Journal articles: 'JAK/STAT'

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Barry, Sean P. "JAK-STAT." JAK-STAT 1, no. 2 (April 2012): 90–91. http://dx.doi.org/10.4161/jkst.20939.

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Minaudo, Carla. "Vía JAK-STAT e inhibidores JAK." Dermatología Argentina 28, no. 2 (June 1, 2022): 55–62. http://dx.doi.org/10.47196/da.v28i2.2324.

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La vía JAK-STAT (Janus Kinasas) es una cadena de traducción de señales intracelulares, que se activa a través de receptores de citoquinas I y II. Mediante esta vía, varias moléculas de importancia en dermatología ejercen sus efectos: IL2, IL4, IL7, IL5, IL6, IL9, IL12, IL13, IL15, IL21, IL23, INFa e INFb, entre otras. También es la señal intracelular de hormonas como la prolactina y la hormona de crecimiento. La inhibición de distintos componentes de esta vía es utilizada como terapéutica en enfermedades reumatológicas y un número cada vez mayor de patologías cutáneas. Los inhibidores JAK surgieron en la práctica médica hace aproximadamente 11 años, con el ruxolitinib y poco tiempo después el tofacitinib. En la actualidad, se dispone de varias moléculas aprobadas y muchas otras en etapa experimental. En este artículo se desarrollarán la organización intracelular y las funciones de la vía JAK-STAT con sus variantes principales relacionadas a enfermedades inmunomediadas, así como las características más relevantes de los inhibidores JAK.

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Galli Sanchez, Ana Paula, Tatiane Ester Aidar Fernandes, and Gustavo Martelli Palomino. "The JAK-STAT Pathway and the JAK Inhibitors." Journal of Clinical Research in Dermatology 7, no. 5 (November 30, 2020): 1–6. http://dx.doi.org/10.15226/2378-1726/7/5/001128.

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Dozens of cytokines that bind Type I and Type II receptors use the Janus Kinases (JAK) and the Signal Transducer and Activator of Transcription (STAT) proteins pathway for intracellular signaling, orchestrating hematopoiesis, inducing inflammation, and controlling the immune response. Currently, oral JAK inhibitors are being used to treat many inflammatory and myeloproliferative diseases and are also under investigation in several clinical trials for skin diseases. Thus, dermatologists should understand how the JAK-STAT pathway works as well as the mechanism of action of the JAK inhibitors which will certainly become an important part of the dermatologist’s treatment armamentarium in the next few years. Keywords: JAK inhibitors; Janus Kinases; JAK-STAT Pathway List of Abbreviations: AD: Atopic Dermatitis ADP: Adenosine diphosphate Dmards: Disease-Modifying Antirheumatic Drugs JAK: Janus kinase(s) Jaki: Janus kinase Inhibitor(s) PIAS: Protein Inhibitor of Activated STAT P-STAT: Phosphorylated STAT STAT: Signal Transducer and Activator of Transcription TYK2: Tyrosine Kinase 2 Wsxws: Tryptophan-Serine-X-Tryptophan-Serine

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Harrison, D. A. "The JAK/STAT Pathway." Cold Spring Harbor Perspectives in Biology 4, no. 3 (March 1, 2012): a011205. http://dx.doi.org/10.1101/cshperspect.a011205.

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Wells, William A. "A JAK/STAT invasion." Journal of Cell Biology 156, no. 3 (January 28, 2002): 413. http://dx.doi.org/10.1083/jcb1563rr2.

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Aaronson, D. S., and C. M. Horvath. "The JAK-STAT Pathway." Science Signaling 2003, no. 197 (August 26, 2003): cm11. http://dx.doi.org/10.1126/stke.2003.197.cm11.

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Myllymäki, H., and M. Rämet. "JAK/STAT Pathway inDrosophilaImmunity." Scandinavian Journal of Immunology 79, no. 6 (May 21, 2014): 377–85. http://dx.doi.org/10.1111/sji.12170.

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Imada, Kazuroni, and Warren J. Leonard. "The Jak-STAT pathway." Molecular Immunology 37, no. 1-2 (January 2000): 1–11. http://dx.doi.org/10.1016/s0161-5890(00)00018-3.

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Ladyman, Sharon R., and David R. Grattan. "JAK-STAT and feeding." JAK-STAT 2, no. 2 (April 2013): e23675. http://dx.doi.org/10.4161/jkst.23675.

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Hombría, James Castelli-Gair, and Sol Sotillos. "JAK-STAT pathway inDrosophilamorphogenesis." JAK-STAT 2, no. 3 (July 15, 2013): e26089. http://dx.doi.org/10.4161/jkst.26089.

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Mertens, Claudia, and James E. Darnell. "SnapShot: JAK-STAT Signaling." Cell 131, no. 3 (November 2007): 612–612. http://dx.doi.org/10.1016/j.cell.2007.10.033.

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Liu, Jia, Faping Wang, and Fengming Luo. "The Role of JAK/STAT Pathway in Fibrotic Diseases: Molecular and Cellular Mechanisms." Biomolecules 13, no. 1 (January 6, 2023): 119. http://dx.doi.org/10.3390/biom13010119.

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There are four members of the JAK family and seven of the STAT family in mammals. The JAK/STAT molecular pathway could be activated by broad hormones, cytokines, growth factors, and more. The JAK/STAT signaling pathway extensively mediates various biological processes such as cell proliferation, differentiation, migration, apoptosis, and immune regulation. JAK/STAT activation is closely related to growth and development, homeostasis, various solid tumors, inflammatory illness, and autoimmune diseases. Recently, with the deepening understanding of the JAK/STAT pathway, the relationship between JAK/STAT and the pathophysiology of fibrotic diseases was noticed, including the liver, renal, heart, bone marrow, and lung. JAK inhibitor has been approved for myelofibrosis, and subsequently, JAK/STAT may serve as a promising target for fibrosis in other organs. Therefore, this article reviews the roles and mechanisms of the JAK/STAT signaling pathway in fibrotic diseases.

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Schieler, Jarod M., and Jeffrey O. Henderson. "Treating a Dysregulated JAK/STAT Pathway in Cancer Cells." Journal of Student Research 5, no. 1 (April 14, 2016): 11–17. http://dx.doi.org/10.47611/jsr.v5i1.282.

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The JAK/STAT pathway is induced by the binding of a cytokine to its cognate receptor. The receptor’s engagement with the cytokine recruits a JAK protein, which activates itself via auto/trans-phosphorylation. In turn, the activated JAKs recruit and phosphorylate STAT proteins. The phosphorylated STAT proteins form a dimer, translocate to the cell nucleus and acts as a transcription factor to induce gene expression. In this way, the JAK/STAT pathway can mediate a cell’s response to extracellular signals. The proteins ultimately induced by the JAK/STAT pathway contribute to processes such as inflammatory response, differentiation, proliferation, and apoptosis. When the JAK/STAT pathway becomes dysregulated, proto-oncogenes and/or tumor-suppressor genes are often inappropriately expressed, commonly resulting in oncogenesis. This review discusses how SOCS, PIAS, and PTPS proteins modulate the JAK/STAT pathway ensuring that it remains cyclic and transient. The use of jakibins, STAT inhibitors, decoy oligonucleotides, RNA interference and genome editing to synthetically regulate a dysregulated JAK/STAT pathway in cancer cells are also considered.

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Zhan, Xinliang, Yan Wang, and Jing Yang. "Janus Kinase/Signal Converters, and the Transcriptional Activator Signaling Pathway Promotes Lung Cancer Through Increasing M2 Macrophage." Journal of Biomaterials and Tissue Engineering 11, no. 4 (April 1, 2021): 605–11. http://dx.doi.org/10.1166/jbt.2021.2566.

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Accumulating evidence highlights the salient function of JAK/STAT signaling pathway in tumorigenesis and development. But the mechanism of JAK/STAT signaling in lung cancer remains elusive. This study assessed the impact of JAK/STAT on lung tumorigenesis and its interaction with microenvironment. Mouse model of primary lung cancer was established and then treated with JAK/STAT inhibitor. Immunofluorescence was performed to analyze fluorescent labels. Transwell assay determined the cell migration ability, and Western blot, immunohistochemistry, and immunofluorescence to detect the expression of JAK/STAT key proteins. Cell proliferation was measured by Kit-8 and colony formation. JAK/STAT key proteins were upregulated in lung cancer models. Inhibition of JAK/STAT led to a decrease in proliferative, migratory and invasive capability of lung cancer cells and macrophages from bone marrow and spleen. The cell invasion ability in the bone marrow and the proliferation of macrophages in the treatment group was weakened. When co-cultured with the treated macrophages, the proliferation of LLC1 cells was inhibited. Furthermore, in vitro flow cytometry indicated that JAK/STAT affected lung cancer progression by affecting the polarization of M1/M2 macrophages. Taken altogether, JAK/STAT signal enhances M2 macrophage expression and promotes lung cancer progression.

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Valle-Mendiola, Arturo, Adriana Gutiérrez-Hoya, and Isabel Soto-Cruz. "JAK/STAT Signaling and Cervical Cancer: From the Cell Surface to the Nucleus." Genes 14, no. 6 (May 24, 2023): 1141. http://dx.doi.org/10.3390/genes14061141.

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The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway constitutes a rapid signaling module from the cell surface to the nucleus, and activates different cellular responses, such as proliferation, survival, migration, invasion, and inflammation. When the JAK/STAT pathway is altered, it contributes to cancer progression and metastasis. STAT proteins play a central role in developing cervical cancer, and inhibiting the JAK/STAT signaling may be necessary to induce tumor cell death. Several cancers show continuous activation of different STATs, including cervical cancer. The constitutive activation of STAT proteins is associated with a poor prognosis and overall survival. The human papillomavirus (HPV) oncoproteins E6 and E7 play an essential role in cervical cancer progression, and they activate the JAK/STAT pathway and other signals that induce proliferation, survival, and migration of cancer cells. Moreover, there is a crosstalk between the JAK/STAT signaling cascade with other signaling pathways, where a plethora of different proteins activate to induce gene transcription and cell responses that contribute to tumor growth. Therefore, inhibition of the JAK/STAT pathway shows promise as a new target in cancer treatment. In this review, we discuss the role of the JAK/STAT pathway components and the role of the HPV oncoproteins associated with cellular malignancy through the JAK/STAT proteins and other signaling pathways to induce tumor growth.

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Rodriguez, Irasema, and Kate J. F. Carnevale. "Systematic Review: JAK-STAT Regulation and Its Impact on Inflammation Response in ARDS from COVID-19." Immuno 4, no. 2 (May 14, 2024): 147–58. http://dx.doi.org/10.3390/immuno4020010.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has had a global impact and resulted in millions of deaths worldwide. The course of the Janus kinase signaling transducers and activators (JAK-STAT) pathway is an important molecular pathway that is involved in the cellular response to various cytokines and growth factors promoting an inflammatory response. The overactivation of the JAK-STAT signaling pathway in coronavirus disease 2019 (COVID-19) and its effect on acute respiratory distress syndrome (ARDS)-induced inflammatory processes was observed in various clinical articles that focused on JAK-STAT regulation regarding angiotensin converting enzyme 2 (ACE2) expression and cytokine storm release. Down-regulation of the JAK-STAT signaling pathway through inhibitors decreases the inflammatory response by decreasing cytokine storm release. However, the increased regulation of JAK-STAT in severe COVID-19 patients caused cytokines such as interferon alpha (IFN-α) to promote the phosphorylation of STATs. This response indicated an imbalance with JAK-STAT regulation and its inability to induce the transcription of interferon stimulated response elements. Furthermore, an increase in ACE2 regulation was noted to also increase JAK-STAT signaling, yet the down-regulation of JAK-STAT signaling can result in the overexpression of ACE2 by binding to SARS-CoV-2 and increasing STAT1 expression. Data suggest that inflammatory cytokines enhance the activation of ACE2 in endothelial cells via JAK-STAT pathway. Increasing the regulation of the JAK-STAT signaling pathway enhances the release of cytokines such as tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), further expressing ACE2. The expression of ACE2 regulates STAT1 and STAT2 expression, leading to the up-regulation of the inflammasomal complexes in hyper-inflammatory responses from the JAK-STAT pathway. Through the review of various clinical reports, the effect of the JAK-STAT signaling pathway on ARDS-induced inflammatory response was observed and correlated with the expression of ACE2 and cytokine storm release in severe COVID-19 cases.

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Bonjardim, C. A. "JAK/STAT-deficient cell lines." Brazilian Journal of Medical and Biological Research 31, no. 11 (November 1998): 1389–95. http://dx.doi.org/10.1590/s0100-879x1998001100004.

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Rabadan, Raul, and Giorgio Inghirami. "JAK-STAT in lymphoproliferative disorders." Oncoscience 2, no. 9 (August 11, 2015): 737–38. http://dx.doi.org/10.18632/oncoscience.189.

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Pernis, Alessandra B., and Paul B. Rothman. "JAK-STAT signaling in asthma." Journal of Clinical Investigation 109, no. 10 (May 15, 2002): 1279–83. http://dx.doi.org/10.1172/jci0215786.

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20

Barwick, Benjamin G., and Sagar Lonial. "We need CD38 STAT-JAK." Blood 136, no. 20 (November 12, 2020): 2246–48. http://dx.doi.org/10.1182/blood.2020007467.

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Rawlings, J. S. "The JAK/STAT signaling pathway." Journal of Cell Science 117, no. 8 (March 15, 2004): 1281–83. http://dx.doi.org/10.1242/jcs.00963.

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Heinrich, Peter C., Serge Haan, Kevin W. Harris, Heike M. Hermanns, Silke Metz, Gerhard Müller-Newen, Fred Schaper, and Monique Wiesinger. "JAK/STAT signaling in cancer." Biomedicine & Pharmacotherapy 60, no. 8 (September 2006): 488. http://dx.doi.org/10.1016/j.biopha.2006.07.058.

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Villarino, Alejandro V., Massimo Gadina, John J. O’Shea, and Yuka Kanno. "SnapShot: Jak-STAT Signaling II." Cell 181, no. 7 (June 2020): 1696–1696. http://dx.doi.org/10.1016/j.cell.2020.04.052.

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Li, Jiliang. "JAK-STAT and bone metabolism." JAK-STAT 2, no. 3 (July 15, 2013): e23930. http://dx.doi.org/10.4161/jkst.23930.

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Schindler, Christian. "Cytokines and JAK–STAT Signaling." Experimental Cell Research 253, no. 1 (November 1999): 7–14. http://dx.doi.org/10.1006/excr.1999.4670.

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Park, Hyunjung, Sangjik Lee, Jaehun Lee, Hyuk Moon, and Simon Weonsang Ro. "Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications." International Journal of Molecular Sciences 24, no. 18 (September 6, 2023): 13764. http://dx.doi.org/10.3390/ijms241813764.

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Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.

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Montero, Paula, Javier Milara, Inés Roger, and Julio Cortijo. "Role of JAK/STAT in Interstitial Lung Diseases; Molecular and Cellular Mechanisms." International Journal of Molecular Sciences 22, no. 12 (June 9, 2021): 6211. http://dx.doi.org/10.3390/ijms22126211.

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Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The JAK/STAT molecular pathway is activated under the interaction of a broad number of profibrotic/pro-inflammatory cytokines, such as IL-6, IL-11, and IL-13, among others, which are increased in different ILDs. Similarly, several growth factors over-expressed in ILDs, such as platelet-derived growth factor (PDGF), transforming growth factor β1 (TGF-β1), and fibroblast growth factor (FGF) activate JAK/STAT by canonical or non-canonical pathways, which indicates a predominant role of JAK/STAT in ILDs. Between the different JAK/STAT isoforms, it appears that JAK2/STAT3 are predominant, initiating cellular changes observed in ILDs. This review analyzes the expression and distribution of different JAK/STAT isoforms in ILDs lung tissue and different cell types related to ILDs, such as lung fibroblasts and alveolar epithelial type II cells and analyzes JAK/STAT activation. The effect of JAK/STAT phosphorylation on cellular fibrotic processes, such as proliferation, senescence, autophagy, endoplasmic reticulum stress, or epithelial/fibroblast to mesenchymal transition will be described. The small molecules directed to inhibit JAK/STAT activation were assayed in vitro and in in vivo models of pulmonary fibrosis, and different JAK inhibitors are currently approved for myeloproliferative disorders. Recent evidence indicates that JAK inhibitors or monoclonal antibodies directed to block IL-6 are used as compassionate use to attenuate the excessive inflammation and lung fibrosis related to SARS-CoV-2 virus. These altogether indicate that JAK/STAT pathway is an attractive target to be proven in future clinical trials of lung fibrotic disorders.

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Damerau, Alexandra, Timo Gaber, Sarah Ohrndorf, and Paula Hoff. "JAK/STAT Activation: A General Mechanism for Bone Development, Homeostasis, and Regeneration." International Journal of Molecular Sciences 21, no. 23 (November 26, 2020): 9004. http://dx.doi.org/10.3390/ijms21239004.

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The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway serves as an important downstream mediator for a variety of cytokines, hormones, and growth factors. Emerging evidence suggests JAK/STAT signaling pathway plays an important role in bone development, metabolism, and healing. In this light, pro-inflammatory cytokines are now clearly implicated in these processes as they can perturb normal bone remodeling through their action on osteoclasts and osteoblasts at both intra- and extra-articular skeletal sites. Here, we summarize the role of JAK/STAT pathway on development, homeostasis, and regeneration based on skeletal phenotype of individual JAK and STAT gene knockout models and selective inhibition of components of the JAK/STAT signaling including influences of JAK inhibition in osteoclasts, osteoblasts, and osteocytes.

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Neeli, Indira, Zhimin Liu, Nagadhara Dronadula, Z. Alex Ma, and Gadiparthi N. Rao. "An Essential Role of the Jak-2/STAT-3/Cytosolic Phospholipase A2Axis in Platelet-derived Growth Factor BB-induced Vascular Smooth Muscle Cell Motility." Journal of Biological Chemistry 279, no. 44 (August 22, 2004): 46122–28. http://dx.doi.org/10.1074/jbc.m406922200.

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Platelet-derived growth factor-BB (PDGF-BB) is a potent motogen for vascular smooth muscle cells (VSMCs). To understand its motogenic signaling events, we have studied the role of the Janus-activated kinase/signal transducers and activators of transcription (Jak/STAT) pathway and cytosolic phospholipase A2(cPLA2). PDGF-BB stimulated tyrosine phosphorylation of Jak-2 and STAT-3 in a time-dependent manner in VSMCs. In addition, AG490 and Jak-2KEpRK5, a selective pharmacological inhibitor and a dominant negative mutant, respectively, of Jak-2, attenuated PDGF-BB-induced STAT-3 tyrosine phosphorylation and its DNA binding and reporter gene activities. PDGF-BB induced VSMC motility in a dose-dependent manner with a maximum effect at 10 ng/ml. Dominant negative mutant-dependent suppression of Jak-2 and STAT-3 blocked PDGF-BB-induced VSMC motility. PDGF-BB induced the expression of cPLA2in a Jak-2/STAT-3-dependent manner, and pharmacological inhibitors of cPLA2prevented PDGFBB-induced VSMC motility. Furthermore, either exogenous addition of arachidonic acid or forced expression of cPLA2rescued PDGF-BB-induced VSMC motility from inhibition by blockade of Jak-2 and STAT-3 activation. Together, these results for the first time show that PDGF-BB-induced VSMC motility requires activation of the Jak-2/STAT-3/cPLA2signaling axis.

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Gorissen, Marnix, Erik de Vrieze, Gert Flik, and Mark O. Huising. "STAT genes display differential evolutionary rates that correlate with their roles in the endocrine and immune system." Journal of Endocrinology 209, no. 2 (February 17, 2011): 175–84. http://dx.doi.org/10.1530/joe-11-0033.

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We identified orthologues of all mammalian Janus kinase (JAK) and signal transducer and activator of transcription (STAT) genes in teleostean fishes, indicating that these protein families were already largely complete before the teleost tetrapod split, 450 million years ago. In mammals, the STAT repertoire consists of seven genes (STAT1, -2, -3, -4, -5a, -5b, and -6). Our phylogenetic analyses show that STAT proteins that are recruited downstream of endocrine hormones (STAT3 and STAT5a and -5b) show a markedly higher primary sequence conservation compared with STATs that convey immune signals (STAT1-2, STAT4, and STAT6). A similar dichotomy in evolutionary conservation is observed for the JAK family of protein kinases, which activate STATs. The ligands to activate the JAK/STAT-signalling pathway include hormones and cytokines such as GH, prolactin, interleukin 6 (IL6) and IL12. In this paper, we examine the evolutionary forces that have acted on JAK/STAT signalling in the endocrine and immune systems and discuss the reasons why the JAK/STAT cascade that conveys classical immune signals has diverged much faster compared with endocrine JAK/STAT paralogues.

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Gerds, Aaron T. "Beyond JAK-STAT: novel therapeutic targets in Ph-negative MPN." Hematology 2019, no. 1 (December 6, 2019): 407–14. http://dx.doi.org/10.1182/hematology.2019000048.

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Abstract The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) share a common pathobiology of constitutive activation of the JAK and STAT pathway, despite having the 3 distinct phenotypes of essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Targeting the JAK-STAT pathway has led to remarkable clinical benefit, including reduction in splenomegaly, amelioration of cytokine-driven symptoms, improvement in quality of life, and even some improvement in survival. However, targeting this pathway has not resulted in consistent disease modification by current metrics, including a reduction in mutant allele burden or reversal of fibrosis. Moreover, targeting JAK-STAT can lead to limiting treatment-emergent side effects, such as anemia and thrombocytopenia. Continued discovery points to a complex system of pathogenesis beyond JAK-STAT driving the formation and evolution of MPNs. This article reviews the successes and limitations of JAK-STAT inhibition, surveys the strategies behind emerging therapies, and discusses the challenges that are present in moving beyond JAK-STAT.

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Jain, Mayank, Mukul Kumar Singh, Hari Shyam, Archana Mishra, Shailendra Kumar, Ambrish Kumar, and Jitendra Kushwaha. "Role of JAK/STAT in the Neuroinflammation and its Association with Neurological Disorders." Annals of Neurosciences 28, no. 3-4 (July 2021): 191–200. http://dx.doi.org/10.1177/09727531211070532.

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Background: Innate immunity is mediated by a variety of cell types, including microglia, macrophages, and neutrophils, and serves as the immune system's first line of defense. There are numerous pathways involved in innate immunity, including the interferon (IFN) pathway, TRK pathway, mitogen-activated protein kinase (MAPK) pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, interleukin (IL) pathways, chemokine pathways (CCR5), GSK signaling, and Fas signaling. Summary: JAK/STAT is one of these important signaling pathways and this review focused on JAK/STAT signaling pathway only. The overactivation of microglia and astrocytes influences JAK/STAT's role in neuroinflammatory disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and ultimately constraining inflammatory and immunological responses. The JAK/STAT signaling pathway is one of the critical factors that promotes neuroinflammation in neurodegenerative diseases. Key message: Given the importance of the JAK/STAT pathway in neurodegenerative disease, this review discussed the feasibility of targeting the JAK/STAT pathway as a neuroprotective therapy for neurodegenerative diseases in near future.

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Karati, Dipanjan, Kakasaheb Ramoo Mahadik, Piyush Trivedi, and Dileep Kumar. "The Emerging Role of Janus Kinase Inhibitors in the Treatment of Cancer." Current Cancer Drug Targets 22, no. 3 (March 2022): 221–33. http://dx.doi.org/10.2174/1568009622666220301105214.

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Abstract: Cancer is a leading cause of death worldwide. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signalling pathway are activated abnormally, which promotes carcinogenesis. Several cytokines are important cancer drivers. These proteins bind to receptors and use the Janus kinase (JAK) and STAT pathways to communicate their responses. Cancer risks are linked to genetic differences in the JAK-STAT system. JAK inhibitors have been shown to reduce STAT initiation, tissue propagation, and cell existence in preclinical investigations involving solid tumour cell line models. JAK inhibitors, notably ruxolitinib, JAK1 or 2 blockers, make cell lines and mouse models more susceptible to radiotherapy, biological response modifier therapy, and oncolytic viral treatment. Numerous JAK antagonists have been or are now being evaluated in cancerous patients as monotherapy or by combining with other drugs in clinical studies. In preclinical investigations, certain JAK inhibitors showed promising anticancer effects; however, clinical trials explicitly evaluating their effectiveness against the JAK/STAT system in solid tumours have yet to be completed. JAK inhibition is a promising strategy to target the JAK/STAT system in solid tumours, and it deserves to be tested further in clinical studies. The function of directing Janus kinases (JAKs), an upstream accelerator of STATs, as a technique for lowering STAT activity in various malignant circumstances is summarized in this article, which will help scientists to generate more specific drug molecules in the future.

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Wahnschaffe, Linus, Till Braun, Sanna Timonen, Anil K. Giri, Alexandra Schrader, Prerana Wagle, Henrikki Almusa, et al. "JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL." Cancers 11, no. 12 (November 21, 2019): 1833. http://dx.doi.org/10.3390/cancers11121833.

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T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. Recent studies detected genomic aberrations affecting JAK and STAT genes in T-PLL. Due to the limited number of primary patient samples available, genomic analyses of the JAK/STAT pathway have been performed in rather small cohorts. Therefore, we conducted—via a primary-data based pipeline—a meta-analysis that re-evaluated the genomic landscape of T-PLL. It included all available data sets with sequence information on JAK or STAT gene loci in 275 T-PLL. We eliminated overlapping cases and determined a cumulative rate of 62.1% of cases with mutated JAK or STAT genes. Most frequently, JAK1 (6.3%), JAK3 (36.4%), and STAT5B (18.8%) carried somatic single-nucleotide variants (SNVs), with missense mutations in the SH2 or pseudokinase domains as most prevalent. Importantly, these lesions were predominantly subclonal. We did not detect any strong association between mutations of a JAK or STAT gene with clinical characteristics. Irrespective of the presence of gain-of-function (GOF) SNVs, basal phosphorylation of STAT5B was elevated in all analyzed T-PLL. Fittingly, a significant proportion of genes encoding for potential negative regulators of STAT5B showed genomic losses (in 71.4% of T-PLL in total, in 68.4% of T-PLL without any JAK or STAT mutations). They included DUSP4, CD45, TCPTP, SHP1, SOCS1, SOCS3, and HDAC9. Overall, considering such losses of negative regulators and the GOF mutations in JAK and STAT genes, a total of 89.8% of T-PLL revealed a genomic aberration potentially explaining enhanced STAT5B activity. In essence, we present a comprehensive meta-analysis on the highly prevalent genomic lesions that affect genes encoding JAK/STAT signaling components. This provides an overview of possible modes of activation of this pathway in a large cohort of T-PLL. In light of new advances in JAK/STAT inhibitor development, we also outline translational contexts for harnessing active JAK/STAT signaling, which has emerged as a ‘secondary’ hallmark of T-PLL.

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Owen, Katie L., Natasha K. Brockwell, and Belinda S. Parker. "JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression." Cancers 11, no. 12 (December 12, 2019): 2002. http://dx.doi.org/10.3390/cancers11122002.

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Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.

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Łączak, Michał, Martyna Kuczyńska, Joanna Grygier, Dominika Andrzejewska, Wiktoria Grochowska, Hanna Gulaczyk, and Krzysztof Lewandowski. "JAK and STAT gene mutations and JAK-STAT pathway activation in lympho- and myeloproliferative neoplasms." Hematology in Clinical Practice 12, no. 3-4 (February 18, 2022): 89–104. http://dx.doi.org/10.5603/hcp.a2021.0013.

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Hin Tang, Justin Jit, Dexter Kai Hao Thng, Jhin Jieh Lim, and Tan Boon Toh. "JAK/STAT signaling in hepatocellular carcinoma." Hepatic Oncology 7, no. 1 (March 1, 2020): HEP18. http://dx.doi.org/10.2217/hep-2020-0001.

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Liver cancer is the second most lethal cancer in the world with limited treatment options. Hepatocellular carcinoma (HCC), which accounts for more than 80% of all liver cancers, has had increasing global incidence over the past few years. There is an urgent need for novel and better therapeutic intervention for HCC patients. The JAK/STAT signaling pathway plays a multitude of important biological functions in both normal and malignant cells. In a subset of HCC, JAK/STAT signaling is aberrantly activated, leading to dysregulation of downstream target genes that controls survival, angiogenesis, stemness, immune surveillance, invasion and metastasis. In this review, we will focus on the role of JAK/STAT signaling in HCC and discuss the current clinical status of several JAK/STAT inhibitors.

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Gutiérrez-Hoya, Adriana, and Isabel Soto-Cruz. "Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins." Cells 9, no. 10 (October 15, 2020): 2297. http://dx.doi.org/10.3390/cells9102297.

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The janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is associated with the regulation of essential cellular mechanisms, such as proliferation, invasion, survival, inflammation, and immunity. Aberrant JAK/STAT signaling contributes to cancer progression and metastatic development. STAT proteins play an essential role in the development of cervical cancer, and the inhibition of the JAK/STAT pathway may be essential for enhancing tumor cell death. Persistent activation of different STATs is present in a variety of cancers, including cervical cancer, and their overactivation may be associated with a poor prognosis and poor overall survival. The oncoproteins E6 and E7 play a critical role in the progression of cervical cancer and may mediate the activation of the JAK/STAT pathway. Inhibition of STAT proteins appears to show promise for establishing new targets in cancer treatment. The present review summarizes the knowledge about the participation of the different components of the JAK/STAT pathway and the participation of the human papillomavirus (HPV) associated with the process of cellular malignancy.

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Pazdrak, K., S. Stafford, and R. Alam. "The activation of the Jak-STAT 1 signaling pathway by IL-5 in eosinophils." Journal of Immunology 155, no. 1 (July 1, 1995): 397–402. http://dx.doi.org/10.4049/jimmunol.155.1.397.

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Abstract The intracellular signal transduction of IL-5 in eosinophils is unknown. The objective of this study was to investigate the involvement of the newly discovered Jak-STAT pathway in the IL-5 signal transduction mechanism. Eosinophils were purified from peripheral blood by discontinuous Percoll gradients and stimulated with IL-5. The involvement of Jak 2 was investigated by immunoprecipitation followed by immunoblotting for tyrosine phosphorylation. The activation of Jak 2 was studied by autophosphorylation of the immunoprecipitated kinase. Jak 2 was tyrosine phosphorylated within 1 to 3 min after stimulation of eosinophils with IL-5. Further, the immunoprecipitated Jak 2 obtained from IL-5-stimulated cells underwent autophosphorylation. Jak 2 coprecipitated with the beta-subunit of the IL-5 receptor, suggesting a physical association of the kinase with the receptor. The nuclear factor STAT-1 (p91) was investigated by immunoprecipitation followed by immunoblotting for tyrosine phosphorylation. STAT-1 was tyrosine phosphorylated within 15 min of IL-5 stimulation. The presence of STAT-1 in the nuclear extract was studied by electrophoretic mobility shift assay. IL-5 induced two proteins that bound to the gamma-activating sequence. In the presence of an anti-STAT-1 Ab, the band was supershifted. Thus, we demonstrated that IL-5 activated the Jak 2-STAT 1 signaling pathway in eosinophils. We speculate that the Jak 2-STAT 1 pathway may be involved in the activation of IL-5-inducible genes in eosinophils.

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Li, Boheng, Qin Wan, Zhubo Li, and Wee-Joo Chng. "Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers." Cancers 13, no. 20 (October 14, 2021): 5147. http://dx.doi.org/10.3390/cancers13205147.

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The Janus kinase (JAK) family are known to respond to extracellular cytokine stimuli and to phosphorylate and activate signal transducers and activators of transcription (STAT), thereby modulating gene expression profiles. Recent studies have highlighted JAK abnormality in inducing over-activation of the JAK/STAT pathway, and that the cytoplasmic JAK tyrosine kinases may also have a nuclear role. A couple of anti-JAK therapeutics have been developed, which effectively harness lymphoid cancer cells. Here we discuss mutations and fusions leading to JAK deregulations, how upstream nodes drive JAK expression, how classical JAK/STAT pathways are represented in lymphoid malignancies and the noncanonical and nuclear role of JAKs. We also summarize JAK inhibition therapeutics applied alone or synergized with other drugs in treating lymphoid malignancies.

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Li, Boheng, Qin Wan, Zhubo Li, and Wee-Joo Chng. "Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers." Cancers 13, no. 20 (October 14, 2021): 5147. http://dx.doi.org/10.3390/cancers13205147.

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The Janus kinase (JAK) family are known to respond to extracellular cytokine stimuli and to phosphorylate and activate signal transducers and activators of transcription (STAT), thereby modulating gene expression profiles. Recent studies have highlighted JAK abnormality in inducing over-activation of the JAK/STAT pathway, and that the cytoplasmic JAK tyrosine kinases may also have a nuclear role. A couple of anti-JAK therapeutics have been developed, which effectively harness lymphoid cancer cells. Here we discuss mutations and fusions leading to JAK deregulations, how upstream nodes drive JAK expression, how classical JAK/STAT pathways are represented in lymphoid malignancies and the noncanonical and nuclear role of JAKs. We also summarize JAK inhibition therapeutics applied alone or synergized with other drugs in treating lymphoid malignancies.

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Serbina, Inessa Mykhailivna, and Yu S. Ovcharenko. "JANUS KINASE INHIBITORS IN DERMATOLOGY: PRESENT AND FUTURE." International Medical Journal, no. 4(108) (December 10, 2021): 70–76. http://dx.doi.org/10.37436/2308-5274-2021-4-13.

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New facts about the importance of the JAK−STAT signaling system in development of a number of inflammatory and autoimmune diseases are now emerging. The JAK−STAT system, or pathway consisting of Janus kinase (JAK) and signal transducer protein as well as transcription activator (STAT), transmits information from extracellular polypeptide signals through transmembrane receptors directly to target gene promoters in the nucleus without the involvement of secondary messengers. The JAK−STAT system plays an important role in the implementation of immunological processes and is considered a therapeutic target in immune−mediated inflammatory diseases. JAK inhibitors are so−called yakinibs, low molecular weight chemically synthesized targeted drugs that inhibit intracellular JAK signaling molecules and interrupt the effect of interleukins on the cell. Drugs have an acceptable benefit−risk ratio. The most common side effects are infections of the upper respiratory tract, urinary tract and gastrointestinal tract. The safety profile of topical JAK inhibitors is better than that of oral drugs due to their minimal systemic absorption. For the first time, JAK inhibitors have been shown to be effective in rheumatoid arthritis and myelofibrosis. Disordered regulation of the JAK−STAT signaling pathway is observed in various inflammatory and autoimmune skin diseases. JAK molecules are overexpressed in epidermis, dermis in psoriasis, atopic dermatitis, alopecia areata and vitiligo. Decoding the new mechanisms of pathogenesis of psoriasis, atopic dermatitis, alopecia areata, vitiligo created the preconditions for improving their pharmacotherapy with the use of inhibitors of Janus kinases. Today, JAK inhibitors are the most promising specific target agents when treating the immune−mediated dermatoses. Key words: JAK−STAT system, Janus kinase inhibitors, psoriasis, atopic dermatitis, alopecia areata, vitiligo.

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Moser, Bernhard, Sophie Edtmayer, Agnieszka Witalisz-Siepracka, and Dagmar Stoiber. "The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia." Biomedicines 9, no. 8 (August 19, 2021): 1051. http://dx.doi.org/10.3390/biomedicines9081051.

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Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management.

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Roger, Inés, Javier Milara, Paula Montero, and Julio Cortijo. "The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension." International Journal of Molecular Sciences 22, no. 9 (May 7, 2021): 4980. http://dx.doi.org/10.3390/ijms22094980.

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Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

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Conzelmann, Michael, Elena Rodionova, Michael Hess, Thomas Giese, Anthony D. Ho, Peter Dreger, and Thomas Luft. "Complementary JAK/STAT Signalling Is Required for the Pro-Inflammatory Effects of CD40 Ligation: Differential Effects in Human Myeloid and B Cells." Blood 110, no. 11 (November 16, 2007): 2413. http://dx.doi.org/10.1182/blood.v110.11.2413.2413.

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Abstract CD40L represents a strong endogenous danger signal that induces pro-inflammatory activation of CD40-expressing cells such as dendritic cells (DC), monocytes, and B cells. However, since CD40 activation alone is insufficient to induce pro-inflammatory cytokines such as IL-12p70, we studied whether CD40-mediated pro-inflammatory activity might be dependent on co-signalling pathways involving JAK/STAT. Using quantitative Western blotting, we demonstrate that JAK/STAT signalling is induced by cytokines such as IL-4, GM-CSF and IFNg, whereas CD40 activation mediates NFkB signalling. CD40L-induced IL-12p70 and IL-10 secretion in human DC, monocytes, B cells, and chronic lymphocytic leukemia (CLL) cells was measured upon complementary JAK/STAT activation by IL-4, GM-CSF and IFNg in the presence and absence of specific inhibitors of JAK2, JAK3, and pan-JAK. Whereas IL-12p70 could not be induced by CD40 ligation or by cytokines alone, IL-12p70 secretion and suppression of IL-10 was reproducibly observed after co-stimulation of CD40L with IL-4, GM-CSF, or IFNg. This effect could be completely reversed by pan-JAK inhibition. Persistence of IL-4/GM-CSF/IFNg-mediated JAK/STAT signalling as late as 12 hours following cellular activation via CD40 was required for IL-12p70 secretion as shown by the effects of delayed JAK inhibition. Similarly, persistence between 12 and 24 hours of IL-12p35 and p40 mRNA expression correlated best with the level of IL-12p70 secretion. Specific inhibition of JAK2 and JAK3 further revealed a context-dependent action of the distinct JAK family members: JAK2 showed a strong co-dominant effect in the setting of IL-4-induced JAK/STAT activity. Both, JAK2 and JAK3 were required for IL-12p70 secretion, whereas JAK2 alone was sufficient to modulate IL-10 secretion. However, in the context of IFNg-induced JAK/STAT signalling in DC, neither JAK2 nor JAK3 inhibition had effects on IL-12p70. Here, only inhibition by the pan-JAK inhibitor involving JAK1 abrogated IL-12p70 secretion, indicating that in IFNg-dependent signalling, JAK2 is apparently sub-dominant to JAK1 and had only a small enhancing effect on IL-10. This context dependence markedly differed in myeloid cells and B cells, as normal and malignant (CLL) B cells maintain a co-dominant JAK2 activity in the context of IFNg-induced JAK/STAT-signalling. In conclusion, complementary JAK/STAT signalling is required for the pro-inflammatory effects of CD40 ligation in humans, with different JAK subset predominance in myeloid and B cells. These results may open new ways of lineage-specific interfering with CD40 signals by modulating JAK/STAT activity using tyrosine kinase inhibitors.

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Trivedi, Sunny, and Michelle Starz-Gaiano. "Drosophila Jak/STAT Signaling: Regulation and Relevance in Human Cancer and Metastasis." International Journal of Molecular Sciences 19, no. 12 (December 14, 2018): 4056. http://dx.doi.org/10.3390/ijms19124056.

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Over the past three-decades, Janus kinase (Jak) and signal transducer and activator of transcription (STAT) signaling has emerged as a paradigm to understand the involvement of signal transduction in development and disease pathology. At the molecular level, cytokines and interleukins steer Jak/STAT signaling to transcriptional regulation of target genes, which are involved in cell differentiation, migration, and proliferation. Jak/STAT signaling is involved in various types of blood cell disorders and cancers in humans, and its activation is associated with carcinomas that are more invasive or likely to become metastatic. Despite immense information regarding Jak/STAT regulation, the signaling network has numerous missing links, which is slowing the progress towards developing drug therapies. In mammals, many components act in this cascade, with substantial cross-talk with other signaling pathways. In Drosophila, there are fewer pathway components, which has enabled significant discoveries regarding well-conserved regulatory mechanisms. Work across species illustrates the relevance of these regulators in humans. In this review, we showcase fundamental Jak/STAT regulation mechanisms in blood cells, stem cells, and cell motility. We examine the functional relevance of key conserved regulators from Drosophila to human cancer stem cells and metastasis. Finally, we spotlight less characterized regulators of Drosophila Jak/STAT signaling, which stand as promising candidates to be investigated in cancer biology. These comparisons illustrate the value of using Drosophila as a model for uncovering the roles of Jak/STAT signaling and the molecular means by which the pathway is controlled.

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Chen, Pei-Chi, Chen-Hsun Ho, Chia-Kwung Fan, Shih-Ping Liu, and Po-Ching Cheng. "Antimicrobial Peptide LCN2 Inhibited Uropathogenic Escherichia coli Infection in Bladder Cells in a High-Glucose Environment through JAK/STAT Signaling Pathway." International Journal of Molecular Sciences 23, no. 24 (December 12, 2022): 15763. http://dx.doi.org/10.3390/ijms232415763.

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JAK/STAT plays a key role in regulating uropathogenic Escherichia coli (UPEC) infection in urothelial cells, probably via antimicrobial peptide (AMP) production, in diabetic patients with urinary tract infections. Whether multiple pathways regulate AMPs, especially lipid-carrying protein-2 (LCN2), to achieve a vital effect is unknown. We investigated the effects of an LCN2 pretreatment on the regulation of the JAK/STAT pathway in a high-glucose environment using a bladder cell model with GFP-UPEC and phycoerythrin-labeled TLR-4, STAT1, and STAT3. Pretreatment with 5 or 25 μg/mL LCN2 for 24 h dose-dependently suppressed UPEC infections in bladder cells. TLR-4, STAT1, and STAT3 expression were dose-dependently downregulated after LCN2 pretreatment. The LCN2-mediated alleviation of UPEC infection in a high-glucose environment downregulated TLR-4 and the JAK/STAT transduction pathway and decreased the UPEC-induced secretion of exogenous inflammatory interleukin (IL)-6 and IL-8. Our study provides evidence that LCN2 can alleviate UPEC infection in bladder epithelial cells by decreasing JAK/STAT pathway activation in a high-glucose environment. LCN2 dose-dependently inhibits UPEC infection via TLR-4 expression and JAK/STAT pathway modulation. These findings may provide a rationale for targeting LCN2/TLR-4/JAK/STAT regulation in bacterial cystitis treatment. Further studies should explore specific mechanisms by which the LCN2, TLR-4, and JAK/STAT pathways participate in UPEC-induced inflammation to facilitate the development of effective therapies for cystitis.

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Hombría, James Castelli-Gair, and Sol Sotillos. "JAK/STAT Signalling: STAT Cannot Play with Ken and Barbie." Current Biology 16, no. 3 (February 2006): R98—R100. http://dx.doi.org/10.1016/j.cub.2006.01.021.

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Godoi, Mariely A., Angelo C. Camilli, Karen G. A. Gonzales, Vitória B. Costa, Evangelos Papathanasiou, Fábio R. M. Leite, and Morgana R. Guimarães-Stabili. "JAK/STAT as a Potential Therapeutic Target for Osteolytic Diseases." International Journal of Molecular Sciences 24, no. 12 (June 17, 2023): 10290. http://dx.doi.org/10.3390/ijms241210290.

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Several cytokines with major biological functions in inflammatory diseases exert their functions through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction pathway. JAKs phosphorylate the cytoplasmic domain of the receptor, inducing the activation of its substrates, mainly the proteins known as STATs. STATs bind to these phosphorylated tyrosine residues and translocate from the cytoplasm to the nucleus, further regulating the transcription of several genes that regulate the inflammatory response. The JAK/STAT signaling pathway plays a critical role in the pathogenesis of inflammatory diseases. There is also increasing evidence indicating that the persistent activation of the JAK/STAT signaling pathway is related to several inflammatory bone (osteolytic) diseases. However, the specific mechanism remains to be clarified. JAK/STAT signaling pathway inhibitors have gained major scientific interest to explore their potential in the prevention of the destruction of mineralized tissues in osteolytic diseases. Here, our review highlights the importance of the JAK/STAT signaling pathway in inflammation-induced bone resorption and presents the results of clinical studies and experimental models of JAK inhibitors in osteolytic diseases.

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Thomas, Sally J., Katherine Fisher, Stephen Brown, John A. Snowden, Sarah Danson, and Martin Zeidler. "Methotrexate Is a Suppressor of JAK/STAT Pathway Activation Which Inhibits JAK2V617F Induced Signalling." Blood 124, no. 21 (December 6, 2014): 4577. http://dx.doi.org/10.1182/blood.v124.21.4577.4577.

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Abstract The classical myeloproliferative neoplasms (MPNs) are a group of disorders characterised by activation of the JAK/STAT signalling pathway. A large proportion of patients with MPNs have an acquired mutation, JAK2V617F, which causes constitutive kinase activity. Patients with wild-type JAK2 show gene expression patterns characteristic of JAK/STAT activation, and the majority have mutations in other genes associated with increased pathway activation. Inhibition of JAK/STAT activation represents an attractive therapeutic approach for these disorders. In myelofibrosis, treatment with a JAK inhibitor reduces spleen volume, improves quality of life and prolongs life expectancy, whereas there is evidence that other therapies are no better than placebo. This study aimed to find new treatments for MPNs by identifying compounds that suppress JAK/STAT activation. We screened a small-molecule library consisting of FDA approved drugs, cytotoxic drugs, agrochemicals, and pure natural products to identify modulators of STAT-responsive transcription in the low complexity Drosophila model. We independently identified methotrexate (z-score -8.72) and the chemically similar aminopterin (z-score -8.2) as strong inhibitors of Drosophila JAK/STAT activation. The suppression of transcriptional reporter activity was dose dependent and was observed following activation of the pathway with the Drosophila JAK/STAT ligand Upd and by the gain of function Drosophila JAK HopTuml. To examine whether these results translated to the more complex JAK/STAT signalling pathway of humans we examined the effect of methotrexate in the Hodgkin Lymphoma cell line HDLM-2, which shows constitutive phosphorylation of several JAK/STAT family members. Immunoblotting for phosphorylated pathway components showed that methotrexate produced a dose dependent reduction in levels of tyrosine phosphorylated STAT5 (Y694), without affecting total STAT5 levels. Methotrexate did not affect phosphorylated proteins in other signalling pathways, including pAKT, p c-Jun or pMAPK. To examine the potential of methotrexate as a treatment for MPNs, we used the HEL cell line, which is homozygous for JAK2V617F and shows STAT5 phosphorylation that is dependent on JAK2 activity. Immunoblotting showed that methotrexate produced a dose dependent reduction in levels of pSTAT5. Significant suppression of STAT5 phosphorylation was seen following treatment with methotrexate at concentrations equivalent to those measured in the serum of patients taking low dose oral methotrexate (0.4 – 0.8 mM, p<0.001, one-way ANOVA with Dunnett’s multiple comparisons test). Suppression of STAT5 phosphorylation persisted in the presence of folinic acid at concentrations used to prevent methotrexate toxicity, suggesting that the effect on JAK/STAT signalling is not mediated by impairment of folate metabolism. Methotrexate did not completely prevent signalling via the JAK/STAT pathway, as methotrexate-treated cells were still able to phosphorylate STAT5 following stimulation with the EpoR/JAK2/STAT5 pathway ligand erythropoietin. The reduction in STAT5 phosphorylation produced by treatment with methotrexate was comparable to that produced by the JAK1/JAK2 inhibitor ruxolitinib, although ruxolitinib was a more potent inhibitor of pathway activation. Given that methotrexate is used to treat inflammatory disorders and activation of JAK/STAT signalling is involved in the inflammatory response we examined the effect of methotrexate on rheumatoid arthritis fibroblast-like synoviocytes. Methotrexate also reduced constitutive STAT phosphorylation in these primary cells. Our results suggest that low-dose oral methotrexate should be investigated as a potential treatment for patients with MPNs. We suggest that methotrexate may suppress pathological over-activation of the JAK/STAT pathway sufficiently to control disease and bring about the benefits demonstrated with specific JAK inhibitors, without preventing physiological activation required for haematopoiesis and response to infection. Methotrexate is inexpensive and has advantages as a potential treatment as its safety and adverse effects are already well understood. Furthermore, our results suggest that suppression of JAK/STAT pathway activation may be a mechanism through which methotrexate exerts anti-inflammatory and immunosuppressive effects. Disclosures Off Label Use: Methotrexate is widely used as a chemotherapy drug and to treat inflammatory disorders. This work includes a discussion of the potential use of methotrexate to treat myeloproliferative neoplasms, based on experiments in cell lines.

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Journal articles on the topic 'JAK/STAT'

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