Department of Experimental Therapeutics, Thoreau Laboratory for Global Health, University of Massachusetts, Lowell, MA 01854, USA.
Biomol Concepts. 2022 Sep 1;13(1):298-313. doi: 10.1515/bmc-2022-0023. eCollection 2022 Jan 1.
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 reveal novel signaling modules. Analysis of rotein nteraction onnectome by enn (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 hubs into signaling modules. Transcriptional regulation of critical hubs may play a major role in the lung epithelial cells in response to SARS-CoV-2 and in COVID-19 patients. Mutations and differential expression levels of these critical nodes and modules 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. The main objectives of this study are to identify critical hubs, critical nodes, and modules involved in the signal transduction pathways of innate and adaptive immunity. Application of PIC-Venn to several signaling hubs might reveal novel nodes and modules that can be targeted by small regulatory molecules to simultaneously activate or inhibit cell signaling in health and disease.
生长因子和细胞因子激活信号转导途径，并调节真核生物的基因表达。激活受体的细胞内结构域募集几种蛋白激酶以及转录因子，它们作为多蛋白复合物组装的平台或枢纽。涉及相关生物学功能的信号枢纽通常共享共同的相互作用蛋白和靶基因。这种功能连接性表明，信号枢纽的蛋白相互作用伙伴的成对比较和共同伙伴及其表达分析的网络分析可能导致细胞信号转导中关键节点的识别。几个相关途径中信号枢纽的成对比较可能会揭示新的信号模块。通过 PIC-Venn（转录因子 STAT1、STAT3、NFKB1、RELA、FOS 和 JUN 的蛋白质相互作用连接组分析）对转录因子 STAT1、STAT3、NFKB1、RELA、FOS 和 JUN 及其共同相互作用网络的蛋白质相互作用连接组分析表明，BRCA1 和 TSC22D3 通过将信号枢纽连接到信号模块中，作为免疫反应中的关键节点发挥作用。关键枢纽的转录调控可能在 SARS-CoV-2 反应中的肺上皮细胞和 COVID-19 患者中发挥主要作用。这些关键节点和模块在病理条件下的突变和差异表达水平可能会使参与炎症的信号通路及其靶基因失活。生物连接性源自几个相关途径中的信号枢纽的相互作用网络的结构连接性。本研究的主要目的是确定先天和适应性免疫信号转导途径中涉及的关键枢纽、关键节点和模块。PIC-Venn 在几个信号枢纽中的应用可能会揭示新的节点和模块，这些节点和模块可以被小分子调节剂靶向，以在健康和疾病中同时激活或抑制细胞信号转导。
