GSK3: A Kinase Balancing Promotion and Resolution of Inflammation.
Ontology highlight
ABSTRACT:
SUBMITTER: Hoffmeister L
PROVIDER: S-EPMC7226814 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:This study examined if there are interactions between two key proteins that oppositely regulate intrinsic apoptosis, X-linked inhibitor of apoptosis protein (XIAP), a key suppressor of apoptosis that binds to inhibit active caspases, and glycogen synthase kinase-3 (GSK3), which promotes intrinsic apoptosis. Immunoprecipitation of GSK3beta revealed that XIAP associates with GSK3beta, as do two other members of the IAP family, cIAP-1, and cIAP-2. Cell fractionation revealed that XIAP is predominantly cytosolic, cIAP-1 is predominantly nuclear and nearly all of the nuclear cIAP-1 and cIAP-2 are associated with GSK3. Expression of individual domains of XIAP demonstrated that the RING domain of XIAP associates with GSK3. Inhibition of GSK3 did not alter the binding of XIAP to active caspase-9 or caspase-3 after stimulation of apoptosis with staurosporine. However, inhibition of GSK3 reduced apoptosis and apoptosome formation, including the recruitments of caspase-9 and XIAP to Apaf-1, in response to staurosporine treatment. Cell free measurements of apoptosome-induced caspase-3 activation demonstrated that GSK3 acts upstream of the apoptosome to facilitate intrinsic apoptotic signaling. This facilitation was blocked by overexpression of XIAP. These findings indicate that the RING domain of XIAP (and probably cIAP-1 and cIAP-2) associates with GSK3, GSK3 acts upstream of the apoptosome to promote intrinsic apoptosis, and the association between XIAP and GSK3 may block the pro-apoptotic function of GSK3.
| S-EPMC2760639 | biostudies-literature
Project description:The restoration of dentine lost in deep caries lesions in teeth is a routine and common treatment that involves the use of inorganic cements based on calcium or silicon-based mineral aggregates. Such cements remain in the tooth and fail to degrade and thus normal mineral volume is never completely restored. Here we describe a novel, biological approach to dentine restoration that stimulates the natural formation of reparative dentine via the mobilisation of resident stem cells in the tooth pulp. Biodegradable, clinically-approved collagen sponges are used to deliver low doses of small molecule glycogen synthase kinase (GSK-3) antagonists that promote the natural processes of reparative dentine formation to completely restore dentine. Since the carrier sponge is degraded over time, dentine replaces the degraded sponge leading to a complete, effective natural repair. This simple, rapid natural tooth repair process could thus potentially provide a new approach to clinical tooth restoration.
| S-EPMC5220443 | biostudies-literature
Project description:Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.
| S-EPMC6839918 | biostudies-literature
Project description:The inflammatory response is integral to maintaining health by functioning to resist microbial infection and repair tissue damage. Large numbers of neutrophils are recruited to inflammatory sites to neutralize invading bacteria through phagocytosis and the release of proteases and reactive oxygen species into the extracellular environment. Removal of the original inflammatory stimulus must be accompanied by resolution of the inflammatory response, including neutrophil clearance, to prevent inadvertent tissue damage. Neutrophil apoptosis and its temporary inhibition by survival signals provides a target for anti-inflammatory therapeutics, making it essential to better understand this process. GM-CSF, a neutrophil survival factor, causes a significant increase in mRNA levels for the known anti-apoptotic protein serum and glucocorticoid-regulated kinase 1 (SGK1). We have characterized the expression patterns and regulation of SGK family members in human neutrophils and shown that inhibition of SGK activity completely abrogates the antiapoptotic effect of GM-CSF. Using a transgenic zebrafish model, we have disrupted sgk1 gene function and shown this specifically delays inflammation resolution, without altering neutrophil recruitment to inflammatory sites in vivo. These data suggest SGK1 plays a key role in regulating neutrophil survival signaling and thus may prove a valuable therapeutic target for the treatment of inflammatory disease.
| S-EPMC3921102 | biostudies-literature
Project description:Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.
| S-EPMC4340754 | biostudies-literature
Project description:Lithium salt is a classic glycogen synthase kinase 3 (GSK3) inhibitor. Beryllium is a structurally related inhibitor that is more potent but relatively uncharacterized. This study examined the effects of these inhibitors on the phosphorylation of endogenous GSK3 substrates. In NIH-3T3 cells, both salts caused a decrease in phosphorylated glycogen synthase, as expected. GSK3 inhibitors produce enhanced phosphorylation of Ser9 of GSK3? via a positive feedback mechanism, and both salts elicited this enhancement. Another GSK3 substrate is ?-catenin, which has a central role in Wnt signaling. In A172 human glioblastoma cells, lithium treatment caused a surprising increase in phospho-Ser33/Ser37-?-catenin, which was quantified using an antibody-coupled capillary electrophoresis method. The ?-catenin hyperphosphorylation was unaffected by p53 RNAi knockdown, indicating that p53 is not involved in the mechanism of this response. Lithium caused a decrease in the abundance of axin, a component of the ?-catenin destruction complex that has a role in coordinating ?-catenin ubiquitination and protein turnover. The axin and phospho-?-catenin results were reproduced in U251 and U87MG glioblastoma cell lines. These observations run contrary to the conventional view of the canonical Wnt signaling pathway, in which a GSK3 inhibitor would be expected to decrease, not increase, phospho-?-catenin levels.This article has an associated First Person interview with the first author of the paper.
| S-EPMC5829510 | biostudies-literature
Project description:Salmonella Typhimurium (S. Typhimurium) is an enteric bacterium capable of invading a wide range of host cell types and adopting different intracellular lifestyles for survival. Host endocytic trafficking and autophagy have been implied to regulate the S. Typhimurium subcellular localization and survival. To reveal alternative host regulators on S. Typhimurium lifestyle, we combined a novel fluorescent reporter, Salmonella Intracellular Analyzer (SINA) with haploid forward genetic screening. This identified transcription factor c-MYC as a negative regulator of S. Typhimurium cytosolic lifestyle via stabilizing the Salmonella-containing vacuole (SCV). We further confirmed that c-MYC downstream regulated LC3 acts to maintain SCV stability and limits S. Typhimurium cytosolic lifestyle. We demonstrated that LC3 is recruited to the SCV prior to the endomembrane damage marker Galectin 3, and it regulates SCV stability independent of the autophagosome adaptor NDP52. The LC3 processing enzymes ATG3 and ATG4 reciprocally act on SCV stability, where the loss of LC3-PE conjugation in the absence of ATG3 limits SCV damages. We further identified the dosage-dependent function of the S. Typhimurium effector SopF in mediating SCV stability by actively avoiding LC3 recruitment to the proximity of the SCV to reduce its catastrophic rupture and host cell death. Altogether, we offer insights on the significance of cellular transcription profile in the determination of S. Typhimurium pathophysiology as well as the underlying host-evasion strategy of S. Typhimurium.
2022-09-25 | GSE161812 | GEO
Project description:Plant GSK3-like kinases are key regulators that modulate a broad range of physiological processes such as cell growth, stomatal and flower development, responses for abiotic and biotic stress, and carbohydrate metabolism. Arabidopsis Shaggy/GSK3-like kinases (AtSK) consist of ten members that are classified into four subfamilies (I∼IV). Only one of these Arabidopsis GSK3s, BIN2 (also named AtSK21), has been characterized by biochemical and genetic studies. BIN2 acts as a negative regulator in brassinosteroid (BR) signaling that controls cell growth and differentiation. Recent studies suggest that at least seven AtSKs are involved in BR signaling. However, specificities for the substrates and the functional differences of each member of the family remain to be determined. Here we report structural characteristics and distinct function of AtSK12 compared with BIN2. AtSK12 has a longer N-terminal extension, which is absent in BIN2. Transgenic plants overexpressing the AtSK12 mutant carrying deletion of Nterminal region display more severe dwarf phenotypes than those of the wild-type AtSK12. Microscopic analysis reveals that N-terminal-deleted AtSK12 accumulates in the nucleus. This implies that structural difference in the Nterminal region of AtSK members contributes to their subcellular localization. In contrast to BIN2, overexpression of AtSK12 does not cause a stomatal cluster. Furthermore, we show that YODA MAPKKK, which controls stomatal development, interacts with BIN2 but not with AtSK12. Our results suggest that AtSK12 mediates BR-regulated cell growth but not stomatal development while BIN2 regulates both processes. Our study provides evidence that different GSK3 members can have overlapping but non-identical functions.
| S-EPMC3887958 | biostudies-literature
Project description:The intrinsic connection between inflammation and tumor promotion is well characterized and is a key pathogenic event in patients with colorectal cancer (CRC), the second most common cause of tumor-related death in western countries. Environmental factors and chronic inflammation represent the major causes of intestinal carcinogenesis. In fact, patients suffering from inflammatory bowel diseases, including Crohn’s disease and Ulcerative Colitis (UC), have high risk of developing colitis-associated CRC with poor prognoses. Therefore, targeting the cancer-associated inflammation may offer new avenues for cancer treatment. In fact, several anti-inflammatory drugs, have been used for prophylaxis and have shown efficacy in contrasting cancer, despite various adverse side effects. Thus, there is an urgent need to discover novel cancer-associated mechanisms to develop alternative therapies that may reduce aberrant inflammatory responses without interfering with physiological defenses against infection and functional anti-tumor immunity. A novel approach promoting anti-tumor immunity has been recently proposed after the discovery of potent, endogenous, specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins, mainly derived from omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) via COX, LOX and CYP450 pathways, mediated by MFSD2A. Due to the potent bioactivity of SPMs in resolving inflammation and because of the correlation between inflammation and cancer, the roles of these lipid mediators have attracted great attention for their potential therapeutic role in cancer treatment, including CRC. Nevertheless, the understanding of the endogenous mechanisms that limit the inflammatory response during CRC development is incomplete and requires further investigation.
Based on the preliminary results indicating that dysfunctional MFSD2A-dependent pro-resolving pathways may foster CRC development, the investigators aim to define the functional role of MFSD2A in orchestrating pro-resolving pathways in the intestinal endothelium of metastatic and not metastatic CRC patients.
This is a cross-sectional single-center observational study involving patients with CRC. The investigators will enroll 15 patients with colorectal cancer (CRC) stratified by tumor stage (T0 / T1-T4, M0 / M1, N0 / N1 / N2) undergoing surgery in the Gastroenterology and Digestive Endoscopy unit within Gastro Center (IRCCS Ospedale San Raffaele).
Human Intestinal Microvascular Endothelial Cells (HIMEC) will be generated from each sample of cancer surgical specimens, while the healthy cells will be derived from the healthy margins of the colorectal resection of the same CRC patients.
MFSD2A will be overexpressed or silenced and the investigators will evaluate its biological effects in both tumor-derived HIMECs and healthy tissue-derived HIMECs through transcriptomics and lipidomics analysis. The investigators will also exploit a possible novel therapy based on the delivery of MFSD2A encoding plasmid-conjugated liposomes.
| 108244 | ecrin-mdr-crc
Project description:The signaling complex around voltage-gated sodium (Nav) channels includes accessory proteins and kinases crucial for regulating neuronal firing. Previous studies showed that one such kinase, WEE1-critical to the cell cycle-selectively modulates Nav1.2 channel activity through the accessory protein fibroblast growth factor 14 (FGF14). Here, we tested whether WEE1 exhibits crosstalk with the AKT/GSK3 kinase pathway for coordinated regulation of FGF14/Nav1.2 channel complex assembly and function. Using the in-cell split luciferase complementation assay (LCA), we found that the WEE1 inhibitor II and GSK3 inhibitor XIII reduce the FGF14/Nav1.2 complex formation, while the AKT inhibitor triciribine increases it. However, combining WEE1 inhibitor II with either one of the other two inhibitors abolished its effect on the FGF14/Nav1.2 complex formation. Whole-cell voltage-clamp recordings of sodium currents (INa) in HEK293 cells co-expressing Nav1.2 channels and FGF14-GFP showed that WEE1 inhibitor II significantly suppresses peak INa density, both alone and in the presence of triciribine or GSK3 inhibitor XIII, despite the latter inhibitor's opposite effects on INa. Additionally, WEE1 inhibitor II slowed the tau of fast inactivation and caused depolarizing shifts in the voltage dependence of activation and inactivation. These phenotypes either prevailed or were additive when combined with triciribine but were outcompeted when both WEE1 inhibitor II and GSK3 inhibitor XIII were present. Concerted regulation by WEE1 inhibitor II, triciribine, and GSK3 inhibitor XIII was also observed in long-term inactivation and use dependency of Nav1.2 currents. Overall, these findings suggest a complex role for WEE1 kinase-in concert with the AKT/GSK3 pathway-in regulating the Nav1.2 channelosome.
| S-EPMC11311446 | biostudies-literature