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Genetics at the Cell Level
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Valentina Lorenzi, Roser Vento-Tormo
Prompted by the in vivo findings about the potential role of JAK-STAT signaling in the ascites of HGSOC patients, Izar et al. (2020) used primary HGSOC cell lines and patient ascites-derived xenograft models to test the effects of JAK-STAT signaling inhibition. They performed a drug screen with compounds targeting different nodes of the JAK-STAT signaling pathway and identified one compound, JSI-124, as having potent anti-tumor activity. Taken together, the results from the in vivo and in vitro analyses revealed that inhibition of the JAK-STAT signaling pathway may be a therapeutic option for HGSOC patients (Izar et al., 2020).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Since members of the Type I and II cytokine receptor families on the cell surface have no catalytic kinase activity of their own, they rely on the internal JAK kinases to phosphorylate and activate downstream proteins involved in the signalling pathways (Figure 6.65). The receptors exist as paired polypeptides, thus exhibiting two intracellular signal-transducing domains. After the receptor associates with its respective ligand or cytokine it undergoes a conformational change, bringing the two JAK kinases close enough for mutual phosphorylation. This JAK autophosphorylation induces a conformational change, enabling further intracellular signalling by phosphorylating and activating the STAT (Signal Transducer and Activator of Transcription) transcription factors. The activated STAT proteins dissociate from the receptor and form dimers before translocating to the cell nucleus where they interact with their cognate DNA sequence and regulate the transcription of selected genes. Examples of extracellular signalling molecules that act as ligands for the JAK/STAT signalling pathway include many cytokines, colony-stimulating factor (CSF), growth hormone, and prolactin.
Etiopathogenesis
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Dario Didona, Biagio Didona, Giovanni Paolino, Raffaele Dante Caposiena Caro
The JAK-STAT signaling pathway is essential to transmit extracellular signals of several cytokines to the nucleus, including IL-12, IL-6, IL-17, IL-21, IL-23, and IFN-γ [22]. It mediates the biological activities of these cytokines and is essential for the development and regulation of immune responses. Dysregulation of the JAK-STAT pathway contributes to numerous autoimmune diseases, including vitiligo [22]. Four members of the JAK family have been described: JAK1, JAK2, JAK3, and tyrosine kinase 2. Among these, JAK1 and JAK2 are directly involved in IFN-γ signaling, which activates STAT1 and thus induces the transcription of IFN-γ–induced genes, including CXCL10, which through its receptor CXCR3 recruits more autoreactive T cells to the epidermis, resulting in widespread melanocyte destruction [22].
Emerging therapeutic targets for retinoblastoma
Published in Expert Opinion on Therapeutic Targets, 2022
Radhika Manukonda, Revu VL Narayana, Swathi Kaliki, Dilip K Mishra, Geeta K Vemuganti
Key signaling pathways disrupted in CSCs are listed in Figure 3. Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Wnt/β-catenin, notch, NF-kB, hedgehog, and transforming growth factor beta (TGF-β) are the common signaling pathways involved in all CSCs. The irregularities in these pathways lead to the acquisition of self-renewal, differentiation, proliferative, and survival properties of CSCs through anomalous regulation of target genes, such as transcription factors (Oct-4 Nanog, Sox2), c-Myc, cyclins (cyclin D1) and pro-apoptotic gene (survivin) and others. Notch signaling is the evolutionary conserved and one of the most activated pathways in cancer cells. It has a vital role in cell differentiation and cell cycle progression [89]. Wingless/Integrated (Wnt) signaling pathway includes both β-catenin-dependent (canonical) and β-catenin-independent (noncanonical) pathways, which regulate asymmetric cell division, cell polarity, migration, survival, and proliferation of cells [90]. The JAK/STAT signaling pathway has a critical role in cytokines and growth factor signaling. Aberrant regulation of this pathway leads to the maintenance of CSC-like cells in various cancers [91]. Understanding the molecular mechanisms responsible for deregulation in these pathways would help to develop new therapeutic approaches that directly target CSCs.
Janus kinase versus TNF inhibitors: where we stand today in rheumatoid arthritis
Published in Expert Review of Clinical Immunology, 2022
Aliki I. Venetsanopoulou, Paraskevi V. Voulgari, Alexandros A. Drosos
JAKi antagonize JAK protein function and block the JAK-STAT signaling pathway, which influences the response to many cytokines. JAKi have demonstrated efficacy for RA and are currently under investigation for other autoimmune diseases, such as psoriasis, spondyloarthropathies, and systemic erythematosus lupus [67]. They act differently from bDMARDs as they inhibit multiple cytokines. Compared to the treatment with TNFi, JAKi have the advantage of oral application, short half-life, and rapid improvement of disease activity driven by pain and inflammation control [68,69]. There are four approved JAKi by the Food and Drug Administration (FDA); Tofacitinib, Baricitinib, Upacitinib, and Filgotinib. So far, all JAKi show benefit in clinical trials for patients with moderate or severe RA. After discontinuation of the first JAKi, either for inefficacy or side effects, switching to a second JAKi seems a safe and efficacious option [70].
JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy
Published in Postgraduate Medicine, 2021
Sairaj Satarker, Antriya Annie Tom, Roshitha Ann Shaji, Aaja Alosious, Mariya Luvis, Madhavan Nampoothiri
The JAK/STAT signaling pathway can influence the immune system functioning to a significant extent. The JAK/STAT signaling components like JAK1-3 and STAT1-6 have been associated with various roles in immune responses like IL-2, IL-4, IL-6, IL-12 signaling, Th (T-helper)1, Th2, Treg cell and Th9, Th 17 cell differentiation, the proliferation of viral selective CD8+ T cells and B-cell lymphoma 2 (Bcl-2) [2,56]. It is evident that cytokines are necessary for combating viral infections but the hyperinflammatory conditions created by SARS-CoV-2 infection due to cytokine storm could lead to conditions like ARDS and even death [9]. To prevent this, the inhibition of the JAK/STAT pathway may look to be a promising strategy but having said that, prolonged inhibition of this pathway could lead to compromised immune responses in the body that could promote the proliferation of the SARS-CoV-2. The viral infection could also further promote inhibition of inflammatory signaling pathways causing immunosuppression [57]. Recently, Bouwman and colleagues reported that JAK/STAT signaling system could be a valuable indicator of a strong immune response to SARS-CoV-2 infections [58]. Interestingly, another report stated that the inhibition of the JAK/STAT pathway could reduce the hyperinflammatory conditions but not the viral clearance [59]. This could suggest that COVID-19 patients who are immunocompromised could be susceptible to superinfection via inhibition of the JAK/STAT pathway that would call for cautionary use of JAK/STAT inhibitors.