ABSTRACT
The serine/threonine phosphatase calcineurin is a component of the T cell receptor (TCR) signalosome, where it promotes T cell activation by dephosphorylating LckS59. Using small interfering RNA (siRNA)-mediated knockdown and CRISPR-Cas9-targeted genetic disruption of the calcineurin A chain α and ß isoforms, we find that calcineurin also functions as an adaptor in TCR-signaled human T cells. Unlike inhibition of its phosphatase activity, in the absence of calcineurin A, TCR signaling results in attenuated actin rearrangement, markedly reduced TCR-Lck microcluster formation and recruitment of the adaptor RhoH, and diminished phosphorylation of critical targets downstream of Lck such as TCRζ and ZAP-70. Reconstitution of deficient T cells with either calcineurin Aα or Aß restores TCR microcluster formation and signaling, as does reconstitution with a phosphatase-inactive Aα chain. These results assign a non-enzymatic adaptor function to calcineurin in the formation and stabilization of a functional TCR signaling complex.
ABSTRACT
Pulmonary hypertension associated to left heart disease (PH-LHD) refers to a clinical and haemodynamic condition of pulmonary hypertension associated with a heterogeneous group of diseases affecting any of the compartments that form the left ventricle and left atrium. PH-LHD is the most common cause of PH, accounting for 65-80 % of diagnoses. Based on the haemodynamic phase of the disease, PH-LDH is classified into three subgroups: postcapillary PH, isolated postcapillary PH and combined pre-postcapillary PH (CpcPH). Several signaling pathways involved in the regulation of vascular tone are dysfunctional in PH-LHD, including nitric oxide, MAP kinase and endothelin-1 pathways. These pathways are the same as those altered in PH group 1, however PH-LHD can heardly be treated by specific drugs that act on the pulmonary circulation. In this manuscript we provide a state of the art of the available clinical trials investigating the safety and efficacy of PAH-specific drugs, as well as drugs active in patients with heart failure and PH-LHD. We also discuss the different phenotypes of PH-LHD, as well as molecular targets and signaling pathways potentially involved in the pathophysiology of the disease. Finally we will mention some new emerging therapies that can be used to treat this form of PH.
ABSTRACT
Retinal progenitor cells (RPCs) are a multipotent and highly proliferative population that give rise to all retinal cell types during organogenesis. Defining their molecular signature is a key step towards identifying suitable approaches to treat visual impairments. Here, we performed RNA-sequencing of whole eyes from Xenopus at three embryonic stages and used differential expression analysis to define the transcriptomic profiles of optic tissues containing proliferating and differentiating RPCs during retinogenesis. Gene Ontology and KEGG pathway analyses showed that genes associated with developmental pathways (including Wnt and Hedgehog signaling) were upregulated during the period of active RPC proliferation in early retinal development (Nieuwkoop Faber st. 24 and 27). Developing eyes had dynamic expression profiles and shifted to enrichment for metabolic processes and phototransduction during RPC progeny specification and differentiation (st. 35). Furthermore, conserved adult eye regeneration genes were also expressed during early retinal development including sox2, pax6, nrl, and Notch signaling components. The eye transcriptomic profiles presented here span RPC proliferation to retinogenesis and included regrowth-competent stages. Thus, our dataset provides a rich resource to uncover molecular regulators of RPC activity and will allow future studies to address regulators of RPC proliferation during eye repair and regrowth.
ABSTRACT
Cancer is a difficult-to-cure disease with high worldwide incidence and mortality, in large part due to drug resistance and disease relapse. Glycosylation, which is a common modification of cellular biomolecules, was discovered decades ago and has been of interest in cancer research due to its ability to influence cellular function and to promote carcinogenesis. A variety of glycosylation types and structures regulate the function of biomolecules and are potential targets for investigating and treating cancer. The link between glycosylation and carcinogenesis has been more recently revealed by the role of p53 in energy metabolism, including the p53 target gene alpha-L-fucosidase 1 (FUCA1), which plays an essential role in fucosylation. In this review, we summarize roles of glycan structures and glycosylation-related enzymes to cancer development. The interplay between glycosylation and tumor microenvironmental factors is also discussed, together with involvement of glycosylation in well-characterized cancer-promoting mechanisms, such as the epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and p53-mediated pathways. Glycan structures also modulate cell-matrix interactions, cell-cell adhesion as well as cell migration and settlement, dysfunction of which can contribute to cancer. Thus, further investigation of the mechanistic relationships among glycosylation, related enzymes and cancer progression may provide insights into potential novel cancer treatments.
ABSTRACT
Circular RNAs (circRNAs) are endogenous covalently closed single-stranded RNAs produced by reverse splicing of pre-mRNA. Emerging evidence suggests that circRNAs contribute to cancer progression by modulating the oncogenic STAT3 signaling pathway, which plays key roles in human malignancies. STAT3 signaling-related circRNAs expression appears to be extensively dysregulated in diverse cancer types, where they function either as tumor suppressors or oncogenes. However, the biological effects of STAT3 signaling-related circRNAs and their associations with cancer have not been systematically studied before. Given this, shedding light on the interaction between circRNAs and STAT3 signaling pathway in human malignancies may provide several novel insights into cancer therapy. In this review, we provide a comprehensive introduction to the molecular mechanisms by which circRNAs regulate STAT3 signaling in cancer progression, and the crosstalk between STAT3 signaling-related circRNAs and other signaling pathways. We also further discuss the role of the circRNA/STAT3 axis in cancer chemotherapy sensitivity.
ABSTRACT
AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that monitors the cellular energy status to adapt it to the fluctuating nutritional and environmental conditions in an organism. AMPK plays an integral part in a wide array of physiological processes, such as cell growth, autophagy and mitochondrial function, and is implicated in diverse diseases, including cancer, metabolic disorders, cardiovascular diseases and neurodegenerative diseases. AMPK orchestrates many different physiological outcomes by phosphorylating a broad range of downstream substrates. However, the importance of AMPK-mediated regulation of these substrates in vivo remains an ongoing area of investigation to better understand its precise role in cellular and metabolic homeostasis. Here, we provide a comprehensive overview of our understanding of the kinase function of AMPK in vivo, as uncovered from mouse models that harbor phosphorylation mutations in AMPK substrates. We discuss some of the inherent limitations of these mouse models, highlight the broader implications of these studies for understanding human health and disease, and explore the valuable insights gained that could inform future therapeutic strategies for the treatment of metabolic and non-metabolic disorders.
Subject(s)
AMP-Activated Protein Kinases , Disease Models, Animal , Animals , AMP-Activated Protein Kinases/metabolism , Humans , Mice , Disease , PhosphorylationABSTRACT
Stomata serve as the battleground between plants and plant pathogens. Plants can perceive pathogens, inducing closure of the stomatal pore, while pathogens can overcome this immune response with their phytotoxins and elicitors. In this review, we summarize new discoveries in stomata-pathogen interactions. Recent studies have shown that stomatal movement continues to occur in a close-open-close-open pattern during bacterium infection, bringing a new understanding of stomatal immunity. Furthermore, the canonical pattern-triggered immunity pathway and ion channel activities seem to be common to plant-pathogen interactions outside of the well-studied Arabidopsis-Pseudomonas pathosystem. These developments can be useful to aid in the goal of crop improvement. New technologies to study intact leaves and advances in available omics data sets provide new methods for understanding the fight at the stomatal gate. Future studies should aim to further investigate the defense-growth trade-off in relation to stomatal immunity, as little is known at this time.
Subject(s)
Plant Immunity , Plant Stomata , Plant Stomata/physiology , Host-Pathogen Interactions/immunology , Arabidopsis/immunology , Arabidopsis/microbiology , Arabidopsis/physiology , Plant Diseases/microbiology , Plant Diseases/immunologyABSTRACT
Tumor necrosis factor receptors (TNFRs) control pleiotropic pro-inflammatory functions that range from apoptosis to cell survival. The ability to trigger a particular function will depend on the upstream cues, association with regulatory complexes, and downstream pathways. In Drosophila melanogaster, two TNFRs have been identified, Wengen (Wgn) and Grindelwald (Grnd). Although several reports associate these receptors with JNK-dependent apoptosis, it has recently been found that Wgn activates a variety of other functions. We demonstrate that Wgn is required for survival by protecting cells from apoptosis. This is mediated by dTRAF1 and results in the activation of p38 MAP kinase. Remarkably, Wgn is required for apoptosis-induced regeneration and is activated by the reactive oxygen species (ROS) produced following apoptosis. This ROS activation is exclusive for Wgn, but not for Grnd, and can occur after knocking down Eiger/TNFα. The extracellular cysteine-rich domain of Grnd is much more divergent than that of Wgn, which is more similar to TNFRs from other animals, including humans. Our results show a novel TNFR function that responds to stressors by ensuring p38-dependent regeneration.
ABSTRACT
Background: Betel nut/areca nut/Areca catechu is one of the most commonly used psychoactive substance, and is also a major preventable cause of cancer. Unlike other psychoactive substances, such as nicotine, the mechanisms underlying addiction to areca nuts and related oncogenesis remain elusive. Recent reports suggest a possible overlap in the mechanisms of action of nicotine and areca nuts in the human body. Thus, this study aimed to investigate the interactome of human proteins associated with areca nut exposure and the intricate similarities and differences in the effects of the two psychoactive substances on humans. Methods: A list of proteins associated with areca nut use was obtained from the available literature using terms from Medical Subject Headings (MeSH). Protein-protein interaction (PPI) networks and functional enrichment were analyzed. The results obtained for both psychoactive substances were compared. Results: Given the limited number of common proteins (36/226, 16%) in the two sets, a substantial overlap (612/1176 nodes, 52%) was observed in the PPI networks, as well as in Gene Ontology. Areca nuts mainly affect signaling pathways through three hub proteins (alpha serine/threonine-protein kinase, tumor protein 53, and interleukin-6), which are common to both psychoactive substances, as well as two unique hub proteins (epidermal growth factor receptor and master regulator of cell cycle entry and proliferative metabolism). Areca nut-related proteins are associated with unique pathways, such as extracellular matrix organization, lipid storage, and metabolism, which are not found in nicotine-associated proteins. Conclusions: Areca nuts affect regulatory mechanisms, leading to systemic toxicity and oncogenesis. Areca nuts also affect unique pathways that can be studied as potential markers of exposure, as well as targets for anticancer therapeutic agents.
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Depression is the most common chronic mental illness and is characterized by low mood, insomnia, and affective disorders. However, its pathologic mechanisms remain unclear. Numerous studies have suggested that the ghrelin/GHSR system may be involved in the pathophysiologic process of depression. Ghrelin plays a dual role in experimental animals, increasing depressed behavior and decreasing anxiety. By combining several neuropeptides and traditional neurotransmitter systems to construct neural networks, this hormone modifies signals connected to depression. The present review focuses on the role of ghrelin in neuritogenesis, astrocyte protection, inflammatory factor production, and endocrine disruption in depression. Furthermore, ghrelin/GHSR can activate multiple signaling pathways, including cAMP/CREB/BDNF, PI3K/Akt, Jak2/STAT3, and p38-MAPK, to produce antidepressant effects, given which it is expected to become a potential therapeutic target for the treatment of depression.
ABSTRACT
Bruton's tyrosine kinase (BTK) regulates diverse cellular signaling of the innate and adaptive immune system in response to microbial pathogens. Downregulation or constitutive activation of BTK is reported in patients with autoimmune diseases or various B-cell leukemias. BTK is a multidomain protein tyrosine kinase that adopts an Src-like autoinhibited conformation maintained by the interaction between the kinase and PH-TH domains. The PH-TH domain plays a central role in regulating BTK function. BTK is activated by binding to PIP3 at the plasma membrane upon stimulation by the B-cell receptor (BCR). The PIP3 binding allows dimerization of the PH-TH domain and subsequent transphosphorylation of the activation loop. Alternatively, a recent study shows that the multivalent T-cell-independent (TI) antigen induces BCR response by activating BTK independent of PIP3 binding. It was proposed that a transiently stable IP6-dependent PH-TH dimer may activate BTK during BCR activation by the TI antigens. However, no IP6-dependent PH-TH dimer has been identified yet. Here, we investigated a constitutively active PH-TH mutant (E41K) to determine if the elusive IP6-dependent PH-TH dimer exists. We showed that the constitutively active E41K mutation activates BTK by stabilizing the IP6-dependent PH-TH dimer. We observed that a downregulating mutation in the PH-TH domain (R28H) linked to X-linked agammaglobulinemia impairs BTK activation at the membrane and in the cytosol by preventing PH-TH dimerization. We conclude that the IP6 dynamically remodels the BTK active fraction between the membrane and the cytoplasm. Stimulating with IP6 increases the cytosolic fraction of the activated BTK.
ABSTRACT
Signaling pathways are responsible for transmitting information between cells and regulating cell growth, differentiation, and death. Proteins in cells form complexes by interacting with each other through specific structural domains, playing a crucial role in various biological functions and cell signaling pathways. Protein-protein interactions (PPIs) within cell signaling pathways are essential for signal transmission and regulation. The spatiotemporal features of PPIs in signaling pathways are crucial for comprehending the regulatory mechanisms of signal transduction. Bimolecular fluorescence complementation (BiFC) is one kind of imaging tool for the direct visualization of PPIs in living cells and has been widely utilized to uncover novel PPIs in various organisms. BiFC demonstrates significant potential for application in various areas of biological research, drug development, disease diagnosis and treatment, and other related fields. This review systematically summarizes and analyzes the technical advancement of BiFC and its utilization in elucidating PPIs within established cell signaling pathways, including TOR, PI3K/Akt, Wnt/ß-catenin, NF-κB, and MAPK. Additionally, it explores the application of this technology in revealing PPIs within the plant hormone signaling pathways of ethylene, auxin, Gibberellin, and abscisic acid. Using BiFC in conjunction with CRISPR-Cas9, live-cell imaging, and ultra-high-resolution microscopy will enhance our comprehension of PPIs in cell signaling pathways.
Subject(s)
Signal Transduction , Humans , Animals , Protein Interaction Mapping/methods , FluorescenceABSTRACT
Neurokinin receptors are a family of G protein-coupled receptors that were first identified in the central and peripheral nervous systems. However these receptors were later found in other types of cells, therefore, new perspectives concerning their novel roles were described. Mammalian has three neurokinin receptors, among which neurokinin-1 receptors [NK1R] have been indicated to be involved in most, if not all, intracellular functions, primarily the regulation of cell proliferation. By interacting with its potent agonist, substance P [SP], NK1R can engage a variety of signaling pathways and serve as a platform for cells to proliferate by regulating the expression of the cell cycle-related genes. Furthermore, the activity of SP/NK1R is stimulated by various oncogenes, indicating the involvement of this pathway in human cancers. As a result, numerous NK1R antagonists have been investigated in oncology trials, and the promising anti-- cancer effect of these receptors has opened up new possibilities for incorporating these antagonists into cancer treatment. Considering these factors, gaining a deeper understanding of the SP/NK1R pathway could offer significant advantages for cancer patients. The more knowledge we acquire about this pathway, the greater the potential for exploiting it in the development of effective treatment strategies. Here, we present a comprehensive review of the current knowledge pertaining to the biological function of the SP/NK1R, with a specific emphasis on its recently discovered role in the regulation of cell proliferation. Moreover, we provide insights into the impact of this pathway in human cancers, along with an overview of the most significant NK1R antagonists currently utilized in cancer research studies.
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This Future Challenges article summarizes views on future directions in immunological research presented at round-table discussions at the 4th Immunology workshop in the Lofoten Islands in Norway, held in August 2023, and subsequent responses to surveys sent to meeting participants. It also summarizes some of the conversations around the responsibility of scientists to communicate with the non-science community, and the approaches that we may use to meet this obligation.
ABSTRACT
Age-related macular degeneration (AMD) is characterized by visual impairment observed in elderly population. Two forms of the disease are generally described, the atrophic (AMDa) and exudative forms (AMDe). Up until now, no curative treatment is available for this disease. The retinal pigment epithelium (RPE) plays a central role in the pathogenesis of age-related macular degeneration. Here, involvement of RPE dysfunction in AMD onset and progression was analyzed by a comparison of transcriptome profiles of hiPSC-RPE derived from healthy individuals or individuals affected by AMDa or AMDe. The analysis highlighted almost 1000 genes differentially expressed between the three comparison groups. Among these genes, 33 genes were already known to be involved in AMD pathogenesis. To establish an AMD genetic signature, we focused on genes differentially expressed in both AMDa/e cell lines compared to control cells and focused on the three genes (ABCA1, RPN2, RB1CC1) that were related to lipidic homeostasis. Differences in level expression of these three genes are found not only in control and AMDa/e cell lines, but also between AMDa and AMDe populations.
ABSTRACT
Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute members of the dual-specificity family of protein phosphatases that dephosphorylate the MAPKs. MKP-5 dephosphorylates the stress-responsive MAPKs, p38 MAPK and JNK, and has been shown to promote tissue fibrosis. Here, we provide insight into how MKP-5 regulates the transforming growth factor-ß (TGF-ß) pathway, a well-established driver of fibrosis. We show that MKP-5-deficient fibroblasts in response to TGF-ß are impaired in SMAD2 phosphorylation at canonical and non-canonical sites, nuclear translocation, and transcriptional activation of fibrogenic genes. Consistent with this, pharmacological inhibition of MKP-5 is sufficient to block TGF-ß signaling, and that this regulation occurs through a JNK-dependent pathway. By utilizing RNA sequencing and transcriptomic analysis, we identify TGF-ß signaling activators regulated by MKP-5 in a JNK-dependent manner, providing mechanistic insight into how MKP-5 promotes TGF-ß signaling. This study elucidates a novel mechanism whereby MKP-5-mediated JNK inactivation is required for TGF-ß signaling and provides insight into the role of MKP-5 in fibrosis.
ABSTRACT
The CLAVATA pathway plays a key role in the regulation of multicellular shoot and root meristems in flowering plants. In Arabidopsis, CLAVATA 3-like signaling peptides (CLEs) act via receptor-like kinases CLAVATA 1 and CRINKLY 4 (CR4). In the moss Physcomitrium patens, PpCLAVATA and PpCR4 were previously studied independently and shown to play conserved roles in the regulation of cell proliferation and differentiation. The plant calpain DEFECTIVE KERNEL 1 (DEK1) has been identified as another key regulator of cell division and cell fate in vascular plants and bryophytes. The functional interaction between CLAVATA, CR4, and DEK1 remains unknown. Here, we show that P. patens crinkly4 and dek1 mutants respond differently to CLE peptide treatments suggesting their distinct roles in the CLAVATA pathway. Reduced CLAVATA-mediated suppression of leafy shoot growth in Δcr4 mutants indicates that PpCR4 is involved in CLV3p perception, most likely as a receptor. The CLV3p strongly suppressed leaf vein development in Δcr4 mutants, suggesting that other receptors are involved in these processes and indicating a potential role of PpCR4 in organ sensitization to CLEs.
Subject(s)
Bryopsida , Plant Proteins , Bryopsida/genetics , Bryopsida/growth & development , Bryopsida/metabolism , Plant Proteins/metabolism , Plant Proteins/genetics , Gene Expression Regulation, Plant , Peptides/metabolism , Germ Cells, Plant/growth & development , Germ Cells, Plant/metabolismABSTRACT
BACKGROUND: Despite extensive efforts, empirical techniques have yielded limited progress in finding effective anticancer medications, with chemotherapy drugs often associated with drug resistance and serious side effects. Thus, there is a pressing need for novel agents with minimal adverse effects. Natural substances, widely used in treating various illnesses, including cancer, offer promising alternatives. Among these, mushrooms, rich in low molecular weight secondary metabolites, polysaccharides, and polysaccharide-protein complexes, have gained attention for their potential anticancer properties. RESULTS: Mushroom polysaccharides have been found to impede oncogenesis and tumor metastasis by directly inhibiting tumor cell growth and indirectly enhancing immune system functions. These polysaccharides engage with numerous cell signaling pathways that influence cancer development and progression. They affect pathways that control cell survival, growth, and differentiation, and they also play a role in adjusting the tumor immune microenvironment. CONCLUSION: This review highlights the potential of mushroom polysaccharides as promising anticancer agents due to their ability to modulate cell signaling pathways crucial for cancer development. Understanding the mechanisms underlying their effects on these pathways is essential for harnessing their therapeutic potential and developing novel strategies for cancer treatment.
Subject(s)
Agaricales , Neoplasms , Polysaccharides , Signal Transduction , Agaricales/chemistry , Humans , Signal Transduction/drug effects , Neoplasms/drug therapy , Neoplasms/prevention & control , Polysaccharides/pharmacology , Antineoplastic Agents/pharmacology , Animals , Tumor Microenvironment/drug effectsABSTRACT
Nanomaterial advancements have driven progress in central and peripheral nervous system applications such as tissue regeneration and brain-machine interfacing. Ideally, neural interfaces with native tissue shall seamlessly integrate, a process that is often mediated by the interfacial material properties. Surface topography and material chemistry are significant extracellular stimuli that can influence neural cell behavior to facilitate tissue integration and augment therapeutic outcomes. This review characterizes topographical modifications, including micropillars, microchannels, surface roughness, and porosity, implemented on regenerative scaffolding and brain-machine interfaces. Their impact on neural cell response is summarized through neurogenic outcome and mechanistic analysis. The effects of surface chemistry on neural cell signaling with common interfacing compounds like carbon-based nanomaterials, conductive polymers, and biologically inspired matrices are also reviewed. Finally, the impact of these extracellular mediated neural cues on intracellular signaling cascades is discussed to provide perspective on the manipulation of neuron and neuroglia cell microenvironments to drive therapeutic outcomes.