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Signal Transduction and Targeted Therapy Nov 2021The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital... (Review)
Review
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.
Topics: Autoimmune Diseases; Humans; Janus Kinases; Neoplasm Proteins; Neoplasms; STAT Transcription Factors; Signal Transduction
PubMed: 34824210
DOI: 10.1038/s41392-021-00791-1 -
Frontiers in Immunology 2021Vitiligo is a multifactorial reversible skin disorder characterized by distinct white patches that result from melanocyte destruction. Activated CXCR3 CD8 T cells... (Review)
Review
Vitiligo is a multifactorial reversible skin disorder characterized by distinct white patches that result from melanocyte destruction. Activated CXCR3 CD8 T cells promote melanocyte detachment and apoptosis through interferon-gamma (IFN-γ secretion and chemokines secreted by keratinocytes through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-1 signaling pathway results in further recruitment of CXCR3 CD8 T cells and the formation of a positive-feedback loop. JAK inhibitors target the JAK/STAT pathway and are now approved to treat many immune-related diseases. In the treatment of vitiligo, JAK inhibitors, including ruxolitinib, baricitinib, and tofacitinib, are effective, supporting the implication of the IFN-γ-chemokine signaling axis in the pathogenesis of vitiligo. However, more studies are required to determine the ideal dosage of JAK inhibitors for the treatment of vitiligo, and to identify other inflammatory pathways that may be implicated in the pathogenesis of this condition.
Topics: Biomarkers; Cytokines; Disease Management; Disease Susceptibility; Humans; Interferon-gamma; Janus Kinase Inhibitors; Janus Kinases; Molecular Targeted Therapy; STAT1 Transcription Factor; Signal Transduction; Treatment Outcome; Vitiligo
PubMed: 34868078
DOI: 10.3389/fimmu.2021.790125 -
Frontiers in Immunology 2022Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality of life.... (Review)
Review
Atopic dermatitis (AD) is a chronic, inflammatory, pruritic form of dermatosis with heterogeneous manifestations that can substantially affect patients' quality of life. AD has a complex pathogenesis, making treatment challenging for dermatologists. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a central role in modulating multiple immune axes involved in the immunopathogenesis of AD. In particular, Th2 cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin, which contribute to the symptoms of chronic inflammation and pruritus in AD, are mediated by JAK-STAT signal transduction. Furthermore, JAK-STAT is involved in the regulation of the epidermal barrier and the modulation of peripheral nerves related to the transduction of pruritus. Targeting the JAK-STAT pathway may attenuate these signals and show clinical efficacy through the suppression of various immune pathways associated with AD. Topical and oral JAK inhibitors with variable selectivity have emerged as promising therapeutic options for AD. Notably, topical ruxolitinib, oral upadacitinib, and oral abrocitinib were approved by the U.S. Food and Drug Administration for treating patients with AD. Accordingly, the present study reviewed the role of JAK-STAT pathways in the pathogenesis of AD and explored updated applications of JAK inhibitors in treating AD.
Topics: United States; Humans; Janus Kinases; Dermatitis, Atopic; Janus Kinase Inhibitors; Quality of Life; STAT Transcription Factors; Signal Transduction; Cytokines; Inflammation; Pruritus
PubMed: 36569854
DOI: 10.3389/fimmu.2022.1068260 -
Autoimmunity Reviews Apr 2023The four Janus kinase (JAK) proteins and the seven Signal Transducers of Activated Transcription (STAT) mediate intracellular signal transduction downstream of cytokine... (Review)
Review
The four Janus kinase (JAK) proteins and the seven Signal Transducers of Activated Transcription (STAT) mediate intracellular signal transduction downstream of cytokine receptors, which are involved in the pathology of allergic, autoimmune, and inflammatory diseases. The development of targeted small-molecule treatments with diverse selective inhibitory profiles, such as JAK inhibitors (JAKi), has supported an important change in the treatment of multiple disorders. Indeed, JAKi inhibit intracellular signalling controlled by numerous cytokines implicated in the disease process of rheumatoid arthritis and several other inflammatory and immune diseases. Therefore, JAKi have the capacity to target multiple pathways of those diseases. Other autoimmune diseases treated with JAKi include systemic sclerosis, systemic lupus erythematosus, dermatomyositis, primary Sjogren's syndrome, and vasculitis. In all of these cases, innate immunity stimulation activates adaptive immunity, resulting in the production of autoreactive T cells as well as the stimulation and differentiation of B cells. Mechanism-based treatments that target JAK-STAT pathways have the possibility of improving outcomes by reducing the consumption of glucocorticoids and/or non-specific immunosuppressive drugs in the management of systemic immune-mediated inflammatory diseases.
Topics: Humans; Janus Kinase Inhibitors; Autoimmune Diseases; Arthritis, Rheumatoid; Lupus Erythematosus, Systemic; Immunity, Innate; Janus Kinases
PubMed: 36649877
DOI: 10.1016/j.autrev.2023.103276 -
Expert Opinion on Investigational Drugs Apr 2023JAK (Janus kinase) is a type of non-receptor tyrosine kinase that includes JAK1, JAK2, JAK3, and Tyk2. Currently, there are five JAK inhibitors approved for treating... (Review)
Review
INTRODUCTION
JAK (Janus kinase) is a type of non-receptor tyrosine kinase that includes JAK1, JAK2, JAK3, and Tyk2. Currently, there are five JAK inhibitors approved for treating rheumatoid arthritis. These inhibitors vary in their selectivity for different JAK isoforms.
AREA COVERED
This review outlines the mode of actions and the results of Phase III trials of the JAK inhibitors which have been approved for the treatment of rheumatoid arthritis.
EXPERT COMMENTARY
JAK inhibitors have the potential to finely tune immunity and inflammation in patients with rheumatoid arthritis. The in vitro data indicates that IL-6 signaling is suppressed by all JAK inhibitors, while tofacitinib exhibits the most extensive suppression of cytokines via the JAK pathway. Peficitinib suppresses common gamma cytokines, and filgotinib suppresses interferon. Furthermore, baricitinib and upadacitinib appear to be inclined toward suppressing interferon and the IL-12 family. Despite their specific target profiles, any of these drugs can inhibit other JAKs if their blood levels surpass a certain threshold. As a result, predicting in vivo selectivity remains a challenging task. JAK inhibitor seems to be a vital treatment option for difficult-to-treat rheumatoid arthritis patients, and it is expected that precision medicine approaches will enhance its effectiveness in the future.
Topics: Humans; Janus Kinase Inhibitors; Arthritis, Rheumatoid; Janus Kinases; Cytokines; Interferons
PubMed: 37014106
DOI: 10.1080/13543784.2023.2199919 -
Indian Journal of Dermatology,... 2023The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a key regulatory signaling system for cellular proliferation, differentiation,... (Review)
Review
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a key regulatory signaling system for cellular proliferation, differentiation, and apoptosis. In addition, JAK signaling pathway plays critical roles in orchestrating immune response through its interactions with the cytokine receptors and the transcriptions factors. Several key cytokines use JAK-STAT signaling proteins to transduce intra-cellular signals which are involved in the pathogenesis of autoimmune and inflammatory diseases such as in psoriatic disease (psoriasis, psoriatic arthritis), atopic dermatitis, alopecia areata, vitiligo, rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, Sjogren's syndrome, and other autoimmune diseases. In recent years, understandings of the molecular mechanisms of JAK-STAT pathway in the inflammatory proliferative cascades of autoimmune diseases has led to the development of JAK inhibitors and has opened a new dimension for the treatment of systemic and cutaneous inflammatory diseases. In this symposium we have provided a broad perspective on the use of Janus kinase inhibitors in cutaneous autoimmune diseases.
Topics: Humans; Janus Kinase Inhibitors; Janus Kinases; STAT Transcription Factors; Signal Transduction; Skin Diseases; Autoimmune Diseases
PubMed: 37609754
DOI: 10.25259/IJDVL_8_2023 -
Skin Therapy Letter Jan 2022Janus kinase inhibitors, also commonly referred to as JAK inhibitors, are a novel drug class that target and block cytokine signaling mediated by the Janus kinase-signal... (Review)
Review
Janus kinase inhibitors, also commonly referred to as JAK inhibitors, are a novel drug class that target and block cytokine signaling mediated by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, thereby regulating immune response and cell growth. Although JAK inhibitors are mainly used for rheumatological conditions such as rheumatoid arthritis, their application in the field of dermatology is actively being investigated. Tofacitinib is US FDA-approved for psoriatic arthritis and showing promise for treating psoriasis. Most recently, regulatory approvals for the US were gained by ruxolitinib as a first-inclass, selective, topical therapy for atopic dermatitis and oral upadacitinib for active psoriatic psoriasis. Additionally, abrocitinib and upadacitinib have demonstrated efficacy in atopic dermatitis and are pending FDA approval for this indication. The therapeutic potential of JAK inhibitors in dermatological conditions such as alopecia areata, psoriasis, atopic dermatitis, vitiligo, and dermatomyositis are showing promising results in clinical trials. Adverse events for JAK inhibitors seem to be similar to that of biologic drugs. Common adverse effects include increased risk of infections and thromboembolic events. Further investigation is needed to not only better understand the safety profile of JAK inhibitors, but also their full utility within the field of dermatology.
Topics: Alopecia Areata; Dermatology; Humans; Janus Kinase Inhibitors; Janus Kinases; Vitiligo
PubMed: 35081305
DOI: No ID Found -
Molecular Cancer Therapeutics Dec 2022The JAK/STAT axis is implicated in cancer, inflammation, and immunity. Numerous cytokines/growth factors affect JAK/STAT signaling. JAKs (JAK1, JAK2, JAK3, and TYK2)... (Review)
Review
The JAK/STAT axis is implicated in cancer, inflammation, and immunity. Numerous cytokines/growth factors affect JAK/STAT signaling. JAKs (JAK1, JAK2, JAK3, and TYK2) noncovalently associate with cytokine receptors, mediate receptor tyrosine phosphorylation, and recruit ≥1 STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). Tyrosine-phosphorylated STATs dimerize and are then transported into the nucleus to function as transcription factors. Signaling is attenuated by specific suppressor of cytokine signaling proteins, creating a negative feedback loop. Both germline mutations and polymorphisms of JAK family members correlate with specific diseases: Systemic lupus erythematosus (TYK2 polymorphisms); severe combined immunodeficiency (JAK3 mutations); pediatric acute lymphoblastic leukemia (TYK2 mutations); and hereditary thrombocytosis (JAK2 mutations). Somatic gain-of-function JAK mutations mainly occur in hematologic malignancies, with the activating JAK2 V617F being a myeloproliferative disorder hallmark; it is also seen in clonal hematopoiesis of indeterminate potential. Several T-cell malignancies, as well as B-cell acute lymphoblastic leukemia, and acute megakaryoblastic leukemia also harbor JAK family somatic alterations. On the other hand, JAK2 copy-number loss is associated with immune checkpoint inhibitor resistance. JAK inhibitors (jakinibs) have been deployed in many conditions with JAK activation; they are approved in myeloproliferative disorders, rheumatoid and psoriatic arthritis, atopic dermatitis, ulcerative colitis, graft-versus-host disease, alopecia areata, ankylosing spondylitis, and in patients hospitalized for COVID-19. Clinical trials are investigating jakinibs in multiple other autoimmune/inflammatory conditions. Furthermore, dermatologic and neurologic improvements have been observed in children with Aicardi-Goutieres syndrome (a genetic interferonopathy) treated with JAK inhibitors.
Topics: Humans; COVID-19; Janus Kinase 1; Janus Kinase 2; Janus Kinase Inhibitors; Janus Kinases; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; STAT Transcription Factors; Tyrosine
PubMed: 36252553
DOI: 10.1158/1535-7163.MCT-22-0323 -
International Immunopharmacology Mar 2020The JAK/STAT signaling pathway is an universally expressed intracellular signal transduction pathway and involved in many crucial biological processes, including cell... (Review)
Review
The JAK/STAT signaling pathway is an universally expressed intracellular signal transduction pathway and involved in many crucial biological processes, including cell proliferation, differentiation, apoptosis, and immune regulation. It provides a direct mechanism for extracellular factors-regulated gene expression. Current researches on this pathway have been focusing on the inflammatory and neoplastic diseases and related drug. The mechanism of JAK/STAT signaling is relatively simple. However, the biological consequences of the pathway are complicated due to its crosstalk with other signaling pathways. In addition, there is increasing evidence indicates that the persistent activation of JAK/STAT signaling pathway is closely related to many immune and inflammatory diseases, yet the specific mechanism remains unclear. Therefore, it is necessary to study the detailed mechanisms of JAK/STAT signaling in disease formation to provide critical reference for clinical treatments of the diseases. In this review, we focus on the structure of JAKs and STATs, the JAK/STAT signaling pathway and its negative regulators, the associated diseases, and the JAK inhibitors for the clinical therapy.
Topics: Animals; Cytokines; Disease Models, Animal; Humans; Immune System Diseases; Inflammation; Janus Kinases; Protein Kinase Inhibitors; STAT Transcription Factors; Signal Transduction
PubMed: 31972425
DOI: 10.1016/j.intimp.2020.106210 -
Pharmacological Research Sep 2022The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK... (Review)
Review
The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.
Topics: Arthritis, Rheumatoid; COVID-19; Humans; Janus Kinase 1; Janus Kinase 2; Janus Kinase Inhibitors; Janus Kinases; Polycythemia Vera; Primary Myelofibrosis; Protein Kinase Inhibitors
PubMed: 35878738
DOI: 10.1016/j.phrs.2022.106362