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Introduction: NTRK-rearranged spindled cell tumors have been increasingly recognized with the widespread use of molecular studies. We describe a pediatric spindle cell neoplasm with MTAP-RAF1 gene fusion that fits into this group. Case report: An 8-year-old girl presented with mandibular mass. Histopathologically, it was a moderate to increased cellular spindle cell tumor with mild-to-moderate nuclear pleomorphism, focal perivascular keloid-like collagen, that was positive for S-100 and CD34. MTAP-RAF1 fusion was detected by next generation sequencing, confirming a low-grade sarcoma with MTAP-RAF1 fusion that is presently included in the category of NTRK-rearranged spindled cell tumors. Discussion: MTAP-RAF1 fusion, in the spectrum of spindle cell neoplasms with kinase gene rearrangements, can occur in the pediatric age group. [ABSTRACT FROM AUTHOR]

The vulnerabilities of cancer cells constitute a promising strategy for drug therapeutics. This paper integrates proteomics, bioinformatics, and cell genotype together with in vitro cell proliferation assays to identify key biological processes and potential novel kinases that could account, at least in part, for the clinical differences observed in colorectal cancer (CRC) patients. This study started by focusing on CRC cell lines stratified by their microsatellite (MS) state and p53 genotype. It shows that cell-cycle checkpoint, metabolism of proteins and RNA, signal transduction, and WNT signaling processes are significantly more active in MSI-High p53-WT cell lines. Conversely, MSI-High cell lines with a mutant (Mut) p53 gene showed hyperactivation of cell signaling, DNA repair, and immune-system processes. Several kinases were linked to these phenotypes, from which RIOK1 was selected for additional exploration. We also included the KRAS genotype in our analysis. Our results showed that RIOK1's inhibition in CRC MSI-High cell lines was dependent on both the p53 and KRAS genotypes. Explicitly, Nintedanib showed relatively low cytotoxicity in MSI-High with both mutant p53 and KRAS (HCT-15) but no inhibition in p53 and KRAS WT (SW48) MSI-High cells. This trend was flipped in CRC MSI-High bearing opposite p53-KRAS genotypes (e.g., p53-Mut KRAS-WT or p53-WT KRAS-Mut), where observed cytotoxicity was more extensive compared to the p53-KRAS WT-WT or Mut-Mut cells, with HCT 116 (KRAS-Mut and p53-WT) being the most sensitive to RIOK1 inhibition. These results highlight the potential of our in silico computational approach to identify novel kinases in CRC sub-MSI-High populations as well as the importance of clinical genomics in determining drug potency. [ABSTRACT FROM AUTHOR]

mTORC1 regulates mammalian cell metabolism and growth in response to diverse environmental stimuli. Nutrient signals control the localization of mTORC1 onto lysosome surface scaffolds that are critically implicated in its amino acid-dependent activation. Arginine, leucine and S-adenosyl-methionine (SAM) can serve as major mTORC1-signaling activators, with SAM binding to SAMTOR (SAM + TOR), a fundamental SAM sensor, preventing the protein's (SAMTOR's) inhibitory action(s) against mTORC1, thereby triggering its (mTORC1) kinase activity. Given the lack of knowledge regarding the role of SAMTOR in invertebrates, we have identified the Drosophila SAMTOR homologue (dSAMTOR) in silico and have, herein, genetically targeted it through the utilization of the GAL4/UAS transgenic tool. Survival profiles and negative geotaxis patterns were examined in both control and dSAMTOR-downregulated adult flies during aging. One of the two gene-targeted schemes resulted in lethal phenotypes, whereas the other one caused rather moderate pathologies in most tissues. The screening of head-specific kinase activities, via PamGene technology application, unveiled the significant upregulation of several kinases, including the dTORC1 characteristic substrate dp70S6K, in dSAMTOR-downregulated flies, thus strongly supporting the inhibitory dSAMTOR action(s) upon the dTORC1/dp70S6K signaling axis in Drosophila brain settings. Importantly, genetic targeting of the Drosophila BHMT bioinformatics counterpart (dBHMT), an enzyme that catabolizes betaine to produce methionine (the SAM precursor), led to severe compromises in terms of fly longevity, with glia-, motor neuron- and muscle-specific dBHMT downregulations exhibiting the strongest effects. Abnormalities in wing vein architectures were also detected in dBHMT-targeted flies, thereby justifying their notably reduced negative geotaxis capacities herein observed mainly in the brain–(mid)gut axis. In vivo adult fly exposure to clinically relevant doses of methionine revealed the mechanistic synergism of decreased dSAMTOR and increased methionine levels in pathogenic longevity, thus rendering (d)SAMTOR an important component in methionine-associated disorders, including homocystinuria(s). [ABSTRACT FROM AUTHOR]

Cancer continues to be one of the leading causes of death worldwide, with an estimated 28.4 million new cases expected by 2040. Despite the efforts to treat cancer, the current therapeutic options are limited to adjuvant and neoadjuvant chemotherapy with limited alternative therapies. The discovery of chromone scaffold compounds exhibiting promising anticancer activity has led to increased research and clinical trials in recent years. This review aims to provide an overview of the current progress and exciting developments in using chromone scaffold in cancer therapy through inhibiting key kinase pathways, including MAPK, PI3K/Akt/mTOR, CDKs and DNA-dependent protein kinase subunit. In addition, this review highlights the potential of chromone scaffold in the fight against cancer and provides insight into future directions for developing chromone-based therapies. [ABSTRACT FROM AUTHOR]

Background: Dynamic chromatin remodeling is associated with changes in the epigenetic pattern of histone acetylations and methylations required for processes based on dynamic chromatin remodeling and implicated in different nuclear functions. These histone epigenetic modifications need to be coordinated, a role that may be mediated by chromatin kinases such as VRK1, which phosphorylates histones H3 and H2A. Methods: The effect of VRK1 depletion and VRK1 inhibitor, VRK-IN-1, on the acetylation and methylation of histone H3 in K4, K9 and K27 was determined under different conditions, arrested or proliferating cells, in A549 lung adenocarcinoma and U2OS osteosarcoma cells. Results: Chromatin organization is determined by the phosphorylation pattern of histones mediated by different types of enzymes. We have studied how the VRK1 chromatin kinase can alter the epigenetic posttranslational modifications of histones by using siRNA, a specific inhibitor of this kinase (VRK-IN-1), and of histone acetyl and methyl transferases, as well as histone deacetylase and demethylase. Loss of VRK1 implicated a switch in the state of H3K9 posttranslational modifications. VRK1 depletion/inhibition causes a loss of H3K9 acetylation and facilitates its methylation. This effect is similar to that of the KAT inhibitor C646, and to KDM inhibitors as iadademstat (ORY-1001) or JMJD2 inhibitor. Alternatively, HDAC inhibitors (selisistat, panobinostat, vorinostat) and KMT inhibitors (tazemetostat, chaetocin) have the opposite effect of VRK1 depletion or inhibition, and cause increase of H3K9ac and a decrease of H3K9me3. VRK1 stably interacts with members of these four enzyme families. However, VRK1 can only play a role on these epigenetic modifications by indirect mechanisms in which these epigenetic enzymes are likely targets to be regulated and coordinated by VRK1. Conclusions: The chromatin kinase VRK1 regulates the epigenetic patterns of histone H3 acetylation and methylation in lysines 4, 9 and 27. VRK1 is a master regulator of chromatin organization associated with its specific functions, such as transcription or DNA repair. [ABSTRACT FROM AUTHOR]

Protein phosphorylation is a ubiquitous post-translational modification controlled by the opposing activities of protein kinases and phosphatases, which regulate diverse biological processes in all kingdoms of life. One of the key challenges to a complete understanding of phosphoregulatory networks is the unambiguous identification of kinase and phosphatase substrates. Liquid chromatography-coupled mass spectrometry (LC-MS/MS) and associated phosphoproteomic tools enable global surveys of phosphoproteome changes in response to signaling events or perturbation of phosphoregulatory network components. Despite the power of LC-MS/MS, it is still challenging to directly link kinases and phosphatases to specific substrate phosphorylation sites in many experiments. Here, we survey common LC-MS/MS-based phosphoproteomic workflows for identifying protein kinase and phosphatase substrates, noting key advantages and limitations of each. We conclude by discussing the value of inducible degradation technologies coupled with phosphoproteomics as a new approach that overcomes some limitations of current methods for substrate identification of kinases, phosphatases, and other regulatory enzymes. [ABSTRACT FROM AUTHOR]

The residence time of a protein–ligand complex (the inverse of the dissociation rate constant) can be better correlated with drug efficacy in vivo , compared with equilibrium descriptors. Different computational methods, including enhanced sampling in simulations and machine learning, were developed and applied in recent years to efficiently and accurately predict kinetic rates for one protein–ligand complex or for datasets containing many complexes. Accurate estimates of absolute kinetic rates can be achieved with less than 1 μs of simulation time. Enhanced sampling simulations can provide mechanistic insights about selectivity and drug resistance in kinases. Insufficient sampling, and the choice of force field, enhanced sampling method, or experimental reference can lead to high errors in the predicted kinetic rates. Binding kinetic parameters can be correlated with drug efficacy, which in recent years led to the development of various computational methods for predicting binding kinetic rates and gaining insight into protein–drug binding paths and mechanisms. In this review, we introduce and compare computational methods recently developed and applied to two systems, trypsin–benzamidine and kinase–inhibitor complexes. Methods involving enhanced sampling in molecular dynamics simulations or machine learning can be used not only to predict kinetic rates, but also to reveal factors modulating the duration of residence times, selectivity, and drug resistance to mutations. Methods which require less computational time to make predictions are highlighted, and suggestions to reduce the error of computed kinetic rates are presented. [ABSTRACT FROM AUTHOR]

Death‐associated protein kinase‐related apoptosis‐inducing protein kinase 2 (DRAK2) has become a promising target for drug development. In search of novel and selective DRAK2 inhibitor motif, in vitro screen kinase assay was established performed using in‐house chemical libraries. After through hit triage procedure, N2‐(3,5‐dichlorophenyl)‐5‐fluoro‐N4‐methylpyrimidine‐2,4‐diamine (1) was selected as initial hit with structural novelty and drug‐likeness. During hit validation, structure–activity relationship of 1 was thoroughly disclosed and TRD‐93 was finally validated as hit for DRAK2 inhibition. TRD‐93 is small (mw = 290) but selectively potent to DRAK2 (IC50 = 0.16 μM) over other kinases including DAPK family kinases. Molecular binding model study of TRD‐93 to DRAK2 is also discussed. [ABSTRACT FROM AUTHOR]

Transmembrane semaphorins are signaling molecules, controlling axonal wiring and embryo development, which are increasingly implicated in human diseases. Semaphorin 6C (Sema6C) is a poorly understood family member and its functional role is still unclear. Upon targeting Sema6C expression in a range of cancer cells, we observed dramatic growth suppression, decreased ERK phosphorylation, upregulation of cell cycle inhibitor proteins p21, p27 and p53, and the onset of cell senescence, associated with activation of autophagy. These data are consistent with a fundamental requirement for Sema6C to support viability and growth in cancer cells. Mechanistically, we unveiled a novel signaling pathway elicited by Sema6C, and dependent on its intracellular domain, mediated by tyrosine kinases c-Abl and Focal Adhesion Kinase (FAK). Sema6C was found in complex with c-Abl, and induced its phosphorylation, which in turn led to FAK activation, independent of cell–matrix adhesion. Sema6C-induced FAK activity was furthermore responsible for increased nuclear localization of YAP transcriptional regulator. Moreover, Sema6C conferred YAP signaling-dependent long-term cancer cell survival upon nutrient deprivation. In conclusion, our findings demonstrate that Sema6C elicits a cancer promoting-signaling pathway sustaining cell viability and self-renewal, independent of growth factors and nutrients availability. [ABSTRACT FROM AUTHOR]

In humans, more than 500 kinases phosphorylate ~15% of all proteins in an emerging phosphorylation network. Convergent local interaction motifs, in which ≥two kinases phosphorylate the same substrate, underlie feedback loops and signal amplification events but have not been systematically analyzed. Here, we first report a network‐wide computational analysis of convergent kinase‐substrate relationships (cKSRs). In experimentally validated phosphorylation sites, we find that cKSRs are common and involve >80% of all human kinases and >24% of all substrates. We show that cKSRs occur over a wide range of stoichiometries, in many instances harnessing co‐expressed kinases from family subgroups. We then experimentally demonstrate for the prototypical convergent CDK4/6 kinase pair how multiple inputs phosphorylate the tumor suppressor retinoblastoma protein (RB) and thereby hamper in situ analysis of the individual kinases. We hypothesize that overexpression of one kinase combined with a CDK4/6 inhibitor can dissect convergence. In breast cancer cells expressing high levels of CDK4, we confirm this hypothesis and develop a high‐throughput compatible assay that quantifies genetically modified CDK6 variants and inhibitors. Collectively, our work reveals the occurrence, topology, and experimental dissection of convergent interactions toward a deeper understanding of kinase networks and functions. [ABSTRACT FROM AUTHOR]

Although Fischer's extraordinary career came to focus mostly on the protein phosphatases, after his co‐discovery of Phosphorylase Kinase with Ed Krebs he was clearly intrigued not only by cAMP‐dependent protein kinase (PKA), but also by the heat‐stable, high‐affinity protein kinase inhibitor (PKI). PKI is an intrinsically disordered protein that contains at its N‐terminus a pseudo‐substrate motif that binds synergistically and with high‐affinity to the PKA catalytic (C) subunit. The sequencing and characterization of this inhibitor peptide (IP20) were validated by the structure of the PKA C‐subunit solved first as a binary complex with IP20 and then as a ternary complex with ATP and two magnesium ions. A second motif, nuclear export signal (NES), was later discovered in PKI. Both motifs correspond to amphipathic helices that convey high‐affinity binding. The dynamic features of full‐length PKI, recently captured by NMR, confirmed that the IP20 motif becomes dynamically and sequentially ordered only in the presence of the C‐subunit. The type I PKA regulatory (R) subunits also contain a pseudo‐substrate ATPMg2‐dependent high‐affinity inhibitor sequence. PKI and PKA, especially the Cβ subunit, are highly expressed in the brain, and PKI expression is also cell cycle‐dependent. In addition, PKI is now linked to several cancers. The full biological importance of PKI and PKA signaling in the brain, and their importance in cancer thus remains to be elucidated. [ABSTRACT FROM AUTHOR]

PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential antitarget of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target engagement assays to include PLK1, we developed an energy transfer probe based on the anilino-tetrahydropteridine chemotype found in several selective PLK inhibitors. Probe 11 was used to configure NanoBRET target engagement assays for PLK1, PLK2, and PLK3 and measure the potency of several known PLK inhibitors. In-cell target engagement for PLK1 was in good agreement with the reported cellular potency for the inhibition of cell proliferation. Probe 11 enabled the investigation of the promiscuity of adavosertib, which had been described as a dual PLK1/WEE1 inhibitor in biochemical assays. Live cell target engagement analysis of adavosertib via NanoBRET demonstrated PLK activity at micromolar concentrations but only selective engagement of WEE1 at clinically relevant doses. [ABSTRACT FROM AUTHOR]

Simple Summary: Kinases are biomolecules that control cellular reactions essential for life. Disruptions in kinase expression and activity lead to the development of diseases such as cancer. A great deal of funding and scientific effort has been poured into kinase research, leading to great advancement. For example, a groundbreaking discovery was the development of imatinib, a kinase inhibitor, for the treatment of CML. Despite these discoveries, a large portion of the human kinome remains understudied. This review seeks to address this issue by discussing the understudied NEK family of kinases. We do this by discussing existing studies, analyzing correlations between the expression of NEK genes and patient survival outcomes in different cancers, discussing NEK mutations found in different cancer tissue types, and covering potential funding opportunities for those interested in pursuing NEK research. The Never in Mitosis Gene A (NIMA)–related kinases (NEKs) are a group of serine/threonine kinases that are involved in a wide array of cellular processes including cell cycle regulation, DNA damage repair response (DDR), apoptosis, and microtubule organization. Recent studies have identified the involvement of NEK family members in various diseases such as autoimmune disorders, malignancies, and developmental defects. Despite the existing literature exemplifying the importance of the NEK family of kinases, this family of protein kinases remains understudied. This report seeks to provide a foundation for investigating the role of different NEKs in malignancies. We do this by evaluating the 11 NEK family kinase gene expression associations with patients' overall survival (OS) from various cancers using the Kaplan–Meier Online Tool (KMPlotter) to correlate the relationship between mRNA expression of NEK1-11 in various cancers and patient survival. Furthermore, we use the Catalog of Somatic Mutations in Cancer (COSMIC) database to identify NEK family mutations in cancers of different tissues. Overall, the data suggest that the NEK family has varying associations with patient survival in different cancers with tumor-suppressive and tumor-promoting effects being tissue-dependent. [ABSTRACT FROM AUTHOR]

Covalent modifications of chromatin regulate genomic structure and accessibility in diverse biological processes such as transcriptional regulation, cell cycle progression, and DNA damage repair. Many histone modifications have been characterized, yet understanding the interactions between these and their combinatorial effects remains an active area of investigation, including dissecting functional interactions between enzymes mediating these modifications. In budding yeast, the histone acetyltransferase Gcn5 interacts with Rts1, a regulatory subunit of protein phosphatase 2A (PP2A). Implicated in the interaction is the potential for the dynamic phosphorylation of conserved residues on histone H2B and the Cse4 centromere-specific histone H3 variant. To probe these dynamics, we sought to identify kinases which contribute to the phosphorylated state. In a directed screen beginning with in silico analysis of the 127 members of yeast kinome, we have now identified 16 kinases with genetic interactions with GCN5 and specifically found distinct roles for the Hog1 stress-activated protein kinase. Deletion of HOG1 (hog1Δ) rescues gcn5Δ sensitivity to the microtubule poison nocodazole and the lethality of the gcn5Δ rts1Δ double mutant. The Hog1-Gcn5 interaction requires the conserved H2B-T91 residue, which is phosphorylated in vertebrate species. Furthermore, deletion of HOG1 decreases aneuploidy and apoptotic populations in gcn5Δ cells. Together, these results introduce Hog1 as a kinase that functionally opposes Gcn5 and Rts1 in the context of the spindle assembly checkpoint and suggest further kinases may also influence GCN5's functions. [ABSTRACT FROM AUTHOR]

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson's disease. LRRK2 is a multi-domain protein containing a kinase and GTPase. Using correlative light and electron microscopy, in situ cryo-electron tomography, and subtomogram analysis, we reveal a 14-Å structure of LRRK2 bearing a pathogenic mutation that oligomerizes as a right-handed double helix around microtubules, which are left-handed. Using integrative modeling, we determine the architecture of LRRK2, showing that the GTPase and kinase are in close proximity, with the GTPase closer to the microtubule surface, whereas the kinase is exposed to the cytoplasm. We identify two oligomerization interfaces mediated by non-catalytic domains. Mutation of one of these abolishes LRRK2 microtubule-association. Our work demonstrates the power of cryo-electron tomography to generate models of previously unsolved structures in their cellular environment.

Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, suppresses SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.

Apicomplexan parasites use a specialized cilium structure called the apical complex to organize their secretory organelles and invasion machinery. The apical complex is integrally associated with both the parasite plasma membrane and an intermediate filament cytoskeleton called the inner-membrane complex (IMC). While the apical complex is essential to the parasitic lifestyle, little is known about the regulation of apical complex biogenesis. Here, we identify AC9 (apical cap protein 9), a largely intrinsically disordered component of the Toxoplasma gondii IMC, as essential for apical complex development, and therefore for host cell invasion and egress. Parasites lacking AC9 fail to successfully assemble the tubulin-rich core of their apical complex, called the conoid. We use proximity biotinylation to identify the AC9 interaction network, which includes the kinase extracellular signal-regulated kinase 7 (ERK7). Like AC9, ERK7 is required for apical complex biogenesis. We demonstrate that AC9 directly binds ERK7 through a conserved C-terminal motif and that this interaction is essential for ERK7 localization and function at the apical cap. The crystal structure of the ERK7-AC9 complex reveals that AC9 is not only a scaffold but also inhibits ERK7 through an unusual set of contacts that displaces nucleotide from the kinase active site. ERK7 is an ancient and autoactivating member of the mitogen-activated kinase (MAPK) family and its regulation is poorly understood in all organisms. We propose that AC9 dually regulates ERK7 by scaffolding and concentrating it at its site of action while maintaining it in an "off" state until the specific binding of a true substrate.

Neuroblastoma is the most common extracranial solid tumor in childhood. Gain of chromosome 17q material is found in >60% of neuroblastoma tumors and is associated with poor patient prognosis. The NME1 gene is located in the 17q21.3 region, and high NME1 expression is correlated with poor neuroblastoma patient outcomes. However, the functional roles and signaling activity of NME1 in neuroblastoma cells and tumors are unknown. NME1 and NME2 have been shown to possess histidine (His) kinase activity. Using anti-1- and 3-pHis specific monoclonal antibodies and polyclonal anti-pH118 NME1/2 antibodies, we demonstrated the presence of pH118-NME1/2 and multiple additional pHis-containing proteins in all tested neuroblastoma cell lines and in xenograft neuroblastoma tumors, supporting the presence of histidine kinase activity in neuroblastoma cells and demonstrating the potential significance of histidine kinase signaling in neuroblastoma pathogenesis. We have also demonstrated associations between NME1 expression and neuroblastoma cell migration and differentiation. Our demonstration of NME1 histidine phosphorylation in neuroblastoma and of the potential role of NME1 in neuroblastoma cell migration and differentiation suggest a functional role for NME1 in neuroblastoma pathogenesis and open the possibility of identifying new therapeutic targets and developing novel approaches to neuroblastoma therapy.

Small molecules binding at any of the multiple regulatory sites on the molecular surface of a protein kinase may stabilize or disrupt the corresponding interaction, leading to consequent modulation of the kinase cellular activity. As such, each of these sites represents a potential drug target. Even targeting sites outside the immediate ATP site, the so-called exosites, may cause desirable biological effects through an allosteric mechanism. Targeting exosites can alleviate adverse effects and toxicity that is common when ATP-site compounds bind promiscuously to many other types of kinases. In this study we have identified, catalogued, and annotated all potentially druggable exosites on the protein kinase domains within the existing structural human kinome. We then priority-ranked these exosites by those most amenable to drug design. In order to identify pockets that are either consistent across the kinome, or unique and specific to a particular structure, we have also implemented a normalized representation of all pockets, and displayed these graphically. Finally, we have built a database and designed a web-based interface for users interested in accessing the 3-dimensional representations of these pockets. We envision this information will assist drug discovery efforts searching for untargeted binding pockets in the human kinome.

Striated myocytes compose about half of the cells of the heart, while contributing the majority of the heart's mass and volume. In response to increased demands for pumping power, including in diseases of pressure and volume overload, the contractile myocytes undergo non-mitotic growth, resulting in increased heart mass, i.e. cardiac hypertrophy. Myocyte hypertrophy is induced by a change in the gene expression program driven by the altered activity of transcription factors and co-repressor and co-activator chromatin-associated proteins. These gene regulatory proteins are subject to diverse post-translational modifications and serve as nuclear effectors for intracellular signal transduction pathways, including those controlled by cyclic nucleotides and calcium ion. Scaffold proteins contribute to the underlying architecture of intracellular signaling networks by targeting signaling enzymes to discrete intracellular compartments, providing specificity to the regulation of downstream effectors, including those regulating gene expression. Muscle A-kinase anchoring protein β (mAKAPβ) is a well-characterized scaffold protein that contributes to the regulation of pathological cardiac hypertrophy. In this review, we discuss the mechanisms how this prototypical scaffold protein organizes signalosomes responsible for the regulation of class IIa histone deacetylases and cardiac transcription factors such as NFAT, MEF2, and HIF-1α, as well as how this signalosome represents a novel therapeutic target for the prevention or treatment of heart failure.

Persistent activity of protein kinase M (PKM), the truncated form of protein kinase C (PKC), can maintain long-term changes in synaptic strength in many systems, including the hermaphrodite marine mollusk, Aplysia californica Moreover, different types of long-term facilitation (LTF) in cultured Aplysia sensorimotor synapses rely on the activities of different PKM isoforms in the presynaptic sensory neuron and postsynaptic motor neuron. When the atypical PKM isoform is required, the kidney and brain expressed adaptor protein (KIBRA) is also required. Here, we explore how this isoform specificity is established. We find that PKM overexpression in the motor neuron, but not the sensory neuron, is sufficient to increase synaptic strength and that this activity is not isoform-specific. KIBRA is not the rate-limiting step in facilitation since overexpression of KIBRA is neither sufficient to increase synaptic strength, nor to prolong a form of PKM-dependent intermediate synaptic facilitation. However, the isoform specificity of dominant-negative-PKMs to erase LTF is correlated with isoform-specific competition for stabilization by KIBRA. We identify a new conserved region of KIBRA. Different splice isoforms in this region stabilize different PKMs based on the isoform-specific sequence of an α-helix "handle" in the PKMs. Thus, specific stabilization of distinct PKMs by different isoforms of KIBRA can explain the isoform specificity of PKMs during LTF in Aplysia SIGNIFICANCE STATEMENT Long-lasting changes in synaptic plasticity associated with memory formation are maintained by persistent protein kinases. We have previously shown in the Aplysia sensorimotor model that distinct isoforms of persistently active protein kinase Cs (PKMs) maintain distinct forms of long-lasting synaptic changes, even when both forms are expressed in the same motor neuron. Here, we show that, while the effects of overexpression of PKMs are not isoform-specific, isoform specificity is defined by a "handle" helix in PKMs that confers stabilization by distinct splice forms in a previously undefined domain of the adaptor protein KIBRA. Thus, we define new regions in both KIBRA and PKMs that define the isoform specificity for maintaining synaptic strength in distinct facilitation paradigms.

BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation αC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions.

Introduction: Salinity is one of the unfavorable environmental factors for plants that affects their growth and fertility. Rice, as the second grain in the world after wheat, is a relatively sensitive plant to salt stress. Protein kinases are an important group of kinase enzymes that amino acids They phosphorylate a certain part in the protein structure. These enzymes play an important role in cell communication and inducing growth and proliferation messages. Therefore, the identification and evaluation of the function of protein kinase gene family genes in rice will help our understanding of the molecular mechanism of stress resistance.Materials and methods: Examining the expression pattern of SAPK2 gene in two rice varieties tolerant and sensitive to salinity in 1400 in the research greenhouse of the Faculty of Agriculture of Lorestan University was carried out as a factorial experiment in the form of a completely randomized design in three replications. Decisions per meter and time factor were investigated at three levels (6, 12 and 24 hours after applying stress). Sampling of plant leaves at the seedling stage (5-6 leaves) was done to check the expression of SAPK2 gene and internal control gene 18srRNA. took.Results: The results of the analysis of the gene expression pattern using Real Time PCR showed that there is no difference between the tolerant and sensitive cultivars at the salinity level of 3 ds/m and under no stress conditions, but at the levels of 6 and 9 ds/m with increasing time after applying the stress, the expression level The SAPK2 gene increases and the maximum expression of the gene was at the salinity level of 9 ds/m 24 hours after applying the stress. The level of gene expression at the salinity level of 9 in the tolerant variety was very significant compared to the sensitive variety. 12 and 24 hours after the application of stress, the gene expression in the tolerant variety was about 4 times more than the sensitive variety and 9 times more than the non-stressed condition. Also, the examination of the melting curve of SAPK2 gene in both tolerant and sensitive cultivars showed that the melting temperature is about 81 degrees Celsius.Conclusion: With increasing salinity level, the expression level of SAPK1 gene increases in rice plants. Also, investigating the effect of time after applying stress on the level of SAPK1 gene expression showed that in the early hours after applying stress, the level of gene expression was insignificant, but with increasing time up to 24 hours, gene expression increased.

Current research has shown that several imidazolium and chlorinated bispyridinium oximes are cytotoxic and activate different mechanisms or types of cell death. To investigate this further, we analysed interactions between these oximes and acetylcholine receptors (AChRs) and how they affect several signalling pathways to find a relation between the observed toxicities and their effects on these specific targets. Chlorinated bispyridinium oximes caused time-dependent cytotoxicity by inhibiting the phosphorylation of STAT3 and AMPK without decreasing ATP and activated ERK1/2 and p38 MAPK signal cascades. Imidazolium oximes induced a time-independent and significant decrease in ATP and inhibition of the ERK1/2 signalling pathway along with phosphorylation of p38 MAPK, AMPK, and ACC. These pathways are usually triggered by a change in cellular energy status or by external signals, which suggests that oximes interact with some membrane receptors. Interestingly, in silico analysis also indicated that the highest probability of interaction for all of our oximes is with the family of G-coupled membrane receptors (GPCR). Furthermore, our experimental results showed that the tested oximes acted as acetylcholine antagonists for membrane AChRs. Even though oxime interactions with membrane receptors need further research and clarification, our findings suggest that these oximes make promising candidates for the development of specific therapies not only in the field of cholinesterase research but in other fields too, such as anticancer therapy via altering the Ca2+ flux involved in cancer progression.

Abstract Specific members of the Nima-Related Kinase (NEK) family have been linked to cancer development and progression, and a role for NEK5, one of the least studied members, in breast cancer has recently been proposed. However, while NEK5 is known to regulate centrosome separation and mitotic spindle assembly, NEK5 signalling mechanisms and function in this malignancy require further characterization. To this end, we established a model system featuring overexpression of NEK5 in the immortalized breast epithelial cell line MCF-10A. MCF-10A cells overexpressing NEK5 exhibited an increase in clonogenicity under monolayer conditions and enhanced acinar size and abnormal morphology in 3D Matrigel culture. Interestingly, they also exhibited a marked reduction in Src activation and downstream signalling. To interrogate NEK5 signalling and function in an unbiased manner, we applied a variety of MS-based proteomic approaches. Determination of the NEK5 interactome by Bio-ID identified a variety of protein classes including the kinesins KIF2C and KIF22, the mitochondrial proteins TFAM, TFB2M and MFN2, RhoH effectors and the negative regulator of Src, CSK. Characterization of proteins and phosphosites modulated upon NEK5 overexpression by global MS-based (phospho)proteomic profiling revealed impact on the cell cycle, DNA synthesis and repair, Rho GTPase signalling, the microtubule cytoskeleton and hemidesmosome assembly. Overall, the study indicates that NEK5 impacts diverse pathways and processes in breast epithelial cells, and likely plays a multifaceted role in breast cancer development and progression. Video Abstract

Shikimate kinase (SK) enzyme is a suitable target for antimicrobial drugs as it is present in pathogenic microorganisms and absent in mammals. A complete understanding of the functioning of this enzyme can unveil novel methods to inactivate it. To do this, a clear understanding of SK performance is needed. Previously, the chemical step of SK was studied in detail, but a study of longer-term scale simulations is still missing. In the present work, we performed molecular dynamics (MD) simulations in the μs time scale that allowed us to explore further regions of the SK energy landscape than previously. Simulations were conducted on the wild-type (WT) enzyme and the R116A and R116K mutants. We analyzed the dynamics of the enzymes through standard MD tools, and we found that the global motions in the mutants were perturbed. These motions can be linked to the observed undetectable binding affinity of the WT enzyme and the R116A and R116K mutants.

Unveiling the principles governing embryonic stem cell (ESC) differentiation into specific lineages is critical for understanding embryonic development and for stem cell applications in regenerative medicine. Here, we establish an intersection between LIF‐Stat3 signaling that is essential for maintaining murine (m) ESCs pluripotency, and the glycolytic enzyme, the platelet isoform of phosphofructokinase (Pfkp). In the pluripotent state, Stat3 transcriptionally suppresses Pfkp in mESCs while manipulating the cells to lift this repression results in differentiation towards the ectodermal lineage. Pfkp exhibits substrate specificity changes to act as a protein kinase, catalyzing serine phosphorylation of the developmental regulator Lin41. Such phosphorylation stabilizes Lin41 by impeding its autoubiquitination and proteasomal degradation, permitting Lin41‐mediated binding and destabilization of mRNAs encoding ectodermal specification markers to favor the expression of endodermal specification genes. This provides new insights into the wiring of pluripotency‐differentiation circuitry where Pfkp plays a role in germ layer specification during mESC differentiation. Synopsis: Pfkp has a non‐glycolytic activity in mESC differentiation, where it catalyzes Lin41 phosphorylation, protecting Lin41 from proteasomal destruction. In turn, Lin41 promotes endodermal differentiation of mESCs by binding to and destabilizing mRNAs encoding ectodermal specification markers. Pfkp is transcriptionally repressed in mESCs through LIF‐Stat3 signaling.Lifting Stat3 repression promotes Pfkp expression and its phosphorylation of Lin41.Stabilized Lin41 disrupts expression of ectodermal mRNAs during differentiation. [ABSTRACT FROM AUTHOR]

Extracellular signal‐regulated kinase 7 (ERK7), also known as ERK8 and MAPK15, is an atypical member of the MAP kinase family. Compared with other MAP kinases, the biological roles of ERK7 remain poorly understood. Recent work, however, has revealed several novel functions for ERK7. These include a highly conserved essential role in ciliogenesis, the ability to control cell growth, metabolism and autophagy, as well as the maintenance of genomic integrity. ERK7 functions through phosphorylation‐dependent and ‐independent mechanisms and it is activated by cellular stressors, including DNA‐damaging agents, and nutrient deprivation. Here, we summarize recent developments in understanding ERK7 function, emphasizing its conserved roles in cellular and physiological regulation. [ABSTRACT FROM AUTHOR]

Alterations in significant genes located on chromosome 7 - including epidermal growth factor receptor (EGFR) and also v-Raf murine sarcoma viral oncogene homolog B (BRAF) as a mitogen-activated protein kinase (MAPK) - combined or not with numerical imbalances of the whole chromosome (aneuploidy-polysomy) are crucial genetic events involved in the development and progression of malignancies. Identification of EGFR/BRAF-dependent specific somatic mutations and other mechanisms of deregulation (i.e., amplification) is critical for applying targeted therapeutic approaches [tyrosine kinase inhibitors (TKIs] or monoclonal antibodies (mAbs). Thyroid carcinoma is a specific pathological entity characterized by a variety of histological sub-types. Follicular thyroid carcinoma (FTC), papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC) represent its main sub-types. In the current review, we explore the role of EGFR/BRAF alterations in thyroid carcinoma in conjunction with the corresponding antiEGFR/BRAF TKI-based novel therapeutic strategies for patients with specific genetic signatures. [ABSTRACT FROM AUTHOR]

Doublecortin-like kinase 1 (DCLK1) is a functional serine/threonine (S/T)-kinase and a member of the doublecortin family of proteins which are characterized by their ability to bind to microtubules (MTs). DCLK1 is a proposed cancer driver gene, and its upregulation is associated with poor overall survival in several solid cancer types. However, how DCLK1 associates with MTs and how its kinase function contributes to pro-tumorigenic processes is poorly understood. This review builds on structural models to propose not only the specific functions of the domains but also attempts to predict the impact of individual somatic missense mutations on DCLK1 functions. Somatic missense mutations in DCLK1 are most frequently located within the N-terminal MT binding region and likely impact on the ability of DCLK1 to bind to αβ-tubulin and to polymerize and stabilize MTs. Moreover, the MT binding affinity of DCLK1 is negatively regulated by its auto-phosphorylation, and therefore mutations that affect kinase activity are predicted to indirectly alter MT dynamics. The emerging picture portrays DCLK1 as an MT-associated protein whose interactions with tubulin heterodimers and MTs are tightly controlled processes which, when disrupted, may confer pro-tumorigenic properties. [ABSTRACT FROM AUTHOR]

With No Lysine kinases (WNKs) represents a gene family that encodes Ser/Thr kinases, with anomalous disposition of catalytic lysine residue in subdomain I. In plants, WNKs had been linked to circadian rhythm, photoperiodic response and abiotic stress tolerance with mechanism yet undeciphered. In the present study, full-length CDS sequences of rice WNKs (OsWNK1 to 8) were cloned from indica cultivar IR64. A total of six highly conserved kinase subdomains were identified. Comparative analysis of protein sequences from six different species of rice showed varying magnitudes of substitution (76.2 %), deletion (15.4 %), and addition (8.4 %) events. ConSurf analysis coupled with CASTp results identified functional residues that were clustered together in modelled 3-D structures. Among post-translational modifications (PTMs) studied, 87.7 % of phosphorylation sites were predicted. Mined protein-protein interactions (PPIs) depicted OsWNKs to interact notably with other OsWNK members and with key proteins like PRR95 involved in photoperiodic response and protein phosphatase like PP2C involved in ABA signalling. Gene duplication analysis revealed two paralogous duplicated gene pairs: WNK6-WNK9 and WNK7-WNK8. Oryza sativa showed maximum syntenic relationship with Sorghum bicolor among the compared species. OsWNKs showed differential transcript expression profiles on treatment with plant growth regulators indicating its versatile role in plant growth and development. • All the members of OsWNK gene family had been cloned and characterized. • OsWNKs have four distinctive highly conserved kinase sub-domains. • Catalytic lysine residue is a highly conserved and exposed. • Under different hormonal treatments, OsWNK members showed differential regulation. [ABSTRACT FROM AUTHOR]

The Calvin-Benson-Bassham (CBB) cycle comprises the metabolic phase of photosynthesis and is responsible for carbon fixation and the production of sugar phosphates. The first step of the cycle involves the enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) which catalyzes the incorporation of inorganic carbon into 3-phosphoglyceric acid (3PGA). The following steps include ten enzymes that catalyze the regeneration of ribulose-1,5-bisphosphate (RuBP), the substrate of Rubisco. While it is well established that Rubisco activity acts as a limiting step of the cycle, recent modeling studies and experimental evidence have shown that the efficiency of the pathway is also impacted by the regeneration of the Rubisco substrate itself. In this work, we review the current understanding of the structural and catalytic features of the photosynthetic enzymes that catalyze the last three steps of the regeneration phase, namely ribose-5-phosphate isomerase (RPI), ribulose-5-phosphate epimerase (RPE), and phosphoribulokinase (PRK). In addition, the redox- and metabolic-based regulatory mechanisms targeting the three enzymes are also discussed. Overall, this review highlights the importance of understudied steps in the CBB cycle and provides direction for future research aimed at improving plant productivity. [ABSTRACT FROM AUTHOR]

Simple Summary: HASPIN plays important roles in chromosome segregation during cell division by phosphorylating histone H3 at threonine. We showed that HASPIN was expressed in the hippocampus and phosphorylated the tau protein, acting as a phosphorylation substrate. Oral administration of soybean sprouts grown for increased coumestrol (a HASPIN inhibitor) decreased the phosphorylated tau protein level in the hippocampus and suppressed short-term memory loss in the Alzheimer's disease model mice (5xFAD). Functional analysis of HASPIN may help treatment of Alzheimer's disease. The MATP/tau protein is hyperphosphorylated in Alzheimer's patients. Therefore, research into the regulation of tau protein phosphorylation is important for understanding Alzheimer's disease. HASPIN is a serine/threonine kinase that is expressed in various cells. To examine whether HASPIN is involved in the onset of Alzheimer's disease through tau protein phosphorylation, we investigated the effects of a diet including soybean sprouts rich in the HASPIN inhibitor coumestrol in a mouse model of Alzheimer's disease (5xFAD). The results showed that HASPIN was expressed in the hippocampus and phosphorylated tau protein, while the ingestion of soybean sprouts containing coumestrol suppressed the development of spatial cognitive dysfunction in 5xFAD. These results indicate that HASPIN may be one of the target molecules for the repression of tau phosphorylation in the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) can regulate a wide variety of cellular fates, such as proliferation, apoptosis, and autophagy. More importantly, changes in the intracellular Ca2+ level can modulate signaling pathways that control a broad range of physiological as well as pathological cellular events, including those important to cellular excitability, cell cycle, gene-transcription, contraction, cancer progression, etc. Not only intracellular Ca2+ level but the distribution of Ca2+ in the intracellular compartments is also a highly regulated process. For this Ca2+ homeostasis, numerous Ca2+ chelating, storage, and transport mechanisms are required. There are also specialized proteins that are responsible for buffering and transport of Ca2+. T-type Ca2+ channels (TTCCs) are one of those specialized proteins which play a key role in the signal transduction of many excitable and non-excitable cell types. TTCCs are low-voltage activated channels that belong to the family of voltage-gated Ca2+ channels. Over decades, multiple kinases and phosphatases have been shown to modulate the activity of TTCCs, thus playing an indirect role in maintaining cellular physiology. In this review, we provide information on the kinase and phosphatase modulation of TTCC isoforms Cav3.1, Cav3.2, and Cav3.3, which are mostly described for roles unrelated to cellular excitability. We also describe possible potential modulations that are yet to be explored. For example, both mitogen-activated protein kinase and citron kinase show affinity for different TTCC isoforms; however, the effect of such interaction on TTCC current/kinetics has not been studied yet. [ABSTRACT FROM AUTHOR]

Virus infection triggers a plethora of defence reactions in plants to incapacitate the intruder. Viruses, in turn, have added additional functions to their genes so that they acquire capabilities to neutralize the above defence reactions. In plant-infecting viruses, the family Geminiviridae comprises members, majority of whom encode 6–8 genes in their small single-stranded DNA genomes. Of the above genes, one which shows the most variability in its amino acid sequence is the C4/AC4. Recent studies have uncovered evidence, which point towards a wide repertoire of functions performed by C4/AC4 revealing its role as a major player in suppressing plant defence. This review summarizes the various plant defence mechanisms against viruses and highlights how C4/AC4 has evolved to counter most of them. • Geminiviral C4/AC4 is the shortest and the most diverse gene in the viral family. • Plants show several defence pathways against viruses. • C4/AC4 proteins show interactions with most defence pathways at various levels. [ABSTRACT FROM AUTHOR]

Improving screening efficiency is one of the most challenging tasks of virtual screening (VS). In this work, we propose an effective target‐focused scoring criterion for VS and apply it to the screening of a specific target scaffold replacement library constructed by enumeration of suitable substitution fragments and R‐groups of known ligands. This criterion is based on both ligand‐ and structure‐based scoring methods, which includes feature maps, 3D shape similarity, and the pairwise distance information between proteins and ligands (FSDscore). It is precisely due to the hybrid advantages of ligand‐ and structure‐based approaches that FSDscore performs far better on the validation dataset than other scoring methods. We apply FSDscore to the VS of different kinase targets, MERTK (Mer tyrosine kinase) and ABL1 (tyrosine‐protein kinase ABL1) in order to avoid occasionality. Finally, a VS case study shows the potential and effectiveness of our scoring criterion in drug discovery and molecular dynamics simulation further verifies its powerful ability. [ABSTRACT FROM AUTHOR]

The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2. [ABSTRACT FROM AUTHOR]

Phosphorylation of N-methyl-d-aspartate receptor (NMDAR) is widely regarded as a vital modification of synaptic function. Various protein kinases are responsible for direct phosphorylation of NMDAR, such as cyclic adenosine monophosphate-dependent protein kinase A, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, Src family protein tyrosine kinases, cyclin-dependent kinase 5, and casein kinase II. The detailed function of these kinases on distinct subunits of NMDAR has been reported previously and contributes to phosphorylation at sites predominately within the C-terminal of NMDAR. Phosphorylation underlies both structural and functional changes observed in chronic pain, and studies have demonstrated that inhibitors of kinases are significantly effective in alleviating pain behavior in different chronic pain models. In addition, the exploration of drugs that aim to disrupt the interaction between kinases and NMDAR is promising in clinical research. Based on research regarding the modulation of NMDAR in chronic pain models, this review provides an overview of the phosphorylation of NMDAR-related mechanisms underlying chronic pain to elucidate molecular and pharmacologic references for chronic pain management. [ABSTRACT FROM AUTHOR]

Objective(s): To clarify therapeutic potential of albiflorin and its intrinsic mechanisms against dextran sulfate sodium (DSS)-induced Ulcerative colitis (UC) mice. Materials and Methods: Sixty male C57BL/6 mice were randomly divided into five groups: negative control, positive, albiflorin low-dose group, albiflorin high-dose group and treatment control (Salicylazosulfapyridine "SASP", 100 mg/kg) group. Acute colitis was induced in all groups except NC by administration of 3% DSS for 7 days. Albiflorin and SASP were administered via the intragastric route twice a day for 7 days. The changes of colon tissue were assessed by disease activity index (DAI), HE staining, and ELISA. Adrenodoxin expressions of UC colon tissues were evaluated by immunohistochemistry. Western blotting was performed to investigate related protein of the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Results: It has been found that the albiflorin shares similar influences as the SASP in ameliorating the DSS-induced UC. The reduced DAI and alleviated colon tissue damage were observed in albiflorin intervened groups. Moreover, albiflorin significantly inhibited myeloperoxidase activities and attenuated immuno-inflammatory response and elevated Foxp3 mRNA in colon tissue. Furthermore, investigations revealed that albiflorin could inhibit adrenodoxin isoform and activate activated phosphorylated NF-κB p65 and IκBα, which consequently suppressed phosphorylated p38 MAPK, extracellular regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK). Conclusion: These findings showed that albiflorin could alleviate DSS-induced murine colitis by activating inhibiting NF-κB and MAPK signaling pathways. It might be a potential therapeutic reagent for UC treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: α6β4-integrins and plectin are the key structural components of hemidesmosomes that have been implicated in carcinogenesis and which are thus considered as potential cancer biomarkers and drug targets for anti-cancer therapies. In this review, we elaborate on the current knowledge of the kinase signaling pathways regulated by α6β4-integrins and plectin in the context of prostate cancer. We discuss an emerging scenario where hemidesmosomal α6β4-integrins and plectin function as tumor suppressors but adopt new oncogenic roles upon hemidesmosome disassembly in prostate cancer. Hemidesmosomes (HDs) are adhesive structures that ensure stable anchorage of cells to the basement membrane. They are formed by α6β4-integrin heterodimers and linked to intermediate filaments via plectin. It has been reported that one of the most common events during the pathogenesis of prostate cancer (PCa) is the loss of HD organization. While the expression levels of β4-integrins are strongly reduced, the expression levels of α6-integrins and plectin are maintained or even elevated, and seem to promote tumorigenic properties of PCa cells, such as proliferation, invasion, metastasis, apoptosis- and drug-resistance. In this review, we discuss the potential mechanisms of how HD components might contribute to various cellular signaling pathways to promote prostate carcinogenesis. Moreover, we summarize the current knowledge on the involvement of α6β4-integrins and plectin in PCa initiation and progression. [ABSTRACT FROM AUTHOR]

CaMKII (the multifunctional Ca2+ and calmodulin-dependent protein kinase II) is a highly validated signal for promoting a variety of common diseases, particularly in the cardiovascular system. Despite substantial amounts of convincing preclinical data, CaMKII inhibitors have yet to emerge in clinical practice. Therapeutic inhibition is challenged by the diversity of CaMKII isoforms and splice variants and by physiological CaMKII activity that contributes to learning and memory. Thus, uncoupling the harmful and beneficial aspects of CaMKII will be paramount to developing effective therapies. In the last decade, several targeting strategies have emerged, including small molecules, peptides, and nucleotides, which hold promise in discriminating pathological from physiological CaMKII activity. Here we review the cellular and molecular biology of CaMKII, discuss its role in physiological and pathological signaling, and consider new findings and approaches for developing CaMKII therapeutics. [ABSTRACT FROM AUTHOR]

Atropisomerism is a stereochemical phenomenon that describes how groups are arranged in space as a result of their impeded rotation around a single bond. It is one of the frequently underappreciated conformational kinds of chirality. A significant role for atropisomers in drug discovery and development has been established via substantial study on the characteristics of molecules exhibiting this form of chirality. According to studies on the target selectivity of anti‐cancer drugs, it was identified that atropisomers of specific compounds could be examined to modulate the selectivity of promiscuous inhibitors, which are a key target in cancer therapy. Conversely, it was discovered that these deliberate rigidifications of possible molecules along an axis of chirality gave an abundant possibility of acquiring more tailored anti‐cancer action. Atropisomerism plays a significant role in altering pharmacodynamic and pharmacokinetic properties and thereby the success of any proposed drug candidate. It is thus necessary to anticipate the impact of stereogenic centres in such compounds on cancer drug development. Hence, herein we review atropisomeric anti‐cancer moieties which have been investigated based on their target proteins, origin and isomerism. The insights offered herein would be extremely useful in anti‐cancer drug design, pave way for new avenues to development promising potent agents to combat this life‐threatening disease. [ABSTRACT FROM AUTHOR]

Background & Objective: Iran is located in the esophageal cancer geographical belt. As multiple genetic alterations are responsible for the molecular pathogenesis of esophageal squamous cell cancer (ESCC), the role and frequency of HER2 expression, MMR deficiency, and PI3KCA mutation are not well defined. Methods: We carried out HER2/neu expression, dMMR/MSI high, and PI3KCA mutation analysis in specimens of patients with ESCC. We accessed archival tissue blocks related to specimens of 68 ESCC cases at the time of surgery following neoadjuvant chemoradiation. These patients underwent surgery during 2013-2018 at the Cancer Institute of Iran affiliated with the Tehran University of Medical Sciences in Tehran. Results: None of the patients showed HER2 expression, dMMR/MSI high, or PI3K mutations. Conclusion: dMMR/MSI-H and PI3KCA mutation and HER2 expression may not be reliable andfrequent targets for systemic therapy in patients with esophageal SCC. [ABSTRACT FROM AUTHOR]

The liver is a major organ that is involved in essential biological functions such as digestion, nutrient storage, and detoxification. Furthermore, it is one of the most metabolically active organs with active roles in regulating carbohydrate, protein, and lipid metabolism. Hepatocellular carcinoma is a cancer of the liver that is associated in settings of chronic inflammation such as viral hepatitis, repeated toxin exposure, and fatty liver disease. Furthermore, liver cancer is the most common cause of death associated with cirrhosis and is the 3rd leading cause of global cancer deaths.LKB1 signaling has been demonstrated to play a role in regulating cellular metabolism under normal and nutrient deficient conditions. Furthermore, LKB1 signaling has been found to be involved in many cancers with most reports identifying LKB1 to have a tumor suppressive role. In this review, we use the KMPlotter database to correlate RNA levels of LKB1 signaling genes and hepatocellular carcinoma patient survival outcomes with the hopes of identifying potential biomarkers clinical usage. Based on our results STRADß, CAB39L, AMPKα, MARK2, SIK1, SIK2, BRSK1, BRSK2, and SNRK expression has a statistically significant impact on patient survival.

Inter-α-trypsin inhibitor heavy chain 4 (ITI-H4) is one of the acute phase proteins and is mainly related with inflammatory diseases such as bacterial bloodstream infection and recurrent pregnancy loss (RPL). In a previous study, ITI-H4 was reported to be cleaved by kallikrein B1 (KLKB1) and its cleaved form induces the imbalance between pro- and anti-inflammatory cytokines. Therefore, in this study, putative substrates of ITI-H4 were isolated by immunoprecipitation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) analysis. Of those, phosphoglycerate kinase 1 (PGK1) was found to be a binding protein of ITI-H4. PGK1 increases the level of ITI-H4 expression and blocks the cleavage of ITI-H4 mediated by KLKB1. It also inhibits pro-inflammatory response by inhibiting the JAK2/STAT3 signaling pathway. Therefore, PGK1, a novel binding partner of ITI-H4, is expected to have cellular functions in the pathogenesis of ITI-H4-related inflammatory diseases.

Abstract Lung cancer is the most common type of cancer in the world, and alone, in 2020, almost 2.21 million new cases were diagnosed, with 1.80 million deaths, and are increasing daily. Non-small cell lung (NSCLC) is the primary type of lung cancer, predominantly forms around 80% of cases compared to small cell carcinoma, and about 75% of patients are already in an advanced state when diagnosed. Despite notable advances in early diagnosis and treatment, the five-year survival rate for NSCLC is not encouraging. Therefore, it is crucial to investigate the molecular causes of non-small cell lung cancer to create more efficient therapeutic approaches. Lung cancer showed a more significant and persistent binding affinity and energy landscape with the target CDK2 staurosporine and FGF receptor-1. In this study, we have picked two essential target proteins, human cyclin-dependent kinase-2 and Human Protein Kinase CK2 Holoenzyme and screened the entire prepared DrugBank prepared library of 1,55,888 compounds and identified 2-(2-methyl-5-nitroimidazole-1-yl) ethanol (Metralindole) as a major inhibitor. Metralindole has displayed high docking scores of -5.159 Kcal/mol and -5.99 Kcal/mol with good hydrogen bonding and other bonding topologies such as van der Waals force, and ADMET results shown excellent bioavailability, outstanding solubility, no side effects, and toxicity. The molecular dynamics simulation for 100ns in a water medium confirmed the compound's stability and interaction pattern with the lowest deviation and fluctuations. Our in-silico study suggests Metralindole, an experimental compound, can effectively cure lung cancer. Further, the experimental validation of the compound is a must before any prescription.