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P2X 7 receptors are ATP‐gated cation channels; their activation in macrophage also leads to rapid opening of a membrane pore permeable to dyes such as ethidium, and to release of the pro‐inflammatory cytokine, interleukin‐1β (IL‐1β). It has not been known what this dye‐uptake path is, or whether it is involved in downstream signalling to IL‐1β release. Here, we identify pannexin‐1, a recently described mammalian protein that functions as a hemichannel when ectopically expressed, as this dye‐uptake pathway and show that signalling through pannexin‐1 is required for processing of caspase‐1 and release of mature IL‐1β induced by P2X 7 receptor activation.

β‐Catenin (Armadillo in Drosophila ) is a multitasking and evolutionary conserved molecule that in metazoans exerts a crucial role in a multitude of developmental and homeostatic processes. More specifically, β‐catenin is an integral structural component of cadherin‐based adherens junctions, and the key nuclear effector of canonical Wnt signalling in the nucleus. Imbalance in the structural and signalling properties of β‐catenin often results in disease and deregulated growth connected to cancer and metastasis. Intense research into the life of β‐catenin has revealed a complex picture. Here, we try to capture the state of the art: we try to summarize and make some sense of the processes that regulate β‐catenin, as well as the plethora of β‐catenin binding partners. One focus will be the interaction of β‐catenin with different transcription factors and the potential implications of these interactions for direct cross‐talk between β‐catenin and non‐Wnt signalling pathways. Konrad Basler and colleagues survey and interpret the vast literature on armadillo/β‐catenin. The result is a very broad and informative picture of this evolutionary‐conserved, versatile protein.

Agonist‐induced ubiquitination of the β 2 adrenergic receptor (β 2 AR) functions as an important post‐translational modification to sort internalized receptors to the lysosomes for degradation. We now show that this ubiquitination is reversed by two deubiquitinating enzymes, ubiquitin‐specific proteases (USPs) 20 and 33, thus, inhibiting lysosomal trafficking when concomitantly promoting receptor recycling from the late‐endosomal compartments as well as resensitization of recycled receptors at the cell surface. Dissociation of constitutively bound endogenously expressed USPs 20 and 33 from the β 2 AR immediately after agonist stimulation and reassociation on prolonged agonist treatment allows receptors to first become ubiquitinated and then deubiquitinated, thus, providing a ‘trip switch’ between degradative and recycling pathways at the late‐endosomal compartments. Thus, USPs 20 and 33 serve as novel regulators that dictate both post‐endocytic sorting as well as the intensity and extent of β 2 AR signalling from the cell surface.

Molecular knowledge of biological processes is a cornerstone in omics data analysis. Applied to single‐cell data, such analyses provide mechanistic insights into individual cells and their interactions. However, knowledge of intercellular communication is scarce, scattered across resources, and not linked to intracellular processes. To address this gap, we combined over 100 resources covering interactions and roles of proteins in inter‐ and intracellular signaling, as well as transcriptional and post‐transcriptional regulation. We added protein complex information and annotations on function, localization, and role in diseases for each protein. The resource is available for human, and via homology translation for mouse and rat. The data are accessible via OmniPath ’s web service ( https://omnipathdb.org/ ), a Cytoscape plug‐in, and packages in R/Bioconductor and Python, providing access options for computational and experimental scientists. We created workflows with tutorials to facilitate the analysis of cell–cell interactions and affected downstream intracellular signaling processes. OmniPath provides a single access point to knowledge spanning intra‐ and intercellular processes for data analysis, as we demonstrate in applications studying SARS‐CoV‐2 infection and ulcerative colitis. SYNOPSIS Over 100 resources are integrated into OmniPath , a comprehensive knowledge base of intra‐ and inter‐cellular signaling. Workflows are provided and illustrated in case studies analyzing omics data in SARS‐CoV‐2 infection and ulcerative colitis. OmniPath includes 4,000,000 annotations for over 20,000 proteins. A new framework defining transmitter and receiver roles generalizes the concepts of ligand and receptor . Integrated analysis of intra‐ and intercellular signaling can be performed to study how cells affect each other in healthy and diseased conditions. Software tools and workflows in R and Python facilitate the analysis of bulk and single‐cell omics data using tools such as CellPhoneDB , NicheNet and CARNIVAL . Graphical Abstract Over 100 resources are integrated into OmniPath , a comprehensive knowledge base of intra‐ and inter‐cellular signaling. Workflows are provided and illustrated in case studies analyzing omics data in SARS‐CoV‐2 infection and ulcerative colitis.

Stress activates a complex network of hormones known as the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone‐secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland‐mass dynamics may play an important role in the pathophysiology of stress‐related disorders. Synopsis Prolonged activation of the HPA axis leads to dysregulation and has clinical consequences. This study presents a mechanism for HPA dysregulation based on the effect of HPA hormones acting as growth factors for their downstream glands. A mathematical model that includes gland functional mass dynamics introduces a new slow timescale of weeks to the HPA axis. The gland masses grow during prolonged activation, providing dynamical compensation, and recover with overshoots over weeks after withdrawal of activation. These overshoots explain the observed HPA dysregulation in pathological conditions, and clarify the role of glucocorticoid receptors in resilience to prolonged stress. Graphical Abstract Prolonged activation of the HPA axis leads to dysregulation and has clinical consequences. This study presents a mechanism for HPA dysregulation based on the effect of HPA hormones acting as growth factors for their downstream glands.

The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB−/− cells. Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is both necessary and sufficient to regulate starvation‐ and stress‐induced nuclear translocation of TFEB. These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome‐to‐nucleus signalling mechanism that involves TFEB and mTOR. Under basal conditions TFEB, a master regulator of lysosomal biogenesis, is sequestered in the cytosol due to mTORC1‐dependent phosphorylation at the lysosomal membrane. Nutrient starvation or lysosomal dysfunction inhibit mTORC1 activity and induce nuclear translocation of TFEB inducing target gene expression.

Our understanding of the molecular mechanisms that link inflammation and cancer has significantly increased in recent years. Here, we analyse genetic evidence indicating that the transcription factors nuclear factor‐κB (NF‐κB) and signal transducer and activator of transcription 3 (STAT3) have a central role in this context by regulating distinct functions in cancer cells and surrounding non‐tumorigenic cells. In immune cells, NF‐κB induces the transcription of genes that encode pro‐inflammatory cytokines, which can act in a paracrine manner on initiated cells. By contrast, in tumorigenic cells, both NF‐κB and STAT3 control apoptosis, and STAT3 can also enhance proliferation. Consequently, inflammation should be considered as a valuable target for cancer prevention and therapy. An inflammatory microenvironment has been suggested to be the 7th hallmark of cancer. This Reviews constitutes a journey through some of the signalling pathways by which inflammation enables tumour growth and dissemination. The IKK/NF‐κB and Stat3 pathways are important mediators in this process, affecting not only tumour cells but also cells of the surrounding niche.

Signal transduction governs cellular behavior, and its dysregulation often leads to human disease. To understand this process, we can use network models based on prior knowledge, where nodes represent biomolecules, usually proteins, and edges indicate interactions between them. Several computational methods combine untargeted omics data with prior knowledge to estimate the state of signaling networks in specific biological scenarios. Here, we review, compare, and classify recent network approaches according to their characteristics in terms of input omics data, prior knowledge and underlying methodologies. We highlight existing challenges in the field, such as the general lack of ground truth and the limitations of prior knowledge. We also point out new omics developments that may have a profound impact, such as single‐cell proteomics or large‐scale profiling of protein conformational changes. We provide both an introduction for interested users seeking strategies to study cell signaling on a large scale and an update for seasoned modelers. Graphical Abstract Network models based on prior knowledge are used to understand signal transduction. This Review compares and classifies recent network approaches according to their characteristics in terms of input omics data, prior knowledge, and underlying methodologies.

Cellular senescence suppresses cancer by forcing potentially oncogenic cells into a permanent cell cycle arrest. Senescent cells also secrete growth factors, proteases, and inflammatory cytokines, termed the senescence‐associated secretory phenotype (SASP). Much is known about pathways that regulate the senescence growth arrest, but far less is known about pathways that regulate the SASP. We previously showed that DNA damage response (DDR) signalling is essential, but not sufficient, for the SASP, which is restrained by p53. Here, we delineate another crucial SASP regulatory pathway and its relationship to the DDR and p53. We show that diverse senescence‐inducing stimuli activate the stress‐inducible kinase p38MAPK in normal human fibroblasts. p38MAPK inhibition markedly reduced the secretion of most SASP factors, constitutive p38MAPK activation was sufficient to induce an SASP, and p53 restrained p38MAPK activation. Further, p38MAPK regulated the SASP independently of the canonical DDR. Mechanistically, p38MAPK induced the SASP largely by increasing NF‐κB transcriptional activity. These findings assign p38MAPK a novel role in SASP regulation—one that is necessary, sufficient, and independent of previously described pathways. Senescent cells were shown to secrete inflammatory cytokines and growth factors, depending upon activation of the DNA damage response. Campisi and colleagues now show that this also requires additional signalling via the stress‐activated p38MAP kinase pathway.

Wnt genes and components of Wnt signalling pathways have been implicated in a wide spectrum of important biological phenomena, ranging from early organismal development to cell behaviours to several diseases, especially cancers. Emergence of the field of Wnt signalling can be largely traced back to the discovery of the first mammalian Wnt gene in 1982. In this essay, we mark the thirtieth anniversary of that discovery by describing some of the critical scientific developments that led to the flowering of this field of research. Celebrating more than 30 years of Wnt research, Roel Nusse and Harold Varmus share some personal thoughts on the past and the future of this intensely studied field.