Insights into Functional Connectivity in Mammalian Signal Transduction Pathways by Pairwise Comparison of Protein Interaction Partners of Critical Signaling Hubs

Abstract

Growth factors and cytokines activate signal transduction pathways and regulate gene expression in eukaryotes. Intracellular domains of activated receptors recruit several protein kinases as well as transcription factors that serve as platforms or hubs for the assembly of multi-protein complexes. The signaling hubs involved in a related biologic function often share common interaction proteins and target genes. This functional connectivity suggests that a pairwise comparison of protein interaction partners of signaling hubs and network analysis of common partners and their expression analysis might lead to the identification of critical nodes in cellular signaling. A pairwise comparison of signaling hubs across several related pathways might also reveal novel signaling modules. Analysis of Protein Interaction Connectome by Venn (PIC-VENN) of transcription factors STAT1, STAT3, NFKB1, RELA, FOS and JUN, and their common interaction network suggested that BRCA1 and TSC22D3 function as critical nodes in immune responses by connecting the signaling nodes into signaling modules. Mutations or differential expression levels of these critical nodes in pathological conditions might deregulate signaling pathways and their target genes involved in inflammation. Biological connectivity emerges from the structural connectivity of interaction networks across several signaling hubs in related pathways. Application of PIC-VENN to several signaling hubs might reveal novel nodes and modules that can be targeted to simultaneously activate or inhibit cell signaling in health and disease.

Profiling transcription factor sub-networks in type I interferon signaling and in response to SARS-CoV-2 infection

“…In contrast, Irf5 and Sp110 were the lowest-ranked nodes in the sub-network. Furthermore, transcription factors involved in a related biologic function often share common protein interaction partners and target genes as revealed by pairwise analysis of transcription factor hubs involved in innate and adaptive immunity (25). Implementing the pairwise analysis of common protein interaction partners of Stat1 and other hubs in antiviral sub-network in Biogrid database revealed that Rela and Stat3 as additional members of the extended network (data not shown).…”

“…IL-6 by immune cells in response to respiratory virus infection resulting in the cross-talk between Stat1 and other transcription factors such Stat3, Rela, and Jun and fine-tuning of pathogen response (48). The protein interaction module of Stat1, Stat3, Rela, and Jun was shown to be a characteristic feature of innate and adaptive immunity (25)…”

“…Transcription factor profiling is a powerful technique to gain insights into mammalian signal transduction pathways. (24,25). Transcription factor profiling of genes involved in a biologic function such as innate and adaptive immunity led to the identification of functional connectivity of signaling hubs, critical nodes, and modules (25,26).…”

“…(24,25). Transcription factor profiling of genes involved in a biologic function such as innate and adaptive immunity led to the identification of functional connectivity of signaling hubs, critical nodes, and modules (25,26). In this study transcription factor profiling in the transcriptome of immune cells in response to type I Interferon treatment and lung epithelial cells in response to SARS-CoV-2 infection was investigated.…”

Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses

“…Previous studies have shown that transcription factors of innate and adaptive immunity show functional connectivity involving shared interacting protein partners and target genes. (47). Cluster analysis revealed that Egr-1 induction was correlated with the expression of Egr-1 target genes by IFN-α/β in PBMC and in BMDM cells (Figure 7).…”