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A schematic presentation of JAK/STAT pathway in cancer cells. For the full list of proteins regulated by the pathway via different STAT proteins, see Table 3.
Source publication
Janus tyrosine kinase (JAK) family of proteins have been identified as crucial proteins in signal transduction initiated by a wide range of membrane receptors. Among the proteins in this family JAK2 has been associated with important downstream proteins, including signal transducers and activators of transcription (STATs), which in turn regulate th...
Similar publications
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, especially the JAK2/STAT3 pathway, play vital roles in the development of many malignancies. Overactivation of STAT3 promotes cancer cell survival and proliferation. Therefore, the JAK2/STAT3-signaling pathway has been considered a promising target for cancer t...
Citations
... Consequently, in-depth research is still required to validate these assumptions and disclose the underlying molecular mechanism of regulation of IRF9 on sepsis. Janus Kinase (JAK) is a family of non-receptor tyrosine kinases which participate in JAK-STAT pathway including JAK3 (Bousoik and Montazeri Aliabadi, 2018;Agashe et al., 2022). During eryptosis (suicidal programmed death of mature red blood cells) (Jemaa et al., 2017), JAK3 was activated by energy depletion, subsequently stimulated eryptosis in turn, which was blunted by pharmacologic inhibitors or genetic knockout of JAK3 (Bhavsar et al., 2011). ...
Introduction
Sepsis leads to multi-organ dysfunction due to disorders of the host response to infections, which makes diagnosis and prognosis challenging. Apoptosis, a classic programmed cell death, contributes to the pathogenesis of various diseases. However, there is much uncertainty about its mechanism in sepsis.
Methods
Three sepsis gene expression profiles (GSE65682, GSE13904, and GSE26378) were downloaded from the Gene Expression Omnibus database. Apoptosis-related genes were obtained from the Kyoto Encyclopedia of Genes and Genomes Pathway database. We utilized LASSO regression and SVM-RFE algorithms to identify characteristic genes associated with sepsis. CIBERSORT and single cell sequencing analysis were employed to explore the potential relationship between hub genes and immune cell infiltration. The diagnostic capability of hub genes was validated across multiple external datasets. Subsequently, the animal sepsis model was established to assess the expression levels of hub genes in distinct target organs through RT-qPCR and Immunohistochemistry analysis.
Results
We identified 11 apoptosis-related genes as characteristic diagnostic markers for sepsis: CASP8, VDAC2, CHMP1A, CHMP5, FASLG, IFNAR1, JAK1, JAK3, STAT4, IRF9, and BCL2. Subsequently, a prognostic model was constructed using LASSO regression with BCL2, FASLG, IRF9 and JAK3 identified as hub genes. Apoptosis-related genes were closely associated with the immune response during the sepsis process. Furthermore, in the validation datasets, aside from IRF9, other hub genes demonstrated similar expression patterns and diagnostic abilities as observed in GSE65682 dataset. In the mouse model, the expression differences of hub genes between sepsis and control group revealed the potential impacts on sepsis-induced organ injury.
Conclusion
The current findings indicated the participant of apoptosis in sepsis, and apoptosis-related differentially expressed genes could be used for diagnosis biomarkers. BCL2, FASLG, IRF9 and JAK3 might be key regulatory genes affecting apoptosis in sepsis. Our findings provided a novel aspect for further exploration of the pathological mechanisms in sepsis.
... JAK-STAT pathway is an evolutionarily conserved signaling pathway involved in transmitting extracellular signals from cell-membrane receptors to the nucleus to regulate cell growth, survival, differentiation, proliferation, and apoptosis [42]. The extracellular signaling pathways include a wide range of cytokines, interferons, growth factors, and related molecules that upon binding to type I and II cytokine receptors cause dimerization of these receptors and result in receptor activation [43]. ...
... The extracellular signaling pathways include a wide range of cytokines, interferons, growth factors, and related molecules that upon binding to type I and II cytokine receptors cause dimerization of these receptors and result in receptor activation [43]. Upon receptor activation, JAK proteins associate with the juxtamembrane regions of these receptors to initiate transphosphorylation of JAKs, and subsequent recruitment of STAT proteins to this complex [42]. This culminates in the phosphorylationmediated dimerization of STATs which then translocate into the nucleus to regulate transcription of myriad target genes. ...
JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth. Furthermore, MJ04 significantly promoted the growth of human hair follicles under ex-vivo conditions. MJ04 exhibited a reasonably good pharmacokinetic profile and demonstrated a favourable safety profile under in vivo and in vitro conditions. Taken together, we report MJ04 as a highly potent and selective JAK3 inhibitor that exhibits overall properties suitable for topical drug development and advancement to human clinical trials.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12967-024-05144-4.
... JAK2/STAT3 signaling pathway is one of the main signaling pathways of inflammation and is responsible for the production of cytokines, as well as the recruitment and activation of cytokines [31,32]. Numerous studies have shown that JAK2/STAT3 pathway is an important pathway inflammation influence colitis. ...
Background
Ulcerative colitis (UC) is an inflammatory disease of the digestive tract. Rauwolfia polysaccharide (Rau) has therapeutic effects on colitis in mice, but its mechanism of action needs to be further clarified. In the study, we explored the effect of Rau on the UC cell model induced by Lipopolysaccharide (LPS).
Methods
We constructed a UC cell model by stimulating HT-29 cells with LPS. Dextran sodium sulfate (DSS) was used to induce mice to construct an animal model of UC. Subsequently, we performed Rau administration on the UC cell model. Then, the therapeutic effect of Rau on UC cell model and was validated through methods such as Cell Counting Kit-8 (CCK8), Muse, Quantitative real‑time polymerase chain reaction (RT-qPCR), Western blotting, and Enzyme-linked immunosorbent assay (ELISA).
Results
The results showed that Rau can promote the proliferation and inhibit the apoptosis of the HT-29 cells-induced by LPS. Moreover, we observed that Rau can inhibit the expression of NOS2/JAK2/STAT3 in LPS-induced HT-29 cells. To further explore the role of NOS2 in UC progression, we used siRNA technology to knock down NOS2 and search for its mechanism in UC. The results illustrated that NOS2 knockdown can promote proliferation and inhibit the apoptosis of LPS-induced HT-29 cells by JAK2/STAT3 pathway. In addition, in vitro and in vivo experiments, we observed that the activation of the JAK2/STAT3 pathway can inhibit the effect of Rau on DSS-induced UC model.
Conclusion
In short, Rauwolfia polysaccharide can inhibit the progress of ulcerative colitis through NOS2-mediated JAK2/STAT3 pathway. This study provides a theoretical clue for the treatment of UC by Rau.
... JAKs are a group of protein kinases that are found within cells. The family of JAKs includes JAK1, JAK2, JAK3, and TYK2, which have all been identified so far [78]. STAT is a target protein downstream of JAKs and is distributed in the cytoplasm. ...
Lung fibrosis is a dysregulated repair process caused by excessive deposition of extracellular matrix that can severely affect respiratory function. Macrophages are a group of immune cells that have multiple functions and can perform a variety of roles. Lung fibrosis develops with the involvement of pro-inflammatory and pro-fibrotic factors secreted by macrophages. The balance between M1 and M2 macrophages has been proposed to play a role in determining the trend and severity of lung fibrosis. New avenues and concepts for preventing and treating lung fibrosis have emerged in recent years through research on mitochondria, Gab proteins, and exosomes. The main topic of this essay is the impact that mitochondria, Gab proteins, and exosomes have on macrophage polarization. In addition, the potential of these factors as targets to enhance lung fibrosis is also explored. We have also collated the functions and mechanisms of signaling pathways associated with the regulation of macrophage polarization such as Notch, TGF-β/Smad, JAK-STAT and cGAS-STING. The goal of this article is to explain the potential benefits of focusing on macrophage polarization as a way to relieve lung fibrosis. We aspire to provide valuable insights that could lead to enhancements in the treatment of this condition.
... The STAT family consists of seven members, STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6, and each participates in the signalization; depending on which cytokine binds to its receptor on the cell surface (10). Activation of JAK2 via many hematopoietic and other cytokines leads to phosphorylation, thus activation of STATs (11). Each STAT member is characterized by certain domains that perform specific functions in the activation and transcription process. ...
Aim: Chronic myeloid leukemia (CML) displays a constitutive tyrosine kinase (TK) activity which in turn leads to the activation of various signaling pathways and the outcome of leukemic phenotype. Activated STAT5A and STAT5B from JAK/STAT pathway induce cell growth, proliferation, differentiation, and survival of leukemic cells which are promoted by a cytokine network. Since the second-generation tyrosine kinase inhibitor nilotinib has the advantage of inhibiting this oncogenic TK activity; we aimed to investigate the underlying mechanism of its therapeutic approach and how it induced apoptosis via analyzing the forthcoming molecular targets of the pathway. Methods: By Nilotinib treatments, cell viability and proliferation assays, apoptotic analysis, expressional regulations of STAT5A&5B mRNA transcripts, protein expression levels, and also cytokines’ expressional assessments were determined in CML model K562 cells, in vitro. Results: Nilotinib treatment in a time and dose-dependent manner assessed a therapeutic approach by decreasing leukemic cell proliferation and survival; inducing leukemic cell apoptosis, down-regulating STAT5A&5B mRNA, and protein expression levels, and regulating cytokine expressional network. Conclusion: Nilotinib-mediated therapeutics could be dependent on targeting JAK/STAT pathway members STAT5A and STAT5B, besides; regulating the cytokine network might be another underlying mechanism for sensitization and response of K562 cells to nilotinib in leukemia pathogenesis.
... JAKs non-covalently link to cytokine receptors, which coordinate receptor tyrosine phosphorylation and recruit STATs [14]. Phosphorylated STATs form homodimers or heterodimers with other STAT members harbouring conserved SH2 structural domains [23], which are subsequently transported across the nuclear membrane to the nucleus and bind to specific regulatory DNA sequences to regulate the expression of specific genes, including those related to cell survival, proliferation, angiogenesis, and invasion [24][25][26]. (Fig1A)The JAK/STAT signalling pathway mediates immune responses and is involved in the maintenance of environmental homeostasis in the lymphatic system [23]. ...
... Phosphorylated STATs form homodimers or heterodimers with other STAT members harbouring conserved SH2 structural domains [23], which are subsequently transported across the nuclear membrane to the nucleus and bind to specific regulatory DNA sequences to regulate the expression of specific genes, including those related to cell survival, proliferation, angiogenesis, and invasion [24][25][26]. (Fig1A)The JAK/STAT signalling pathway mediates immune responses and is involved in the maintenance of environmental homeostasis in the lymphatic system [23]. It functions to maintain the balance between Th1 and Th2 cells during the immune response and affects the development of regulatory T cells(Tregs)and the function of memory CD8+ T cells [27]. ...
In recent years, the incidence and mortality rates of lymphoma have gradually increased worldwide. Tumorigenesis and drug resistance are closely related to intracellular inflammatory pathways in lymphoma. Therefore, understanding the biological role of inflammatory pathways and their abnormal activation in relation to the development of lymphoma and their selective modulation may open new avenues for targeted therapy of lymphoma. The biological functions of inflammatory pathways are extensive, and they are central hubs for regulating inflammatory responses, immune responses, and the tumour immune microenvironment. However, limited studies have investigated the role of inflammatory pathways in lymphoma development. This review summarizes the relationship between abnormal activation of common inflammatory pathways and lymphoma development to identify precise and efficient targeted therapeutic options for patients with advanced, drug-resistant lymphoma.
... The oncogenic property of JAK2V617F resides in its ability to initiate ligandindependent signaling downstream of the erythropoietin receptor (EPOR), thrombopoietin receptor (TPOR), and granulocyte-stimulating factor receptor (G-CSFR), resulting in erythrocytosis, thrombocytosis, and neutrophilia, respectively 3 . In addition, JAK2 mediates signals from a multitude of other surface receptors, including receptors for chemokines, interleukins, interferons and receptor tyrosine kinases, many of which are critically involved in inflammatory responses 4 . ...
The development of Philadelphia chromosome-negative classical myeloproliferative neoplasms (MPN) involves an inflammatory process that facilitates outgrowth of the malignant clone and correlates with clinical outcome measures. This raises the question to which extent inflammatory circuits in MPN depend on activation of innate immune sensors. Here, we investigated whether NLRP3, which precipitates inflammasome assembly upon detection of cellular stress, drives murine JAK2V617F mutant MPN. Deletion of Nlrp3 within the hematopoietic compartment completely prevented increased IL-1β and IL-18 release in MPN. NLRP3 in JAK2V617F hematopoietic cells, but not in JAK2 wild type radioresistant cells, promoted excessive platelet production via stimulation of the direct thrombopoiesis differentiation pathway, as well as granulocytosis. It also promoted expansion of the hematopoietic stem and progenitor cell compartment despite inducing pyroptosis at the same time. Importantly, NLRP3 inflammasome activation enhanced bone marrow fibrosis and splenomegaly. Pharmacological blockade of NLRP3 in fully established disease led to regression of thrombocytosis and splenomegaly. These findings suggest that NLRP3 is critical for MPN development and its inhibition represents a new therapeutic intervention for MPN patients.
Key points
The increased IL-1β and IL-18 release in JAK2V617F mutant MPN depends on NLRP3 inflammasome activation
NLRP3 in MPN promotes excess platelet production, granulocytosis, HSPC compartment expansion, splenomegaly and bone marrow fibrosis
... [21][22][23] Furthermore, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway are key players in regulating various cellular functions, including growth, differentiation, and immune responses. 24 Activated JAKs recruit and phosphorylate cytoplasmic STAT proteins, which then dimerize and translocate to the nucleus, bind to specific DNA elements, and control the transcription of genes involved in diverse cellular functions including proliferation and differentiation. 25,26 Notably, JAK2/STAT3 pathway is an important modulator in cancer, as JAK2 functions as a receiving point for external signals from both interleukin receptors and cancer-promoting receptor tyrosine kinases, and subsequently relaying these signals to the oncogenic transcription factor, STAT3. ...
Extracellular matrix (ECM) and its dynamic remodeling contribute to the progression of breast cancer, the most prevailing cancer type in women. Glypicans (GPCs) function as cell co‐receptors by facilitating the formation of ligand–receptor complexes. An important regulator in the context of breast cancer progression is the JAK/STAT signaling pathway that oversees the expression of genes associated with cancer cell characteristics. Epidermal growth factor receptor (EGFR) is a pivotal player in this process. The aim of this study is to examine the effect of the EGFR and JAK/STAT signaling pathways on GPCs expression in breast cancer cells with different estrogen receptor (ER) status, depicting different breast cancer subtypes. To this end, the ERα‐positive MCF‐7, and the ERβ‐positive MDA‐MB‐231 breast cancer cell lines were evaluated in terms of the impact of downstream inhibition of both pathways on the functional properties as well as the expression of GPCs 1‐6 genes. Notably, the downstream inhibition of both EGFR and JAK/STAT cascades mitigate cell proliferation and migration, while increasing cell adhesion on collagen type I in an ER‐independent manner. However, the inhibition exhibited a cell‐line‐dependent effect on GPC expression, as in MCF‐7 cells GPCs expression is mostly downregulated excepting GPC‐4 and GPC‐5. Conversely, in MDA‐MB‐231 cells, EGFR and JAK/STAT activation is essential for maintaining GPCs at low levels. Additionally, STRING analysis identified the small leucine‐rich PG decorin as a putative link between all GPCs and EGFR. Subsequently, a deeper understanding on the effect of EGFR and JAK/STAT signaling may shed light into the role and interplay between GPCs and decorin in breast cancer progression, thus contributing to novel therapeutic solutions.
... JAK 1/2 are intracellular kinases that cause the activation of signal transducer and activation (STAT) proteins, involved in proliferation, activation and survival of cells [16]. The role of this pathway is critical in T lymphocyte function, involved in activation, survival and lineage commitment [17]. It is also important in innate immune response [16]. ...
Steroid-refractory graft-versus-host disease (SR-GvHD) represents a major complication of pediatric allogenic hematopoietic stem cell transplantation. Ruxolitinib, a selective JAK 1–2 inhibitor, showed promising results in the treatment of SR-GvHD in adult trial, including patients >12 years old. This systematic review aims to evaluate ruxolitinib use for SR-GvHD in the pediatric population. Among the 12 studies included, ruxolitinib administration presented slight differences. Overall response rate (ORR) ranged from 45% to 100% in both acute and chronic GvHD. Complete response rates (CR) varied from 9% to 67% and from 0% to 28% in aGvHD and cGvHD, respectively. Individual-patient meta-analysis from 108 children under 12 years showed an ORR and CR for aGvHD of 74% and 56%, respectively, while in cGvHD ORR was 78% but with only 11% achieving CR. Treatment-related toxicities were observed in 20% of patients, including cytopenia, liver toxicity, and infections. Age, weight, graft source, previous lines of therapy, and dose did not significantly predict response, while a higher rate of toxicities was observed in aGvHD patients. In conclusion, ruxolitinib shows promising results in the treatment of SR-GvHD in children, including those under 12 years. Specific pediatric perspective trials are currently ongoing to definitely assess its efficacy and safety.
... JAK/STAT pathways are strongly linked to cancer, autoimmunity, and dementia. Cytokine receptors targeted by JAK/STAT signaling are GPCRs [98] and can be activated by autoantibodies [76]. 7 For example, in alopecia areata, an autoimmune disease increased in LC, JAK transducers are upregulated [99]. ...
“All diseases originate in the gut.” Hippocrates (400 BC) A healthy gut microbiome via the gut-brain-axis (GBA) elevates heart rate variability (HRV), a general measure of health and well-being. A dysbiotic gut microbiome, low in biodiversity and butyrate producers, alters tryptophan metabolism with release of proinflammatory cytokines, predominantly TNF-α, IL-6, and IL-1β. These also characterize chronic inflammation, oxidative stress, and a multitude of diseases, all exhibiting low HRV. Gut dysbiosis upregulates IFN-γ and with it IDO (indoleamine 2,3 dioxygenase). Tryptophan pivots from serotonin synthesis to that of IDO induced kynurenine, increasing the kynurenine to tryptophan ratio (KTR). An elevated KTR is positively linked to neurodegenerative and autoimmune diseases and negatively linked to HRV. Elevated IDO activity is not only enzymatic but also an intracellular signal transducer potentiated by TGF-β. This cytokine is the primary determinant of the TME. Also proposed is the gut-lung dysbiosis concept and consequent degradation of ACE2 (richest in lungs and gut). Leaky gut induced autoantibodies related to G-protein coupled receptors (GPCRs) in combination with increased Ang II further potentiate oxidative stress. Aldosterone and paroxysmal orthostatic tachycardia syndrome (POTS) paradoxes are highlighted in the context of GPCR and gut dysbiosis, and the role of Candida is explored. The triple play of a prebiotic (d-mannose), probiotic (bifidobacteria and lactobacilli), and postbiotic (butyrate) might improve intestinal barrier integrity, oppose entry of GPCR antigens, suppress the inflammatory cytokine triad, balance IFN-γ and TGF-β, suppress oxidative stress, depress KTR, elevate HRV, and extend lifespan and its quality.
