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Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase pivotal in cellular signal transduction, regulating cell adhesion, migration, growth, and survival. However, the regulatory mechanisms of FAK during tumorigenesis and progression still need to be fully understood. Our previous study demonstrated that O-GlcNAcylation regulates integrin-mediated cell adhesion. To further elucidate the underlying molecular mechanism, we focused on FAK in this study and purified it from 293T cells. Using liquid chromatography–mass spectrometry (LC-MS/MS), we identified the O-GlcNAcylation of FAK at Ser708, Thr739, and Ser886. Compared with wild-type FAK expressed in FAK-knockout 293T cells, the FAK mutant, in which Ser708, Thr739, and Ser886 were replaced with Ala, exhibited lower phosphorylation levels of Tyr397 and AKT. Cell proliferation and migration, assessed through MTT and wound healing assays, were significantly suppressed in the FAK mutant cells compared to the wild-type FAK cells. Additionally, the interaction among FAK, paxillin, and talin was enhanced, and cell adhesion was increased in the mutant cells. These data indicate that specific O-GlcNAcylation of FAK plays a critical regulatory role in integrin-mediated cell adhesion and migration. This further supports the idea that O-GlcNAcylation is essential for tumorigenesis and progression and that targeting the O-GlcNAcylation of FAK could offer a promising therapeutic strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

Cells have evolved intricate mechanisms for recognizing and responding to changes in oxygen (O2) concentrations. Here, we have reprogrammed cellular hypoxia (low O2) signaling via gas tunnel engineering of prolyl hydroxylase 2 (PHD2), a non‐heme iron dependent O2 sensor. Using computational modeling and protein engineering techniques, we identify a gas tunnel and critical residues therein that limit the flow of O2 to PHD2's catalytic core. We show that systematic modification of these residues can open the constriction topology of PHD2's gas tunnel. Using kinetic stopped‐flow measurements with NO as a surrogate diatomic gas, we demonstrate up to 3.5‐fold enhancement in its association rate to the iron center of tunnel‐engineered mutants. Our most effectively designed mutant displays 9‐fold enhanced catalytic efficiency (kcat/KM=830±40 M−1 s−1) in hydroxylating a peptide mimic of hypoxia inducible transcription factor HIF‐1α, as compared to WT PHD2 (kcat/KM=90±9 M−1 s−1). Furthermore, transfection of plasmids that express designed PHD2 mutants in HEK‐293T mammalian cells reveal significant reduction of HIF‐1α and downstream hypoxia response transcripts under hypoxic conditions of 1 % O2. Overall, these studies highlight activation of PHD2 as a new pathway to reprogram hypoxia responses and HIF signaling in cells. [ABSTRACT FROM AUTHOR]

Cutaneous melanoma accounts for the majority of skin cancer-related deaths, and its incidence increases each year. The growing number of melanoma cases, especially in advanced stages, poses a significant socio-medical challenge throughout the world. Extensive research on melanoma pathogenesis identifies UV radiation as the most important factor in melanocytic transformation. Oxidative effects of UV irradiation exert their influence on melanoma pathogenesis primarily through modification of nucleic acids, proteins, and lipids, further disrupting cellular signaling and cell cycle regulation. Its effects extend beyond melanocytes, leading to immunosuppression in the exposed skin tissue, which consequently creates conditions for immune surveillance evasion and further progression. In this review, we focus on the specific molecular changes observed in the UV-dependent oxidative stress environment and their biological consequences in the course of the disease, which have not been considered in previous reviews on melanoma. Nonetheless, data show that the exact role of oxidative stress in melanoma initiation and progression remains unclear, as it affects cancerous cells differently depending on the specific context. A better understanding of the pathophysiological basis of melanoma development holds promise for identifying potential targets, which could lead to effective melanoma prevention strategies. [ABSTRACT FROM AUTHOR]

Mechanical stimuli, such as stretch, shear stress, or compression, activate a range of biomolecular responses through cellular mechanotransduction. In the nervous system, studies on mechanical stress have highlighted key pathophysiological mechanisms underlying traumatic injury and neurodegenerative diseases. However, the biomolecular pathways triggered by mechanical stimuli in the nervous system has not been fully explored, especially compared to other body systems. This gap in knowledge may be due to the wide variety of methods and definitions used in research. Additionally, as mechanical stimulation techniques such as ultrasound and electromagnetic stimulation are increasingly utilized in psychological and neurorehabilitation treatments, it is vital to understand the underlying biological mechanisms in order to develop accurate pathophysiological models and enhance therapeutic interventions. This review aims to summarize the cellular signaling pathways activated by various mechanical and electromagnetic stimuli with a particular focus on the mammalian nervous system. Furthermore, we briefly discuss potential cellular mechanosensors involved in these processes. [ABSTRACT FROM AUTHOR]

Dementia is an umbrella term used to describe deterioration of cognitive function. It is the seventh leading cause of death and is one of the major causes of dependence among older people globally. Alzheimer's Disease (AD) contributes to approximately 60-70% of dementia cases and is characterized by the accumulation of amyloid plaques and tau tangles in the brain. Neuroinflammation is now widely accepted as another disease hallmark, playing a role in both the response to and the perpetuation of disease processes. Microglia are brainresident immune cells that are initially effective at clearing amyloid plaques but contribute to the damaging inflammatory milieu of the brain as disease progresses. Circulating peripheral immune cells contribute to this inflammatory environment through cytokine secretion, creating a positive feedback loop with the microglia. One group of these peripherally derived cytokines acting on microglia is the common cytokine receptor chain family. These cytokines bind heterodimer receptors to activate three major signaling pathways: MAPK, PI3K, and JAK/STAT. This perspective will look at the mechanisms of these three pathways in microglia and highlight the future directions of this research and potential therapeutics. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis without nasal polyp (CRSsNP) is characterized by tissue repair/remodeling and the subepithelial stroma region in whose nasal mucosa has been reported by us to have thromboxane A2 (TXA2) prostanoid (TP) receptor and overexpress connective tissue growth factor (CTGF). Therefore, this study aimed to investigate the relationship between TP receptor activation and CTGF production/function in human CRSsNP nasal mucosa stromal fibroblasts. We found that TP agonists including U46619 and IBOP ([1S‐[1α,2α(Z),3β(1E,3 S*),4α]]‐7‐[3‐[3‐hydroxy‐4‐(4‐iodophenoxy)‐1‐butenyl]‐7‐oxabicyclo[2.2.1]hept‐2‐yl]‐5‐heptenoic acid) could promote CTGF protein/messenger RNA expression and secretion. The pharmacological intervention and TP activation assay with U46619 identified the possible participation of PKCμ, PKCδ, nuclear factor‐κB (NF‐κB), and cyclic AMP response element‐binding protein (CREB) phosphorylation/activation in the CTGF induction. Moreover, a phorbol ester—phorbol‐12‐myristate 13‐acetate (PMA) exhibited a similar cellular signaling and CTGF production profile to that elicited by TP activation. However, further small interfering RNA interference analysis revealed that only NF‐κB and PKCδ‐CREB pathways were necessarily required for TP‐mediated CTGF production, which could not be completely supported by those findings from PMA. Finally, in a functional assay, although CTGF did not affect fibroblast proliferation, TP‐mediated CTGF could drive novel self‐migration in fibroblasts both in the scratch/wound healing and transwell apparatus assays. Meanwhile, the overall staining for stress fibers and formation of the lamellipodia and filopodia‐like structures was concomitantly increased in the treated migrating cells. Collectively, we provided here that novel TP mediates CTGF production and self‐migration in human nasal fibroblasts through NF‐κB and PKCδ‐CREB signaling pathways. More importantly, we also demonstrated that thromboxane, TP receptor, CTGF, and stromal fibroblasts may act in concert in the tissue remodeling/repair process during CRSsNP development and progression. [ABSTRACT FROM AUTHOR]

Introduction: Exosomes, a subset of extracellular vesicles (EVs), are crucial for intercellular communication in various contexts. Despite their small size, they carry diverse cargo, including RNA, proteins, and lipids. Internalization by recipient cells raises concerns about potential disruptions to cellular functions. Notably, the ability of exosomes to traverse the blood-brain barrier (BBB) has significant implications. Methods: To conduct a thorough investigation into the existing academic literature on exosomes within the framework of neuron-glia communication, a comprehensive search strategy was implemented across the PubMed, Google Scholar, and Science Direct databases. Multiple iterations of the keywords "exosome," "neuron-glia communication," and "neurological disorders" were employed to systematically identify relevant publications. Furthermore, an exploration of the Clinicaltrials. gov database was undertaken to identify clinical trials related to cellular signaling, utilizing analogous terminology. Results: Although the immediate practical applications of exosomes are somewhat limited, their potential as carriers of pathogenic attributes offers promising opportunities for the development of precisely targeted therapeutic strategies for neurological disorders. This review presents a comprehensive overview of contemporary insights into the pivotal roles played by exosomes as agents mediating communication between neurons and glial cells within the central nervous system (CNS). Conclusion: By delving into the intricate dynamics of exosomal communication in the CNS, this review contributes to a deeper understanding of the roles of exosomes in both physiological and pathological processes, thereby paving the way for potential therapeutic advancements in the field of neurological disorders. [ABSTRACT FROM AUTHOR]

The mitogen‐activated protein kinase kinase 4 (MKK4), a member of the MAP kinase kinase family, directly phosphorylates and activates the c‐Jun NH2‐terminal kinases (JNK), in response to proinflammatory cytokines and cellular stresses. Regulation of the MKK4 activity is considered to be a novel approach for the prevention and treatment of inflammation. The aim of this study was to identify whether fisetin, a potential anti‐inflammatory compound, targets MKK4‐JNK cascade to inhibit lipopolysaccharide (LPS)‐stimulated inflammatory response. RAW264 macrophage pretreated with fisetin following LPS stimulation was used as a cell model to investigate the transactivation and expression of related‐inflammatory genes by transient transfection assay, electrophoretic mobility shift assay (EMSA), or enzyme‐linked immunosorbent assay (ELISA), and cellular signaling as well as binding of related‐signal proteins by Western blot, pull‐down assay and kinase assay, and molecular modeling. The transactivation and expression of cyclooxygenase‐2 (COX‐2) gene as well as prostaglandin E2 (PGE2) secretion induced by LPS were inhibited by fisetin in a dose‐dependent manner. Signaling transduction analysis demonstrated that fisetin selectively inhibited MKK4‐JNK1/2 signaling to suppress the phosphorylation of transcription factor AP‐1 without affecting the NF‐κB and Jak2‐Stat3 signaling as well as the phosphorylation of Src, Syk, and TAK1. Furthermore, in vitro and ex vivo pull‐down assay using cell lysate or purified protein demonstrated that fisetin could bind directly to MKK4. Molecular modeling using the Molecular Operating Environment™ software indicated that fisetin docked into the ATP‐binding pocket of MKK4 with a binding energy of −71.75 kcal/mol and formed a 1.70 Å hydrogen bound with Asp247 residue of MKK4. The IC50 of fisetin against MKK4 was estimated as 2.899 μM in the kinase assay, and the ATP‐competitive effect was confirmed by ATP titration. Taken together, our data revealed that fisetin is a potent selective ATP‐competitive MKK4 inhibitor to suppress MKK4‐JNK1/2‐AP‐1 cascade for inhibiting LPS‐induced inflammation. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a chronic progressive inflammatory disease of the vascular wall and the primary pathological basis of cardiovascular and cerebrovascular disease. Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2), two highly homologous members of the FAK family kinases, play critical roles in integrin signaling. They also serve as scaffolding proteins that contribute to the assembly of cellular signaling complexes that regulate cell survival, cell cycle progression, and cell motility. Research indicates that the FAK family kinases is involved in the gene regulation of vascular cells and that aberrant expression of this family is associated with pathological changes in vascular disease. These findings establish the FAK family kinases as a critical signaling mediator in atherosclerotic lesions and inhibition of its activity has the potential to attenuate the pathological progression of AS. This review highlights the indispensable role of the FAK family kinases in abnormal vascular smooth muscle cell proliferation, endothelial cell dysfunction, inflammation, and lipid metabolism associated with AS. We also summarize therapeutic targets against the FAK family kinases, providing valuable insights into therapeutic strategies for AS. [ABSTRACT FROM AUTHOR]

Successful pregnancy depends on precise molecular regulation of uterine physiology, especially during the menstrual cycle. Deregulated oxidative stress (OS), often influenced by inflammatory changes but also by environmental factors, represents a constant threat to this delicate balance. Oxidative stress induces a reciprocally regulated nuclear factor erythroid 2-related factor 2/peroxisome proliferator-activated receptor-gamma (Nrf2/PPARγ) pathway. However, increased PPARγ activity appears to be a double-edged sword in endometrial physiology. Activated PPARγ attenuates inflammation and attenuates OS to restore redox homeostasis. However, it also interferes with physiological processes during the menstrual cycle, such as hormonal signaling and angiogenesis. This review provides an elucidation of the molecular mechanisms that support the interplay between PPARγ and OS. Additionally, it offers fresh perspectives on the Nrf2/PPARγ pathway concerning endometrial receptivity and its potential implications for infertility. [ABSTRACT FROM AUTHOR]

Cilia are organelles extend from cells to sense external signals for tuning intracellular signaling for optimal cellular functioning. They have evolved sensory and motor roles in various cells for tissue organization and homeostasis in development and post-development. More than a thousand genes are required for cilia function. Mutations in them cause multisystem disorders termed ciliopathies. The null mutations in CC2D2A result in Meckel syndrome (MKS), which is embryonic lethal, whereas patients who have missense mutations in the C2 domain of CC2D2A display Joubert syndrome (JBTS). They survive with blindness and mental retardation. How C2 domain defects cause disease conditions is not understood. To answer this question, C2 domain of Cc2d2a (mice gene) was knocked down (KD) in IMCD-3 cells by shRNA. This resulted in defective cilia morphology observed by immunofluorescence analysis. To further probe the cellular signaling alteration in affected cells, gene expression profiling was done by RNAseq and compared with the controls. Bioinformatics analysis revealed that the differentially expressed genes (DEGs) have functions in cilia. Among the 61 cilia DEGs identified, 50 genes were downregulated and 11 genes were upregulated. These cilia genes are involved in cilium assembly, protein trafficking to the cilium, intraflagellar transport (IFT), cellular signaling like polarity patterning, and Hedgehog signaling pathway. This suggests that the C2 domain of CC2D2A plays a critical role in cilia assembly and molecular signaling hosted in cilia for cellular homeostasis. Taken together, the missense mutations in the C2 domain of CC2D2A seen in JBTS might have affected cilia-mediated signaling in neurons of the retina and brain. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression. [ABSTRACT FROM AUTHOR]

Since the evolution of the aerobic metabolism, reactive oxygen species (ROS) have represented significant challenges to diverse life forms. In recent decades, increasing knowledge has revealed a dual role for ROS in cell physiology, showing they serve as a major source of cellular damage while also functioning as important signaling molecules in various biological processes. Our understanding of ROS homeostasis and ROS-mediated cellular signaling pathways has presumed that they are ancient and highly conserved mechanisms shared by most organisms. However, emerging evidence highlights the complexity and plasticity of ROS signaling, particularly in animals that have evolved in extreme environments. In this review, we focus on ROS generation, antioxidative systems and the main signaling pathways that are influenced by ROS. In addition, we discuss ROS's responsive transcription regulation and how it may have been shaped over the course of evolution. [ABSTRACT FROM AUTHOR]

Ether-lipids (EL) are specific lipids bearing a characteristic sn- 1 ether bond. Depending on the ether or vinyl-ether nature of this bond, they are present as alkyl- or alkenyl-EL, respectively. Among EL, alkenyl-EL, also referred as plasmalogens in the literature, attract most of the scientific interest as they are the predominant EL species in eukaryotic cells, thus less is known about alkyl-EL. EL have been implicated in various signaling pathways and alterations in their quantity are frequently observed in pathologies such as neurodegenerative and cardiovascular diseases or cancer. However, it remains unknown whether both alkyl- and alkenyl-EL play the same roles in these processes. This review summarizes the roles and mechanisms of action of EL in cellular signaling and tries to discriminate between alkyl- and alkenyl-EL. We also focus on the involvement of EL-mediated alterations of cellular signaling in diseases and discuss the potential interest for EL in therapy. • Ether-lipids are specific lipids existing either as alkyl- or alkenyl-ether-lipids. • Ether-lipids have been involved in the regulation of cellular signaling. • In various pathologies, quantities of ether-lipids are altered. • It remains unknown whether alkyl- and alkenyl-ether-lipids play differential roles. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) has emerged as an increasing public health problem but has not been well studied, particularly the mechanisms of brain cellular behaviors during TBI. Methods: In this study, we established an ischemia/reperfusion (I/R) brain injury mice model using transient middle cerebral artery occlusion (tMCAO) strategy. After then, RNA-sequencing of frontal lobes was performed to screen key inducers during TBI. To further verify the selected genes, we collected peripheral blood mononuclear cells (PBMCs) from TBI patients within 24 h who attended intensive care unit (ICU) in the Affiliated Hospital of Yangzhou University and analyzed the genes expression using RT-qPCR. Finally, the receiver operator characteristic (ROC) curves and co-expression with cellular senescence markers were applied to evaluate the predictive value of the genes. Results: A total of six genes were screened out from the RNA-sequencing based on their novelty in TBI and implications in apoptosis and cellular senescence signaling. RT-qPCR analysis of PBMCs from patients showed the six genes were all up-regulated during TBI after comparing with healthy volunteers who attended the hospital for physical examination. The area under ROC (AUC) curves were all >0.7, and the co-expression scores of the six genes with senescence markers were all significantly positive. We thus identified TGM1, TGM2, ATF3, RCN3, ORAI1 and ITPR3 as novel key markers that are induced during TBI, and these markers may also serve as potential predictors for the progression of TBI. [ABSTRACT FROM AUTHOR]

The development and maturation of cortical GABAergic interneurons has been extensively studied, with much focus on nuclear regulation via transcription factors. While these seminal events are critical for the establishment of interneuron developmental milestones, recent studies on cellular signaling cascades have begun to elucidate some potential contributions of cell signaling during development. Here, we review studies underlying three broad signaling families, mTOR, MAPK, and Wnt/beta-catenin in cortical interneuron development. Notably, each pathway harbors signaling factors that regulate a breadth of interneuron developmental milestones and properties. Together, these events may work in conjunction with transcriptional mechanisms and other events to direct the complex diversity that emerges during cortical interneuron development and maturation. [ABSTRACT FROM AUTHOR]

Sterol regulatory element-binding proteins (SREBPs) play vital roles in fatty acid metabolism and other metabolic processes in mammals. However, in penaeid shrimp, the repertoire of genes modulated by SREBP is unknown. Here, RNA interference-mediated knockdown followed by transcriptome sequencing on the Illumina Novaseq 6000 platform was used to explore the genes modulated by SREBP in Penaeus vannamei hepatopancreas. A total of 706 differentially expressed genes (DEGs) were identified, out of which 282 were upregulated and 424 downregulated. Although gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that most of the downregulated DEGs were involved in physiological processes related to immunity, metabolism, and cellular signaling pathways, many of the dysregulated genes have uncharacterized functions. While most of the dysregulated genes were annotated in metabolic processes, such as carbohydrate metabolism, lipid metabolism, signal transduction, and immune system, a large number (42.21%) are uncharacterized. Collectively, our current data revealed that SREBP modulates many genes involved in crucial physiological processes, such as energy metabolism, immune response, and cellular signaling pathways, as well as numerous genes with unannotated functions, in penaeid shrimp. These findings indicated that our knowledge of the repertoire of genes modulated by SREBP in shrimp lags behind that of mammals, probably due to limited research or because the complete genome of P. vannamei has just been sequenced. [ABSTRACT FROM AUTHOR]

Cells convey information about their extracellular environment to their core functional machineries. Studying the capacity of intracellular signaling pathways to transmit information addresses fundamental questions about living systems. Here, we review how information-theoretic approaches have been used to quantify information transmission by signaling pathways that are functionally pleiotropic and subject to molecular stochasticity. We describe how recent advances in machine learning have been leveraged to address the challenges of complex temporal trajectory datasets and how these have contributed to our understanding of how cells employ temporal coding to appropriately adapt to environmental perturbations. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) ions play a pivotal role in physiology and cellular signaling. The intracellular Ca2+ concentration ([Ca2+]i) is about three orders of magnitude lower than the extracellular concentration, resulting in a steep transmembrane concentration gradient. Thus, the spatial and the temporal dynamics of [Ca2+]i are ideally suited to modulate Ca2+-mediated cellular responses to external signals. A variety of highly sophisticated methods have been developed to gain insight into cellular Ca2+ dynamics. In addition to electrophysiological measurements and the application of synthetic dyes that change their fluorescent properties upon interaction with Ca2+, the introduction and the ongoing development of genetically encoded Ca2+ indicators (GECI) opened a new era to study Ca2+-driven processes in living cells and organisms. Here, we have focused on one well-established GECI, i.e., GCaMP3.0. We have systematically modified the protein with sequence motifs, allowing localization of the sensor in the nucleus, in the mitochondrial matrix, at the mitochondrial outer membrane, and at the plasma membrane. The individual variants and a cytosolic version of GCaMP3.0 were overexpressed and purified from E. coli cells to study their biophysical properties in solution. All versions were examined to monitor Ca2+ signaling in stably transfected cell lines and in primary cortical neurons transduced with recombinant Adeno-associated viruses (rAAV). In this comparative study, we provide evidence for a robust approach to reliably trace Ca2+ signals at the (sub)-cellular level with pronounced temporal resolution. [ABSTRACT FROM AUTHOR]

TANK-binding kinase 1 (TBK1) plays a fundamental role in regulating the cellular responses and controlling several signaling cascades. It regulates inflammatory, interferon, NF-κB, autophagy, and Akt pathways. Post-translational modifications (PTM) of TBK1 control its action and subsequent cellular signaling. The dysregulation of the TBK1 pathway is correlated to many pathophysiological conditions, including cancer, that implicates the promising therapeutic advantage for targeting TBK1. The present study summarizes current updates on the molecular mechanisms and cancer-inducing roles of TBK1. Designed inhibitors of TBK1 are considered a potential therapeutic agent for several diseases, including cancer. Data from pre-clinical tumor models recommend that the targeting of TBK1 could be an attractive strategy for anti-tumor therapy. This review further highlighted the therapeutic potential of potent and selective TBK1 inhibitors, including Amlexanox, Compound II, BX795, MRT67307, SR8185 AZ13102909, CYT387, GSK8612, BAY985, and Domainex. These inhibitors may be implicated to facilitate therapeutic management of cancer and TBK1-associated diseases in the future. • TBK1 is linked with activating mTOR/Akt and S6K signaling and stimulates cancer growth and survival. • TBK1 is considered an attractive drug target for the development of anticancer therapy. • The present study summarizes the molecular mechanisms of TBK1-signaling in cancer development. • Several potent and selective TBK1-inhibitors are showing great anticancer potential. [ABSTRACT FROM AUTHOR]

Polycystin-1 (PC1) is an important unusual G protein-coupled receptor (GPCR) with 11 transmembrane domains, and its mutations account for 85% of cases of autosomal dominant polycystic kidney disease (ADPKD). PC1 shares multiple characteristics with Adhesion GPCRs. These include a GPCR proteolysis site that autocatalytically divides these proteins into extracellular, N-terminal, and membrane-embedded, C-terminal fragments (CTF), and a tethered agonist (TA) within the N-terminal stalk of the CTF that is suggested to activate signaling. However, the mechanism by which a TA can activate PC1 is not known. Here, we have combined functional cellular signaling experiments of PC1 CTF expression constructs encoding wild type, stalkless, and three different ADPKD stalk variants with all-atom Gaussian accelerated molecular dynamics (GaMD) simulations to investigate TA-mediated signaling activation. Correlations of residue motions and free-energy profiles calculated from the GaMD simulations correlated with the differential signaling abilities of wild type and stalk variants of PC1 CTF. They suggested an allosteric mechanism involving residue interactions connecting the stalk, Tetragonal Opening for Polycystins (TOP) domain, and putative pore loop in TA-mediated activation of PC1 CTF. Key interacting residues such as N3074–S3585 and R3848–E4078 predicted from the GaMD simulations were validated by mutagenesis experiments. Together, these complementary analyses have provided insights into a TA-mediated activation mechanism of PC1 CTF signaling, which will be important for future rational drug design targeting PC1. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC), a leading cause of cancer-related mortalities globally, results from the accumulation of multiple genetic and epigenetic alterations in the normal colonic and rectum epithelium, leading to the progression from colorectal adenomas to invasive carcinomas. Almost half of CRC patients will develop metastases in the course of the disease and most patients with metastatic CRC are incurable. Particularly, the 5-year survival rate of patients with stage 4 CRC at diagnosis is less than 10%. Although genetic understanding of these CRC tumors and paired metastases has led to major advances in elucidating early driver genes responsible for carcinogenesis and metastasis, the pathophysiological contribution of transcriptional and epigenetic aberrations in this malignancy which influence many central signaling pathways have attracted attention recently. Therefore, treatments that could affect several different molecular pathways may have pivotal implications for their efficacy. In this review, we summarize our current knowledge on the molecular network of CRC, including cellular signaling pathways, CRC microenvironment modulation, epigenetic changes, and CRC biomarkers for diagnosis and predictive/prognostic use. We also provide an overview of opportunities for the treatment and prevention strategies in this field. [ABSTRACT FROM AUTHOR]

The ATP synthase is an essential multifunctional enzyme complex of mitochondria that produces most of cellular ATP, shapes the structure of the inner membrane into cristae and regulates the signals that control cell fate or demise. The ATPase Inhibitory Factor 1 (IF1) functions in vivo as a physiological regulator of the ATP synthase and thereby controls mitochondrial structure and function, and the retrograde signaling pathways that reprogram nuclear gene expression. However, IF1 is not ubiquitously expressed in mammals, showing tissue-restricted expression in humans and mice and large expression differences between the two species in some tissues. Herein, we summarized key regulatory functions of IF1 for tissue homeostasis, with special emphasis on the deleterious effects that its genetic ablation in neurons has in learning. The development and characterization of tissue-specific mouse models with regulated expression of IF1 will be crucial to disentangle the contribution of the ATP synthase/IF1 axis in pathophysiology. [ABSTRACT FROM AUTHOR]

Systematic interrogation of correlative signaling components in their native environment is of great interest for dissecting sophisticated cellular signaling. However, it remains a challenge because of the lack of versatile and effective approaches. Herein, we propose a cell membrane‐anchored DNA multitasking processor acting as a "traffic light" for integrated analyses of cellular signal transduction. Enhanced and controllable inhibition of c‐Met signaling was achieved by membrane‐anchoring of DNA processors. Moreover, the multitasking capability of the DNA processor allowed the monitoring of correlative VEGF secretion induced by c‐Met activity regulation directly. By exploiting versatile aptameric nucleic acids, this modular designed DNA multitasking processor dissected how cell surface receptors coordinated with related components in live cells systematically. Therefore, it provides a powerful chemical tool for both fundamental cell biology research and precision medicine applications. [ABSTRACT FROM AUTHOR]

Vertebrates have an elaborate and functionally segmented body. It evolves from a single cell by systematic cell proliferation but attains a complex body structure with exquisite precision. This development requires two cellular events: cell cycle and ciliogenesis. For these events, the dynamic molecular signaling is converged at the centriole. The cell cycle helps in cell proliferation and growth of the body and is a highly regulated and integrated process. Its errors cause malignancies and developmental disorders. The cells newly proliferated are organized during organogenesis. For a cellular organization, dedicated signaling hubs are developed in the cells, and most often cilia are utilized. The cilium is generated from one of the centrioles involved in cell proliferation. The developmental signaling pathways hosted in cilia are essential for the elaboration of the body plan. The cilium's compartmental seclusion is ideal for noise-free molecular signaling and is essential for the precision of the body layout. The dysfunctional centrioles and primary cilia distort the development of body layout that manifest as serious developmental disorders. Thus, centriole has a dual role in the growth and cellular organization. It organizes dynamically expressed molecules of cell cycle and ciliogenesis and plays a balancing act to generate new cells and organize them during development. A putative master molecule may regulate and co-ordinate the dynamic gene expression at the centrioles. The convergence of many critical signaling components at the centriole reiterates the idea that centriole is a major molecular workstation involved in elaborating the structural design and complexity in vertebrates. [ABSTRACT FROM AUTHOR]

We leveraged variable-temperature 19F-NMR spectroscopy to compare the conformational equilibria of the human A 2A adenosine receptor (A 2A AR), a class A G protein-coupled receptor (GPCR), across a range of temperatures ranging from lower temperatures typically employed in 19F-NMR experiments to physiological temperature. A 2A AR complexes with partial agonists and full agonists showed large increases in the population of a fully active conformation with increasing temperature. NMR data measured at physiological temperature were more in line with functional data. This was pronounced for complexes with partial agonists, where the population of active A 2A AR was nearly undetectable at lower temperature but became evident at physiological temperature. Temperature-dependent behavior of complexes with either full or partial agonists exhibited a pronounced sensitivity to the specific membrane mimetic employed. Cellular signaling experiments correlated with the temperature-dependent conformational equilibria of A 2A AR in lipid nanodiscs but not in some detergents, underscoring the importance of the membrane environment in studies of GPCR function. [Display omitted] • Active A 2A AR population increases with increasing temperature in lipid nanodiscs • Active A 2A AR population exhibits different temperature dependence in detergents • Partial agonist complexes present a unique conformational state in nanodiscs • Temperature dependence of partial agonist equilibria depends on membrane mimetic Thakur and Ray et al. use 19F-NMR to compare the conformational equilibria of the A 2A adenosine receptor across different temperatures and with different membrane mimetics. They show that NMR data measured in lipid nanodiscs at physiological temperature correlate with signaling assays whereas data from detergent preparations does not. [ABSTRACT FROM AUTHOR]

Objectives: Some organisms are long-lived and naturally resistant to cancer such as naked mole-rats (NMRs). Studies have shown that these animals can better tolerate stress due to mechanisms, such as upregulation of antioxidant pathways and improved proteostasis. In the present study, we aimed to analyze the tolerance against stress and the cellular mechanisms related to the stress response in NMR cells comparative to mouse cells. Materials and methods: NMR and mouse fibroblasts were exposed to cellular stresses including H2O2 and/or NaNO3 and the viability of the cells were analyzed. In addition messanger RNA (mRNA) expression of antioxidant transcription factor Nuclear factor erythroid-derived 2-like 2 (Nrf2) and its target gene NAD(P)H quinone dehydrogenase 1 (NQO1) were determined by qRT-PCR and comprehensive analysis of stress-related gene expression was performed by RNA-Sequencing in fibroblasts and induced pluripotent stem cells (iPSC). Results: Surprisingly, NMR fibroblasts were found to be more sensitive than mouse cells to H2O2 and NaNO3. Furthermore, it was shown that fibroblasts and iPSCs mainly aren't identical in the expression pattern of cellular defense signaling and several factors are mainly downregulated in NMR iPSCs. Conclusions: Collectively, the data gained from the present study help to improve the understanding of evolved mechanisms that contribute to stress resistance, aging and cancer. [ABSTRACT FROM AUTHOR]

Inorganic nanoparticles (NPs) offer significant advantages to the biomedical field owing to their large surface area, controllable structures, diverse surface chemistry, and unique optical and physical properties. Researchers worldwide have shown that inorganic NPs and the released metal ions can act as therapeutic agents in targeted tissues or to cure various diseases without acute toxicity. In this progress report, the recent developments in inorganic NPs with different compositions directly used as therapeutics are discussed. First, the recent convergence of nanotechnology and biotechnology in biomedical applications as well as the unique functions, features, and advantages of inorganic NPs in biomedical applications are summarized. Thereafter, the biological effects of inorganic compositions in NPs which include balancing the intracellular redox environment, regulating the specific cellular signaling and cellular behaviors, and apoptosis are explained. In addition, the emerging therapeutic applications of inorganic NPs in various diseases are exemplified. Finally, the perspectives and challenges for overcoming the weaknesses of inorganic NPs as therapeutics are discussed. By carefully considering and investigating the biological effects of inorganic NPs and metal ions released from NPs, more promising inorganic NPs based therapeutic agents can be developed. [ABSTRACT FROM AUTHOR]

Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients' cells. [ABSTRACT FROM AUTHOR]

Interleukin-17 receptor D (IL17RD or IL-17RD) also known as Sef (similar expression to fibroblast growth factor), is a single pass transmembrane protein that is reported to regulate several signaling pathways. IL17RD was initially described as a feedback inhibitor of fibroblast growth factor (FGF) signaling during zebrafish and frog development. It was subsequently determined to regulate other receptor tyrosine kinase signaling cascades as well as several proinflammatory signaling pathways including Interleukin-17A (IL17A), Toll-like receptors (TLR) and Interleukin-1α (IL1α) in several vertebrate species including humans. This review will provide an overview of IL17RD regulation of signaling pathways and functions with emphasis on regulation of development and pathobiological conditions. We will also discuss gaps in our knowledge about IL17RD function to provide insight into opportunities for future investigation. 7AmP1ZEVoxegCaGBJnH-2X Video Abstract [ABSTRACT FROM AUTHOR]

Extracellular signaling molecules, among them the fibroblast growth factors (FGFs), enable cells to communicate with neighboring cells. Such signaling molecules that receive and transmit a signal require specific tyrosine kinase receptors located at the cell surface (fibroblast growth factor receptors, FGFRs). The binding of a signaling molecule to its specific receptor results in receptor dimerization and conformational changes in the cytoplasmic part of the receptor. The conformational changes lead to trans-autophosphorylation of the tyrosine kinase domains of the receptors and subsequently to induction of several downstream signaling pathways and expression of appropriate genes. The signaling pathways activated by FGFs control and coordinate cell behaviors such as cell division, migration, differentiation, and cell death. FGFs and their transmembrane receptors are widely distributed in different tissues and participate in fundamental processes during embryonic, fetal, and adult human life. The human FGF/FGFR family comprises 22 ligands and 4 high affinity receptors. In addition, FGFs bind to low affinity receptors, heparan sulfate proteoglycans at the cell surface. The availability of appropriate ligand/receptor pair, combined with the co-receptor, initiates signaling. Inappropriate FGF/FGFR signaling can cause skeletal disorders, primarily dwarfism, craniofacial malformation syndromes, mood disorders, metabolic disorders, and Kallman syndrome. In addition, aberrations in FGF/FGFR signaling have already been reported in several types of malignant diseases. Knowledge about the molecular mechanisms of FGF/FGFR activation and signaling is necessary to understand the basis of these diseases. [ABSTRACT FROM AUTHOR]

Budding yeast Saccharomyces cerevisiae survives in microenvironments utilizing networks of regulators and ATP‐binding cassette (ABC) transporters to circumvent toxins and a variety of drugs. Our understanding of transcriptional regulation of ABC transporters in yeast is mainly derived from the study of multidrug resistance protein networks. Over the past two decades, this research has not only expanded the role of transcriptional regulators in pleiotropic drug resistance (PDR) but evolved to include the role that regulators play in cellular signaling and environmental adaptation. Inspection of the gene networks of the transcriptional regulators and characterization of the ABC transporters has clarified that they also contribute to environmental adaptation by controlling plasma membrane composition, toxic‐metal sequestration, and oxidative stress adaptation. Additionally, ABC transporters and their regulators appear to be involved in cellular signaling for adaptation of S. cerevisiae populations to nutrient availability. In this review, we summarize the current understanding of the S. cerevisiae transcriptional regulatory networks and highlight recent work in other notable fungal organisms, underlining the expansion of the study of these gene networks across the kingdom fungi. [ABSTRACT FROM AUTHOR]

The cells of the immune system respond to a great variety of different signals that frequently reach them simultaneously. Computational models of signaling pathways and cellular behavior can help us explore the biochemical mechanisms at play during such responses, in particular when those models aim at incorporating molecular details of intracellular reaction networks. Such detailed models can encompass hypotheses about the interactions among molecular binding domains and how these interactions are modulated by, for instance, post-translational modifications, or steric constraints in multi-molecular complexes. In this way, the models become formal representations of mechanistic immunological hypotheses that can be tested through quantitative simulations. Due to the large number of parameters (molecular abundances, association-, dissociation-, and enzymatic transformation rates) the goal of simulating the models can, however, in many cases no longer be the fitting of particular parameter values. Rather, the simulations perform sweeps through parameter space to test whether a model can account for certain experimentally observed features when allowing the parameter values to vary within experimentally determined or physiologically reasonable ranges. We illustrate how this approach can be used to explore possible mechanisms of immunological pathway crosstalk. Probing the input-output behavior of mechanistic pathway models through systematic simulated variations of receptor stimuli will soon allow us to derive cell population behavior from single-cell models, thereby bridging a scale gap that currently still is frequently addressed through heuristic phenomenological multi-scale models. [ABSTRACT FROM AUTHOR]

• The concept for metabolic reprogramming is introduced. • This special issue centers carbohydrate-related metabolism and its reprogramming. • This special issue discusses it as a mechanism for cellular signaling. • Metabolic reprogramming is a promising target for treating human diseases. [ABSTRACT FROM AUTHOR]

Introduction: Gap junctions (GJs) represent the best known intercellular communication (IC) system and are membrane-spanning channels that facilitate intercellular communication by allowing small signaling molecules to pass from cell to cell. In this study, we constructed an amino terminus of human Cx43 (Cx43NT-GFP), verified the overexpression of Cx43-NT in HUVEC cells and explored the impact of gap junctions (GJs) on multiple myeloma (MM).Material and methods: The levels of phosphorylated Cx43(s368) and the change of MAPK pathway associated molecules (ERK1/2, JNK, p38, NFκB) were also investigated in our cell models. Cx43 mRNA and proteins were detected in both MM cell lines and mesenchymal stem cells (MSCs). Dye transfer assays demonstrated that gap junction intercellular communication (GJIC) occurring via Cx43 situated between MM and MSCs or MM and HUVECCx43NT is functional.Results: Our results present evidence for a channel-dependent modulator action of connexin 43 on the migratory activity of MM cells toward MSCs or HUVECCx43-N was higher than those of spontaneous migration (p < 0.05) and protection them from apoptosis in the presence of dexamethasone via cytokines secretion. In the meantime, the migration of MM cells involves an augmented response of p38 and JNK signaling pathway of carboxyl tail of the protein.Conclusions: Our data suggest that GJIC between MM and MSCs is one of the essential factors in tumor cell proliferation and drug sensitivity, and is implicated in MM pathogenesis. [ABSTRACT FROM AUTHOR]

Nanoparticles (NPs) possess unique physical and chemical properties that make them appropriate for various applications. The structural alteration of metallic NPs leads to different biological functions, specifically resulting in different potentials for the generation of reactive oxygen species (ROS). The amount of ROS produced by metallic NPs correlates with particle size, shape, surface area, and chemistry. ROS possess multiple functions in cellular biology, with ROS generation a key factor in metallic NP-induced toxicity, as well as modulation of cellular signaling involved in cell death, proliferation, and differentiation. In this review, we briefly explained NP classes and their biomedical applications and describe the sources and roles of ROS in NP-related biological functions in vitro and in vivo. Furthermore, we also described the roles of metal NP-induced ROS generation in stem cell biology. Although the roles of ROS in metallic NP-related biological functions requires further investigation, modulation and characterization of metallic NP-induced ROS production are promising in the application of metallic NPs in the areas of regenerative medicine and medical devices. [ABSTRACT FROM AUTHOR]

β-Catenin, the central molecule of canonical Wnt signaling pathway, has multiple binding partners and performs many roles in the cell. Apart from being a transcriptional activator, β-catenin acts as a crucial effector component of cadherin/catenin complex to physically interact with actin cytoskeleton along with α-catenin and E-cadherin for regulating cell-cell adhesion. Here, we have generated a library of β-catenin point and deletion mutants to delineate regions within β-catenin that are important for α-catenin-β-catenin interaction, nuclear localization, and transcriptional activity of β-catenin. We observed a unique mechanism for nuclear localization of β-catenin and its mutants and show that N-terminal exon-3 region and C-terminal domain of β-catenin are critical for this activity of β-catenin. Furthermore, we show HepG2 cells have high β-catenin mediated transcriptional activity due to the presence of an interstitial deletion at the N-terminal region of β-catenin. Due to this deletion mutant (hereupon called TM), GSK3β and HDAC inhibitors failed to show any impact whereas curcumin significantly inhibited β-catenin mediated transcriptional activity reiterating that TM is primarily responsible for the high transcriptional activity of HepG2 cells. Moreover, we show the recombinant TM does not physically interact with α-catenin, localizes predominantly in the nucleus, and has nearly two-fold higher transcriptional activity than the wildtype β-catenin. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinases ( MAPK) are broadly used regulators of cellular signaling. However, how these enzymes can be involved in such a broad spectrum of physiological functions is not understood. Systematic discovery of MAPK networks both experimentally and in silico has been hindered because MAPKs bind to other proteins with low affinity and mostly in less-characterized disordered regions. We used a structurally consistent model on kinase-docking motif interactions to facilitate the discovery of short functional sites in the structurally flexible and functionally under-explored part of the human proteome and applied experimental tools specifically tailored to detect low-affinity protein-protein interactions for their validation in vitro and in cell-based assays. The combined computational and experimental approach enabled the identification of many novel MAPK-docking motifs that were elusive for other large-scale protein-protein interaction screens. The analysis produced an extensive list of independently evolved linear binding motifs from a functionally diverse set of proteins. These all target, with characteristic binding specificity, an ancient protein interaction surface on evolutionarily related but physiologically clearly distinct three MAPKs ( JNK, ERK, and p38). This inventory of human protein kinase binding sites was compared with that of other organisms to examine how kinase-mediated partnerships evolved over time. The analysis suggests that most human MAPK-binding motifs are surprisingly new evolutionarily inventions and newly found links highlight (previously hidden) roles of MAPKs. We propose that short MAPK-binding stretches are created in disordered protein segments through a variety of ways and they represent a major resource for ancient signaling enzymes to acquire new regulatory roles. [ABSTRACT FROM AUTHOR]

Microfluidics offers precise and dynamic control of microenvironments for the study of temporal cellular responses. However, recent research focusing solely on either homocellular (single-cell, population) or heterocellular response may yield insufficient output, which possibly leads to partial comprehension about the underlying mechanisms of signaling events and corresponding cellular behaviors. Here, a universal microfluidic approach is developed for integrated analysis of temporal signaling and cell migration dynamics in multiple cellular contexts (single-cell, population and coculture). This approach allows to confine the desired number or mixture of specific cell sample types in a single device. Precise single cell seeding was achieved manually with bidirectional controllability. Coupled with time-lapse imaging, temporal cellular responses can be observed with single-cell resolution. Using NIH3T3 cells stably expressing signal transducer and activator of transcription 1/2 (STAT1/2) activity biosensors, temporal STAT1/2 activation and cell migration dynamics were explored in isolated single cells, populations and cocultures stimulated with temporal inputs, such as single-pulse and continuous signals of interferon γ (IFNγ) or lipopolysaccharide (LPS). We demonstrate distinct dynamic responses of fibroblasts in different cellular contexts. Our presented approach facilitates a multi-dimensional understanding of STAT signaling and corresponding migration behaviors. • A general microfluidic approach was developed to study temporal cellular responses in multiple cellular contexts in a single device. • Precise single cell seeding with bidirectional controllability was achieved manually. • The applicability of this approach was validated by exploring temporal STAT activation and cell migration dynamics. • Distinct STAT and migration dynamics were observed in stimulated fibroblasts between different cellular contexts. [ABSTRACT FROM AUTHOR]

Primary cilia are unique sensory organelles that coordinate cellular signaling networks in vertebrates. Inevitably, defects in the formation or function of primary cilia lead to imbalanced regulation of cellular processes that causes multisystemic disorders and diseases, commonly known as ciliopathies. Mounting evidence has demonstrated that primary cilia coordinate multiple activities that are required for cell migration, which, when they are aberrantly regulated, lead to defects in organogenesis and tissue repair, as well as metastasis of tumors. Here, we present an overview on how primary cilia may contribute to the regulation of the cellular signaling pathways that control cyclic processes in directional cell migration. [ABSTRACT FROM PUBLISHER]

Abstract: Chemical and electrical interaction within and between cells is well established. Just the opposite is true about cellular interactions via other physical fields. The most probable candidate for an other form of cellular interaction is the electromagnetic field. We review theories and experiments on how cells can generate and detect electromagnetic fields generally, and if the cell-generated electromagnetic field can mediate cellular interactions. We do not limit here ourselves to specialized electro-excitable cells. Rather we describe physical processes that are of a more general nature and probably present in almost every type of living cell. The spectral range included is broad; from kHz to the visible part of the electromagnetic spectrum. We show that there is a rather large number of theories on how cells can generate and detect electromagnetic fields and discuss experimental evidence on electromagnetic cellular interactions in the modern scientific literature. Although small, it is continuously accumulating. [Copyright &y& Elsevier]

The Notch pathway is a highly conserved and ubiquitous signaling system that functions in determining a diverse array of cell fates and regulates many cellular processes during embryonic development and throughout adulthood. Links to cancer, stroke and Alzheimer’s disease underscore the need to define the molecular basis of Notch activation. Notch signaling is induced through direct cell–cell interactions that promote receptor activation following engagement with a membrane-bound Delta, Serrate, Lag-2 (DSL) ligand on adjacent cells. Cells take on distinct fates because Notch signaling is consistently activated in only one of the two interacting cells, highlighting the importance of establishing and maintaining signaling polarity. Studies in flies and worms have identified positive and negative transcriptional feedback mechanisms that amplify small differences in Notch and DSL ligand expression to bias which cells send or receive signals. However, endocytosis by signal-sending and signal-receiving cells also appears critical for directing and regulating Notch activation. In particular, endocytosis and membrane trafficking of DSL ligands, Notch and modulators can determine the competence of cells to send or receive signals that ensure reproducibility in generating cell types regulated by Notch signaling. [ABSTRACT FROM AUTHOR]

Lipid composition in cellular membranes plays an important role in maintaining the structural integrity of cells and in regulating cellular signaling that controls functions of both membrane-anchored and cytoplasmic proteins. ATP-dependent ABC and P4-ATPase lipid transporters, two integral membrane proteins, are known to contribute to lipid translocation across the lipid bilayers on the cellular membranes. In this review, we will highlight current knowledge about the role of cholesterol and phospholipids of cellular membranes in regulating cell signaling and how lipid transporters participate this process. [ABSTRACT FROM AUTHOR]

Main forms of cellular signal transmission are known to be autocrine and paracrine signaling. Several cells secrete messengers called autocrine or paracrine agents that can bind the corresponding receptors on the surface of the cells themselves or their microenvironment. Follistatin and follistatin-like proteins can be called one of the most important bifunctional messengers capable of displaying both autocrine and paracrine activity. Whilst they are not as diverse as protein hormones or protein kinases, there are only five types of proteins. However, unlike protein kinases, there are no minor proteins among them; each follistatin-like protein performs an important physiological function. These proteins are involved in a variety of signaling pathways and biological processes, having the ability to bind to receptors such as DIP2A, TLR4, BMP and some others. The activation or experimentally induced knockout of the protein-coding genes often leads to fatal consequences for individual cells and the whole body as follistatin-like proteins indirectly regulate the cell cycle, tissue differentiation, metabolic pathways, and participate in the transmission chains of the pro-inflammatory intracellular signal. Abnormal course of these processes can cause the development of oncology or apoptosis, programmed cell death. There is still no comprehensive understanding of the spectrum of mechanisms of action of follistatin-like proteins, so the systematization and study of their cellular functions and regulation is an important direction of modern molecular and cell biology. Therefore, this review focuses on follistatin-related proteins that affect multiple targets and have direct or indirect effects on cellular signaling pathways, as well as to characterize the directions of their practical application in the field of biomedicine. [ABSTRACT FROM AUTHOR]

Drought is a severe and complex abiotic stress that negatively affects plant growth and crop yields. Numerous genes with various functions are induced in response to drought stress to acquire drought stress tolerance. The phytohormone abscisic acid (ABA) accumulates mainly in the leaves in response to drought stress and then activates subclass III SNF1-related protein kinases 2 (SnRK2s), which are key phosphoregulators of ABA signaling. ABA mediates a wide variety of gene expression processes through stress-responsive transcription factors, including ABA-RESPONSIVE ELEMENT BINDING PROTEINS (AREBs)/ABRE-BINDING FACTORS (ABFs) and several other transcription factors. Seed plants have another type of SnRK2s, ABA-unresponsive subclass I SnRK2s, that mediates the stability of gene expression through the mRNA decay pathway and plant growth under drought stress in an ABA-independent manner. Recent research has elucidated the upstream regulators of SnRK2s, RAF-like protein kinases, involved in early responses to drought stress. ABA-independent transcriptional regulatory systems and ABA-responsive regulation function in drought-responsive gene expression. DEHYDRATION RESPONSIVE ELEMENT (DRE) is an important cis-acting element in ABA-independent transcription, whereas ABA-RESPONSIVE ELEMENT (ABRE) cis-acting element functions in ABA-responsive transcription. In this review article, we summarize recent advances in research on cellular and molecular drought stress responses and focus on phosphorylation signaling and transcription networks in Arabidopsis and crops. We also highlight gene networks of transcriptional regulation through two major regulatory pathways, ABA-dependent and ABA-independent pathways, that ABA-responsive subclass III SnRK2s and ABA-unresponsive subclass I SnRK2s mediate, respectively. We also discuss crosstalk in these regulatory systems under drought stress. [ABSTRACT FROM AUTHOR]

Abstract: We propose that nitric oxide participated as an extracellular and intracellular messenger in the early evolution of life. From a toxic and noxious substance it evolved into an important material for cellular communication and regulation with unique chemistry and properties. The presence of some nitric oxide complexes in extraterrestrial samples may support evidence for life forms in the past or present. Although nitric oxide probably participated in the evolution and maintenance of life, if pollution continues at an ever-increasing rate, it could also end life on the planet as we know it today. [Copyright &y& Elsevier]

Organelles of the endomembrane system maintain their identity and integrity during growth or stress conditions by homeostatic mechanisms that regulate membrane flux and biogenesis. At lysosomes and endosomes, the Fab1 lipid kinase complex and the nutrient-regulated target of rapamycin complex 1 (TORC1) control the integrity of the endolysosomal homeostasis and cellular metabolism. Both complexes are functionally connected as Fab1-dependent generation of PI(3,5)P 2 supports TORC1 activity. Here, we identify Fab1 as a target of TORC1 on signaling endosomes, which are distinct from multivesicular bodies, and provide mechanistic insight into their crosstalk. Accordingly, TORC1 can phosphorylate Fab1 proximal to its PI3P-interacting FYVE domain, which causes Fab1 to shift to signaling endosomes, where it generates PI(3,5)P 2. This, in turn, regulates (1) vacuole morphology, (2) recruitment of TORC1 and the TORC1-regulatory Rag GTPase-containing EGO complex to signaling endosomes, and (3) TORC1 activity. Thus, our study unravels a regulatory feedback loop between TORC1 and the Fab1 complex that controls signaling at endolysosomes. • The Fab1 lipid kinase is a substrate of the Target of Rapamycin Complex 1 (TORC1) • Fab1 and TORC1 localize to signaling endosomes and the vacuole • Fab1 phosphorylation shifts TORC1 to signaling endosomes and changes its activity • Fab1 and TORC1 function in a regulatory feedback loop, which controls signaling Chen, Malia, Hatakeyama, et al. demonstrate that the yeast Target of Rapamycin Complex 1 (TORC1) phosphorylates the lipid kinase Fab1, a homolog of metazoan PIKfyve. Fab1 phosphorylation shifts both complexes from the vacuole to signaling endosomes and changes TORC1 activity, suggesting a regulatory feedback loop in cellular signaling from these organelles. [ABSTRACT FROM AUTHOR]

• We identify multistability in a two-dimensional ODE macrophage polarization model. • Sensitivity and bifurcation analysis reveal the importance of intrinsic pathways. • We formulate hypotheses to guide the conduction of future laboratory experiments. In this paper, we present and analyze a mathematical model for polarization of a single macrophage which, despite its simplicity, exhibits complex dynamics in terms of multistability. In particular, we demonstrate that an asymmetry in the regulatory mechanisms and parameter values is important for observing multiple phenotypes. Bifurcation and sensitivity analyses show that external signaling cues are necessary for macrophage commitment and emergence to a phenotype, but that the intrinsic macrophage pathways are equally important. Based on our numerical results, we formulate hypotheses that could be further investigated by laboratory experiments to deepen our understanding of macrophage polarization. [ABSTRACT FROM AUTHOR]