Cellular signalling networks

  • Article
    | Open Access

    Complex biomolecular networks are fundamental to the functioning of living systems, both at the cellular level and beyond. In this paper, the authors develop a systems framework to elucidate the interplay of networks and the spatial localisation of network components.

    • Govind Menon
    •  & J. Krishnan
  • Article
    | Open Access

    Our ability to interpret single-cell multivariate signaling responses is still limited. Here the authors introduce fractional response analysis (FRA), involving fractional cell counting, capable of deconvoluting heterogeneous multivariate responses of cellular populations.

    • Karol Nienałtowski
    • , Rachel E. Rigby
    •  & Michał Komorowski
  • Article
    | Open Access

    Network motif models focus on small sub-networks in biological systems to quantitatively describe overall behavior but they often overlook time delays. Here, the authors systematically examine the most common network motifs via delay differential equations (DDE), often leading to more concise descriptions.

    • David S. Glass
    • , Xiaofan Jin
    •  & Ingmar H. Riedel-Kruse
  • Article
    | Open Access

    Oncogenic KRAS signalling is required for tumor initiation; however KRAS-dependency at advanced stages is less understood. Here, the authors show that, in established KRAS-driven pancreatic cancer, KRAS-ablation does not affect intrinsic tumorigenic capacity but elicits antitumor immune response, highlighting the importance of KRAS-driven immune suppression in tumor maintenance.

    • Irene Ischenko
    • , Stephen D’Amico
    •  & Nancy C. Reich
  • Article
    | Open Access

    Understanding how cells discriminate between stimuli is an ongoing challenge. Here, the authors propose a mathematical framework for inferring the mutual information encoded in temporal signaling dynamics and use it to study how information is transmitted over time in response to different stimuli in NFκB, MAPK and p53 signaling pathways.

    • Ying Tang
    • , Adewunmi Adelaja
    •  & Alexander Hoffmann
  • Article
    | Open Access

    Kinases drive fundamental changes in cell state, but predicting kinase activity based on substrate-level changes can be challenging. Here the authors introduce a computational framework that utilizes similarities between substrates to robustly infer kinase activity.

    • Serhan Yılmaz
    • , Marzieh Ayati
    •  & Mehmet Koyutürk
  • Article
    | Open Access

    Single-cell methods record molecule expressions of cells in a given tissue, but understanding interactions between cells remains challenging. Here the authors show by applying systems biology and machine learning approaches that they can infer and analyze cell-cell communication networks in an easily interpretable way.

    • Suoqin Jin
    • , Christian F. Guerrero-Juarez
    •  & Qing Nie
  • Article
    | Open Access

    Bulk and single-cell transcriptomic data can be a source of novel insights into how cells interact with each other. Here the authors develop ICELLNET, a global, biologically validated, and easy-to-use framework to dissect cell communication from individual or multiple cell-based transcriptomic profiles.

    • Floriane Noël
    • , Lucile Massenet-Regad
    •  & Vassili Soumelis
  • Article
    | Open Access

    Single cell expression data allows for inferring cell-cell communication between cells expressing ligands and those expressing their cognate receptors. Here the authors present an updated and curated database of ligand-receptor pairs and a Python-based toolkit to construct and analyse communication networks from single cell and bulk expression data.

    • Rui Hou
    • , Elena Denisenko
    •  & Alistair R. R. Forrest
  • Article
    | Open Access

    Single-cell technologies are increasingly prominent in clinical applications, but predictive modelling with such data in large cohorts has remained computationally challenging. We developed a new algorithm, ‘VoPo’, for predictive modelling and visualization of single cell data for translational applications.

    • Natalie Stanley
    • , Ina A. Stelzer
    •  & Nima Aghaeepour
  • Article
    | Open Access

    Proteome activity has a major role in cancer progression and response to drugs. Here, the authors use comprehensive proteomic and phosphoproteomic data, in conjunction with drug-sensitivity screens, to generate a community resource consisting of landscapes of pathway and kinase activity across different cell lines

    • Martin Frejno
    • , Chen Meng
    •  & Bernhard Kuster
  • Article
    | Open Access

    Predicting an individual's response to therapy is an important goal for precision medicine. Here, the authors use an algorithm that takes into account the interaction type and directionality of signalling pathways in protein–protein interactions and find that their pathway analysis can predict essential genes, which may be a target for therapy.

    • Rotem Ben-Hamo
    • , Adi Jacob Berger
    •  & Ravid Straussman
  • Article
    | Open Access

    Segregation of an MSH1 RNAi transgene produces non-genetic memory that displays transgenerational inheritance in Arabidopsis. Here, the authors compare memory and non-memory full-sib progenies to show the involvement of DNA methylation reprogramming, involving the RdDM pathway, in transition to a heritable memory state.

    • Xiaodong Yang
    • , Robersy Sanchez
    •  & Sally A. Mackenzie
  • Article
    | Open Access

    Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

    • Matthew A. Reyna
    • , David Haan
    •  & Benjamin J. Raphael
  • Article
    | Open Access

    How reproducible human kidney organoids derived from different iPSC lines are, and how faithful they are to human kidney tissue remain unclear. Here, the authors use four human iPSC lines to derive kidney organoids and show how organoid composition is reproducible, comparable to human tissue and of improved quality after transplantation.

    • Ayshwarya Subramanian
    • , Eriene-Heidi Sidhom
    •  & Anna Greka
  • Article
    | Open Access

    Multi-omic profiling is a powerful approach to dissecting molecular mechanisms in disease. Here the authors generate whole proteome, phosphoproteome and transcriptome profiles from two mouse models of high-grade glioma driven by different oncogenes, and validate identified master regulators with a CRISPR screen.

    • Hong Wang
    • , Alexander K. Diaz
    •  & Junmin Peng
  • Article
    | Open Access

    The fraction of protein-protein interactions (PPIs) that can be disrupted without fitness effect is unknown. Here, the authors model how disease-causing mutations and common mutations carried by healthy people perturb the interactome, and estimate that <20% of human PPIs are completely dispensable.

    • Mohamed Ghadie
    •  & Yu Xia
  • Article
    | Open Access

    The directions of most human protein-protein interactions (PPIs) remain unknown. Here, the authors use cancer genomic and drug response data to infer the direction of signal flow in the human PPI network and show that the directed network improves drug target and cancer driver gene prioritization.

    • Dana Silverbush
    •  & Roded Sharan
  • Article
    | Open Access

    The genetic and pathogenetic basis of heart failure is incompletely understood. Here, the authors present a high-fidelity tissue collection from rapidly preserved failing and non-failing control hearts which are used for eQTL mapping and network analysis, resulting in the prioritization of PPP1R3A as a heart failure gene.

    • Pablo Cordero
    • , Victoria N. Parikh
    •  & Euan A. Ashley
  • Article
    | Open Access

    Genome-wide association studies (GWAS) have so far uncovered more than 200 loci for multiple sclerosis (MS). Here, the authors integrate data from various sources for a cell type-specific pathway analysis of MS GWAS results that specifically highlights the involvement of the immune system in disease pathogenesis.

    • Lohith Madireddy
    • , Nikolaos A. Patsopoulos
    •  & Sergio E. Baranzini
  • Article
    | Open Access

    Synergistic interactions may arise between regulators in complex molecular networks. Here, the authors develop OptiCon, a computational method for de novo identification of synergistic key regulators and investigate their potential roles as candidate targets for combination therapy.

    • Yuxuan Hu
    • , Chia-hui Chen
    •  & Kai Tan
  • Article
    | Open Access

    Protein phosphorylation has various regulatory functions. Here, the authors map 241 phosphorylation hotspot regions across 40 eukaryotic species, showing that they are enriched at interfaces and near catalytic residues, and enable the discovery of functionally important phospho-sites.

    • Marta J. Strumillo
    • , Michaela Oplová
    •  & Pedro Beltrao
  • Article
    | Open Access

    With the increasing obtainability of multi-OMICs data comes the need for easy to use data analysis tools. Here, the authors introduce Metascape, a biologist-oriented portal that provides a gene list annotation, enrichment and interactome resource and enables integrated analysis of multi-OMICs datasets.

    • Yingyao Zhou
    • , Bin Zhou
    •  & Sumit K. Chanda
  • Article
    | Open Access

    Chemical perturbation of specific protein–protein interactions is notoriously difficult, yet necessary when complete inhibition of a signalling pathway is detrimental to the cell. Here, the authors use a systems approach and identify two first-in-class small molecules that specifically inhibit TNF-induced NF-κB activation.

    • Nicolas A. Pabon
    • , Qiuhong Zhang
    •  & Robin E. C. Lee
  • Article
    | Open Access

    Many organs develop through branching morphogenesis, but whether the underlying mechanisms are shared is unknown. Here, the authors show that a ligand-receptor based Turing mechanisms, similar to that observed in lung development, likely underlies branching morphogenesis of the kidney.

    • Denis Menshykau
    • , Odyssé Michos
    •  & Dagmar Iber
  • Article
    | Open Access

    Repurposing approved drugs could accelerate treatment options for various diseases. Here, the authors use network proximity of disease gene products and drug targets in the human protein interactome to identify drug-disease associations for cardiovascular disease, and validate these using longitudinal healthcare data.

    • Feixiong Cheng
    • , Rishi J. Desai
    •  & Joseph Loscalzo
  • Article
    | Open Access

    Innate immunity combines intra- and intercellular signalling to develop responses that limit pathogen spread. Here the authors analyse feedback and feedforward loops connecting IRF3, NF-κB and STAT pathways, and suggest they allow coordinating cell fate decisions in cellular populations in response to the virus-mimicking agent poly(I:C).

    • Maciej Czerkies
    • , Zbigniew Korwek
    •  & Tomasz Lipniacki
  • Article
    | Open Access

    The NUDIX hydrolases are known to be involved in several cellular processes and diseases, such as cancer, but remain poorly characterized as a family. Here, the authors provide a comprehensive analysis of the structural, biochemical, and expression properties of 18 human NUDIX proteins, and begin to address their functional inter-relationships.

    • Jordi Carreras-Puigvert
    • , Marinka Zitnik
    •  & Thomas Helleday
  • Article
    | Open Access

    Deregulation of E2F family transcription factors is associated with cancer progression and metastasis. Here, the authors construct a map of the regulatory network around the E2F family, and using gene expression profiles, identify tumour type-specific regulatory cores and receptor expression signatures associated with epithelial-mesenchymal transition in bladder and breast cancer.

    • Faiz M. Khan
    • , Stephan Marquardt
    •  & Brigitte M. Pützer
  • Article
    | Open Access

    mTORC1 is known to mediate the signalling activity of amino acids. Here, the authors combine modelling with experiments and find that amino acids acutely stimulate mTORC2, IRS/PI3K and AMPK, independently of mTORC1. AMPK activation through CaMKKβ sustains autophagy under non-starvation conditions.

    • Piero Dalle Pezze
    • , Stefanie Ruf
    •  & Kathrin Thedieck
  • Article
    | Open Access

    Pathway analysis aids interpretation of large-scale gene expression data, but existing algorithms fall short of providing robust pathway identification. The method introduced here includes coexpression analysis and gene importance estimation to robustly identify relevant pathways and biomarkers for patient stratification.

    • Ivan V. Ozerov
    • , Ksenia V. Lezhnina
    •  & Alex Zhavoronkov
  • Article
    | Open Access

    Many drugs are small molecule inhibitors of cell signalling. Through single cell analysis and mathematical modelling here the authors show that cell-to-cell variability diversifies inhibition response into digital and analogue, and that the two translate into distinct long-term functional responses.

    • Robert M. Vogel
    • , Amir Erez
    •  & Grégoire Altan-Bonnet
  • Article
    | Open Access

    Cell-to-cell communication relies upon interactions between secreted ligands and cell surface receptors. Here, Ramilowski et al.present a draft cell-to-cell communication network based on expression of ligand-receptor pairs in 144 different human cell types.

    • Jordan A. Ramilowski
    • , Tatyana Goldberg
    •  & Alistair R. R. Forrest