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

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.

Comparative Proteomic Analysis Reveals Varying Impact on Immune Responses in Phorbol 12-Myristate-13-Acetate-Mediated THP-1 Monocyte-to-Macrophage Differentiation

“…Our analysis further highlights differentiation protocol-specific subsets with several protein kinases serving as central hubs in mediating the differentiation process. This is of vital importance as cellular signaling is primarily governed by the regulation of expression of kinases and phosphatases in a cell type-specific manner or upon cell activation (32,40,56). Key regulatory kinases implicated in cell cycle regulation including cyclin-dependent kinases and NEK family of serine-threonine kinases were found to be dysregulated and is in concordance with previous study exploring the role of kinases in monocytemacrophage differentiation (22).…”

“…org/gsea/msigdb) (31). Protein kinase and phosphatase lists were obtained, as described previously (32).…”

Leucine Rich Repeat Kinase 2 and Innate Immunity

“…A number of studies have also linked LRRK2 to direct regulation of MAPK (White et al, 2007;Gloeckner et al, 2009;Reinhardt et al, 2013) and NFκB (Russo et al, 2015;Lopez De Maturana et al, 2016;Han et al, 2017) signaling pathways, which may have implications for TLR-mediated inflammatory cytokine production. Omics meta-analysis has also linked LRRK2 to dual specificity phosphatases (DUSPs), DUSP1 and DUSP16 in TLR4 signaling, serving as a potential DUSP-mediated hub in this immune modulating pathway (Subbannayya et al, 2019). Thus, biochemical and functional studies clearly link LRRK2 to TLR signaling, with obvious potential implications for LRRK2 function in inflammatory diseases.…”

The Proteomic Landscape of Resting and Activated CD4+ T Cells Reveal Insights into Cell Differentiation and Function

“…jp/kegg/), while genes list for reactive oxygen species was compiled from the literature [76]. Protein kinase and phosphatase lists were obtained, as described previously [77]. Immune checkpoints receptors and their ligands were compiled from the literature [38,40] and compared with the data from this study.…”