dephosphorylate both serine/threonine and tyrosine residues within the same substrates [6]. Recent studies have proposed that there are about 40 members of the DUSP family and nine subfamilies [7]. These DUSPs have been implicated as critical modulators of several important signaling pathways that are dysregulated in various diseases
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