A MEKK1 – JNK mitogen activated kinase (MAPK) cascade module is active in Echinococcus multilocularis stem cells

Background The metacestode larval stage of the fox-tapeworm Echinococcus multilocularis causes alveolar echinococcosis by tumour-like growth within the liver of the intermediate host. Metacestode growth and development is stimulated by host-derived cytokines such as insulin, fibroblast growth factor, and epidermal growth factor via activation of cognate receptor tyrosine kinases expressed by the parasite. Little is known, however, concerning signal transmission to the parasite nucleus and cross-reaction with other parasite signalling systems. Methodology/Principal findings Using bioinformatic approaches, cloning, and yeast two-hybrid analyses we identified a novel mitogen-activated kinase (MAPK) cascade module that consists of E. multilocularis orthologs of the tyrosine kinase receptor interactor Growth factor receptor-bound 2, EmGrb2, the MAPK kinase kinase EmMEKK1, a novel MAPK kinase, EmMKK3, and a close homolog to c-Jun N-terminal kinase (JNK), EmMPK3. Whole mount in situ hybridization analyses indicated that EmMEKK1 and EmMPK3 are both expressed in E. multilocularis germinative (stem) cells but also in differentiated or differentiating cells. Treatment with the known JNK inhibitor SP600125 led to a significantly reduced formation of metacestode vesicles from stem cells and to a specific reduction of proliferating stem cells in mature metacestode vesicles. Conclusions/Significance We provide evidence for the expression of a MEKK1-JNK MAPK cascade module which, in mammals, is crucially involved in stress responses, cytoskeletal rearrangements, and apoptosis, in E. multilocularis stem cells. Inhibitor studies indicate an important role of JNK signalling in E. multilocularis stem cell survival and/or maintenance. Our data are relevant for molecular and cellular studies into crosstalk signalling mechanisms that govern Echinococcus stem cell function and introduce the JNK signalling cascade as a possible target of chemotherapeutics against echinococcosis.

A semantics, energy-based approach to automate biomodel composition

Hierarchical modelling is essential to achieving complex, large-scale models. However, not all modelling schemes support hierarchical composition, and correctly mapping points of connection between models requires comprehensive knowledge of each model's components and assumptions. To address these challenges in integrating biosimulation models, we propose an approach to automatically and confidently compose biosimulation models. The approach uses bond graphs to combine aspects of physical and thermodynamics-based modelling with biological semantics. We improved on existing approaches by using semantic annotations to automate the recognition of common components. The approach is illustrated by coupling a model of the Ras-MAPK cascade to a model of the upstream activation of EGFR. Through this methodology, we aim to assist researchers and modellers in readily having access to more comprehensive biological systems models.

Information Flow in the Fibroblast Growth Factor Receptor Communication Channel

In this work we analyze the flow of information through the Fibroblast Growth Factor Receptor (FGFR) communication channel when different types of signals are transmitted by the MAPK cascade to the gene regulatory network (GRN) formed by the genes C-Myc, DUSP, and Cdc25A, which control fibroblast proliferation. We used the canonical mathematical model of the MAPK cascade coupled to a stochastic model for the activation of the gene regulatory network, subject to different types of FGF inputs (step, quadratic pulses, Dirac delta, and white noise), in order to analyze the response of the gene regulatory network to each type of signal, and determine the temporal variation of the value of its Shannon entropy in each case. Our model suggests that the sustained activation of the FGFR communication channel with a step of FGF > 1 nM is required for cell cycle progression and that during the G1/S transition the amount of uncertainty of the GRN remains at a steady value of ∼ 2.75 bits, indicating that while the fibroblast stimulation with FGF continues the G1/S transition does not require an additional interchange of information between the emitter and the gene regulatory network to be completed. We also found that either low frequency pulses of FGF or low frequency noise, both with a frequency f ≤ 2.77 Hz, are not filtered by the MAPK cascade and can modify the output of the communication channel, i.e., the amount of the effector proteins c-myc, cdc25A and DUSP. An additional effect suggested by our model is that o low frequency periodic signals and noise possibly blockage cell cycle progression because the threshold value concentration of cdc25A for the G1/S transition is not sustained in the in the nucleus during the 10 hours that this process lasts. Finally, from our model we can estimate the capacity of this communication channel in 0.96 bits/min.

Transcriptome and Metabolomic Analyses Reveal Regulatory Networks Controlling Maize Stomatal Development in Response to Blue Light

(1) Background: Blue light is important for the formation of maize stomata, but the signal network remains unclear. (2) Methods: We replaced red light with blue light in an experiment and provided a complementary regulatory network for the stomatal development of maize by using transcriptome and metabolomics analysis. (3) Results: Exposure to blue light led to 1296 differentially expressed genes and 419 differential metabolites. Transcriptome comparisons and correlation signaling network analysis detected 55 genes, and identified 6 genes that work in the regulation of the HY5 module and MAPK cascade, that interact with PTI1, COI1, MPK2, and MPK3, in response to the substitution of blue light in environmental adaptation and signaling transduction pathways. Metabolomics analysis showed that two genes involved in carotenoid biosynthesis and starch and sucrose metabolism participate in stomatal development. Their signaling sites located on the PHI1 and MPK2 sites of the MAPK cascade respond to blue light signaling. (4) Conclusions: Blue light remarkably changed the transcriptional signal transduction and metabolism of metabolites, and eight obtained genes worked in the HY5 module and MAPK cascade.

The ERK mitogen-activated protein kinase signaling network: the final frontier in RAS signal transduction

The RAF–MEK–ERK mitogen-activated protein kinase (MAPK) cascade is aberrantly activated in a diverse set of human cancers and the RASopathy group of genetic developmental disorders. This protein kinase cascade is one of the most intensely studied cellular signaling networks and has been frequently targeted by the pharmaceutical industry, with more than 30 inhibitors either approved or under clinical evaluation. The ERK–MAPK cascade was originally depicted as a serial and linear, unidirectional pathway that relays extracellular signals, such as mitogenic stimuli, through the cytoplasm to the nucleus. However, we now appreciate that this three-tiered protein kinase cascade is a central core of a complex network with dynamic signaling inputs and outputs and autoregulatory loops. Despite our considerable advances in understanding the ERK–MAPK network, the ability of cancer cells to adapt to the inhibition of key nodes reveals a level of complexity that remains to be fully understood. In this review, we summarize important developments in our understanding of the ERK–MAPK network and identify unresolved issues for ongoing and future study.

BnaA03.WRKY28, interacting with BnaA09.VQ12, acts as a brake factor of activated BnWRKY33-mediated resistance outburst against Sclerotinia sclerotiorum in Brassica napus

ABSTRACTSclerotinia sclerotiorum causes substantial damage to the growth of Brassica napus (rapeseed) and makes a significant loss of crop yield. The plant innate immune system may be the primary solution to defense against S. sclerotiorum for rapeseed. Here, we identify that BnWRKY33, a transcription factor in the innate immune pathway, can be rapidly phosphorylated and activated by the MAPK cascade after rapeseed is infected with S. sclerotiorum. In the MAPK cascade, activated BnaA03.MKK4 phosphorylates and activates BnaA06.MPK3 and BnaC03.MPK3. The activated BnMPK3 acts on the substrate BnWRKY33 to enhance its transcriptional activity and trigger a transcriptional burst of BnWRKY33, which helps plants effectively resist the pathogenic fungi by enhancing the expression of phytoalexin synthesis-related genes. With constant infection, BnaA03.WRKY28 and BnaA09.VQ12 are induced, and BnaA03.WRKY28 physically interacts with BnaA09.VQ12 to form a protein complex. BnaA03.WRKY28 preferentially binds to the promoter of BnWRKY33 with the help of BnaA09.VQ12. Compared with activated BnWRKY33, BnaA03.WRKY28 has a lower transcriptional activity on downstream BnWRKY33, which leads to weaker resistance against S. sclerotiorum for rapeseed in the later stage of infection. Furthermore, the induced BnaA03.WRKY28 may promote axillary bud activity and axillary meristem initiation by regulating the expression of branching-related genes (such as BnBRC1), thus promoting the formation of branches in the leaf axils.One-sentence summaryUnder constant infection by Sclerotinia sclerotiorum, BnaA03.WRKY28 interacts with BnaA09.VQ12 and takes precedence over phosphorylated BnWRKY33 to bind to the BnWRKY33 promoter, thereby weakening resistance but promoting branching.

Molecular Insights into the MAPK Cascade during Viral Infection: Potential Crosstalk between HCQ and HCQ Analogues

The mitogen-activated protein kinase (MAPK) pathway links the cell-surface receptors to the transcription machinery, transducing the extracellular signals into several outputs, which may also adapt the host defense mechanism to viral attacks. The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) that causes the COrona VIrus Disease 2019 (COVID-19) has infected upwards of nearly 70 million people and worldwide has claimed more than 1,600,000 deaths. So far, there continues to be no specific treatment for this novel coronavirus-induced disease. In the search to control the global COVID-19 pandemic, some eastern and developing countries have approved a variety of treatments with controversial efficacy, among which is the use of the antimalarial hydroxychloroquine (HCQ). Interestingly, prior data had indicated that the HCQ/CQ could influence the MAPK cascade. The main aim of this review is to address molecular mechanisms, beyond drugs, that can be helpful against viral infection for this and future pandemics. We will highlight (1) the contribution of the MAPK cascade in viral infection and (2) the possible use of MAPK inhibitors in curbing viral infections, alone or in combination with HCQ and quinoline analogues. We are convinced that understanding the molecular patterns of viral infections will be critical for new therapeutical approaches to control this and other severe diseases.