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Ponsioen et al. use a FRET‐based ERK biosensor EKAREN5 in patient‐derived organoids to show that EGFR activity amplifies signal transduction efficiency in KRAS or BRAF mutant MAPK pathways.

In leukocyte transcriptomes from toddlers with ASD, Gazestani et al. find a perturbed gene network that is involved in fetal brain development and lies downstream of ASD risk genes, and whose dysregulation level correlates with ASD symptom severity.

Two waves of glucose metabolism provide distinct ERK-mediated cellular signals during gastrulation, which regulate cell fate and specialized cellular functions that are necessary for development.

IL11 contributes to the development of non-alcoholic steatohepatitis (NASH) through incompletely understood mechanisms. Here, the authors report that lipotoxicity-driven autocrine IL11 activity underlies hepatocyte metabolic dysfunction and death via a NOX4/ERK-mediated mechanism while paracrine IL11 activity stimulates hepatic stellate cells contributing to fibrosis and inflammation in the context of NASH.

In interstitial lung disease, aberrant KRT8+ basaloid cells impair alveolar repair mechanisms. Here they show that Interleukin-11 expression in KRT8+ cells potentiates their pathological properties and causes lung scarring, which can be prevented by anti-IL11 therapy.

Noonan syndrome (NS) is an autosomal dominant genetic disease that is co-morbid with cognitive deficits in a subset of patients. Using mouse models of NS, a study now shows that the synaptic plasticity and memory deficits in mouse models of NS are due primarily to the dysfunction in the MEK-Erk kinase pathways, and pharmacological intervention that alters MEK-Ras function can alleviate physiological and behavioral deficits in the mouse models of NS.

IL-11 is identified as a key regulator of ERK–AMPK–mTORC1 signalling, metabolism, inflammation and age-related disease and lifespan in mouse and human.

Recent studies suggest spatial segregation of tumor initiation and manifestation in IDH-WT glioblastomas. Here, the authors use serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building to establish this unique evolutionary mode in a murine model.

This is an issue edsumm for ng1926. Identification of the Palaeocene/Eocene thermal maximum in a marine sedimentary sequence. It shows that sea surface temperatures near the North Pole increased from roughly 18 degrees Celsius to over 23 degrees Celsius — such warm values imply the absence of ice and thus exclude the influence of ice-albedo feedbacks on this Arctic warming.

A genome-wide CRISPR screen helps to identify the Epstein–Barr virus receptor desmocollin 2 for primary epithelial cell infection. Additional infection assays revealed that desmocollin 3 also aids infection.

Aharonov et al. use in vivo genetic approaches to show that ErBB2-mediated YAP activation initiates epithelial–mesenchymal transition-like processes and dedifferentiation of cardiomyocytes to drive heart regeneration.

Inhibition of cyclooxygenase 1 releases T cells from immunosuppression by platelet-derived thromboxane A₂, thereby enhancing the immune response against metastasis.

A new methodology, Rewind, traces vemurafenib-resistant melanoma back to its initial cell state before drug treatment, creating, effectively, a cellular time machine.

Parrinello and colleagues show that direct interactions with endothelial cells in the subventricular zone maintain the quiescence and identity of neural stem cells, through a process involving both Notch- and Ephrin-mediated signalling pathways.

Cerebral Cavernous Malformations (CCM) are often caused by mutations in CCM1/KRIT1. Here, Chapman et al. elegantly show that the CCM complex promotes apoptosis by regulating zinc homeostasis and storage via a conserved mechanism that likely generates the pathological defects observed in CCM.

Chordoid glioma is a rare low-grade brain tumor that originates from the anterior wall of the third ventricle where surgical resection is challenging; the clinical outcome of patients after subtotal resection or disease recurrence is poor. Here the authors identify a recurrent missense mutation in PRKCA that may serve as a potential therapeutic target in this uncommon brain cancer.

Single-cell analysis in a mouse model of skin stretching shows that stretching causes a transient expansion bias in a population of epidermal stem cells, which is associated with chromatin remodelling and changes in transcriptional profiles.

Competition between inter- and intra-molecular interactions is a commonly observed property of modular signalling proteins. Here, the authors show that in the phosphatase Shp2, this balance is maintained by a trade-off between binding site affinities and conformational stability.

Wang, Wilfahrt and colleagues show that phosphoethanolamine, a phospholipid intermediate, is enriched in tumour interstitial fluid and induces T cell dysfunction, in part by depleting diacylglycerol and dampening T cell receptor signalling.

The human congenital disorder Noonan Syndrome (NS) is caused by germ-line mutations that hyperactivate the RAS/ERK signalling pathway, and can feature pathologic cardiac enlargement. Here, the authors find that a complex cellular and molecular interplay involving a cytokine hierarchy underlies cardiac hypertrophy caused by a NS-associatedRafallele.

Notch1 mutations have opposing effects on clonal growth in normal and tumor cells of the mouse esophagus. In a mouse model of squamous esophageal tumorigenesis, Notch1 blockade reduced premalignant tumor growth, suggesting that it might be an effective prevention strategy for the disease.

Different activation patterns of Akt kinase direct downstream signaling outcomes. Here, the authors run phosphoproteomics on optogenetically-activated Akt1 to characterize the phosphorylation circuits induced by different intensities, durations, and patterns of stimulation.

Donor-derived dendritic cells (do-DC) in the graft can contribute to the induction of alloimmunity and tissue rejection, but how do-DC can be targeted for improving graft survival is unclear. Here the authors show that reducing MHC-II expression on do-DCs by DnaK pre-treatment can decrease the priming of alloimmunity and prolong graft survival in mouse models.

AMPK activation inhibits cardiac hypertrophy. Here the authors show that this occurs independently of previously proposed mechanisms and that AMPK controls the phosphorylation of the aminotransferase GFAT, thereby preventing cardiac hypertrophy through the reduction of protein O-GlcNAcylation.

Most oncogenic RAS mutants remain undruggable. Here, the authors developed monobodies that selectively recognize the active state of KRAS(G12V) and KRAS(G12C) and demonstrated their utility in inhibiting RAS functions through inhibition and degradation.

ABD957 is a potent and selective inhibitor of the ABHD17 family of depalmitoylases that disrupts N-Ras signaling in human acute myeloid leukemia cells and can synergize with MEK inhibition.

Deletion of Ptpn11 in a newly defined mesenchymal progenitor population in the perichondral groove of Ranvier leads to metachondromatosis by increasing Indian hedgehog expression and activating hedgehog signalling, a process that can be reversed with the use of hedgehog pathway inhibitors.

Braf ^V600E expression in resident macrophage progenitors leads to clonal expansion of ERK-activated microglia, which causes synaptic and neuronal loss in the brain and results in lethal neurodegenerative disease in adult mice.

B cell receptor activation leads to contrary outcomes in the absence and presence of co-stimulation. Here, the authors show transcription factor EB acts as a B cell receptor-controlled rheostat that balances activation-induced cell death with co-stimulatory rescue signals, collectively reprograming antigen-primed germinal center B cells for fate decisions.

The p53 target FBP1 is elevated in senescent-like metabolic-dysfunction-associated steatohepatitis hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human hepatocellular carcinomas.

Trumpp and colleagues develop a method to obtain long-term circulating tumor cell-derived organoids from individuals with metastatic breast cancer and identify the neuregulin 1–HER3 axis as important for organoid growth and a promising therapeutic target.