scholarly journals The Role of LNK (SH2B3) in the Regulation of JAK-STAT Signalling in Haematopoiesis

2021 ◽  
Vol 15 (1) ◽  
pp. 24
Author(s):  
Rhiannon Morris ◽  
Liesl Butler ◽  
Andrew Perkins ◽  
Nadia J. Kershaw ◽  
Jeffrey J. Babon
Keyword(s):  
Inflammatory Diseases ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Janus Kinase ◽  
Target Cells ◽  
Signal Transducer ◽  
Pathway Activation ◽  
Specific Receptors ◽  
Stat Pathway

LNK is a member of the SH2B family of adaptor proteins and is a non-redundant regulator of cytokine signalling. Cytokines are secreted intercellular messengers that bind to specific receptors on the surface of target cells to activate the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling pathway. Activation of the JAK-STAT pathway leads to proliferative and often inflammatory effects, and so the amplitude and duration of signalling are tightly controlled. LNK binds phosphotyrosine residues to signalling proteins downstream of cytokines and constrains JAK-STAT signalling. Mutations in LNK have been identified in a range of haematological and inflammatory diseases due to increased signalling following the loss of LNK function. Here, we review the regulation of JAK-STAT signalling via the adaptor protein LNK and discuss the role of LNK in haematological diseases.

scholarly journals The use of Drosophila Melanogaster as a Model Organism to study the effect of Innate Immunity on Metabolism

2020 ◽  
Author(s):  
Abeer Mohbeddin ◽  
Nawar Haj Ahmed ◽  
Layla Kamareddine
Keyword(s):  
Drosophila Melanogaster ◽  
Fat Body ◽  
Model Organism ◽  
Fruit Fly ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Metabolic Homeostasis ◽  
Stat Signaling ◽  
Stat Pathway

Apart from its traditional role in disease control, recent body of evidence has implicated a role of the immune system in regulating metabolic homeostasis. Owing to the importance of this “immune-metabolic alignment” in dictating a state of health or disease, a proper mechanistic understanding of this alignment is crucial in opening up for promising therapeutic approaches against a broad range of chronic, metabolic, and inflammatory disorders like obesity, diabetes, and inflammatory bowel syndrome. In this project, we addressed the role of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) innate immune pathway in regulating different metabolic parameters using the Drosophila melanogaster (DM) fruit fly model organism. Mutant JAK/STAT pathway flies with a systemic knockdown of either Domeless (Dome) [domeG0282], the receptor that activates JAK/STAT signaling, or the signal-transducer and activator of transcription protein at 92E (Stat92E) [stat92EEY10528], were used. The results of the study revealed that blocking JAK/STAT signaling alters the metabolic profile of mutant flies. Both domeG0282 and stat92EEY10528 mutants had an increase in body weight, lipid deprivation from their fat body (lipid storage organ in flies), irregular accumulation of lipid droplets in the gut, systemic elevation of glucose and triglyceride levels, and differential down-regulation in the relative gene expression of different peptide hormones (Tachykinin, Allatostatin C, and Diuretic hormone 31) known to regulate metabolic homeostasis in flies. Because the JAK/STAT pathway is evolutionary conserved between invertebrates and vertebrates, our potential findings in the fruit fly serves as a platform for further immune-metabolic translational studies in more complex mammalian systems including humans.

scholarly journals The JAK/STAT signaling pathway: from bench to clinic

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiaoyi Hu ◽  
Jing li ◽  
Maorong Fu ◽  
Xia Zhao ◽  
Wei Wang
Keyword(s):  
Signaling Pathway ◽  
Current Knowledge ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Quarter Century ◽  
Cellular Processes ◽  
Stat Signaling ◽  
Cancer And Inflammation ◽  
Stat Pathway

AbstractThe 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.

scholarly journals Role of the JAK-STAT Pathway in Bovine Mastitis and Milk Production

Animals ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 2107
Author(s):  
Muhammad Zahoor Khan ◽  
Adnan Khan ◽  
Jianxin Xiao ◽  
Yulin Ma ◽  
Jiaying Ma ◽  
...  
Keyword(s):  
Dairy Cattle ◽  
Milk Production ◽  
Critical Role ◽  
Bovine Mastitis ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Production Traits ◽  
Stat Pathway

The cytokine-activated Janus kinase (JAK)—signal transducer and activator of transcription (STAT) pathway is a sequence of communications between proteins in a cell, and it is associated with various processes such as cell division, apoptosis, mammary gland development, lactation, anti-inflammation, and immunity. The pathway is involved in transferring information from receptors on the cell surface to the cell nucleus, resulting in the regulation of genes through transcription. The Janus kinase 2 (JAK2), signal transducer and activator of transcription A and B (STAT5 A & B), STAT1, and cytokine signaling suppressor 3 (SOCS3) are the key members of the JAK-STAT pathway. Interestingly, prolactin (Prl) also uses the JAK-STAT pathway to regulate milk production traits in dairy cattle. The activation of JAK2 and STATs genes has a critical role in milk production and mastitis resistance. The upregulation of SOCS3 in bovine mammary epithelial cells inhibits the activation of JAK2 and STATs genes, which promotes mastitis development and reduces the lactational performance of dairy cattle. In the current review, we highlight the recent development in the knowledge of JAK-STAT, which will enhance our ability to devise therapeutic strategies for bovine mastitis control. Furthermore, the review also explores the role of the JAK-STAT pathway in the regulation of milk production in dairy cattle.

scholarly journals Essential Role of Signal Transducer and Activator of Transcription (Stat)5a but Not Stat5b for Flt3-Dependent Signaling

2000 ◽  
Vol 192 (5) ◽  
pp. 719-728 ◽  
Author(s):  
Shuli Zhang ◽  
Seiji Fukuda ◽  
Younghee Lee ◽  
Giao Hangoc ◽  
Scott Cooper ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Receptor Tyrosine Kinase ◽  
Kinase Activity ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Flt3 Ligand ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Stat Pathway

The receptor tyrosine kinase Flt3 plays an important role in proliferation and survival of hematopoietic stem and progenitor cells. Although some post-receptor signaling events of Flt3 have been characterized, the involvement of the Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway in Flt3 signaling has not been thoroughly evaluated. To this aim, we examined whether Flt3 activates the Jak/Stat pathway in Baf3/Flt3 cells, a line stably expressing human Flt3 receptor. Stat5a, but not Stats 1–4, 5b, or 6, was potently activated by Flt3 ligand (FL) stimulation. Interestingly, FL did not activate any Jaks. Activation of Stat5a required the kinase activity of Flt3. A selective role for Stat5a in the proliferative response of primary hematopoietic progenitor cells to FL was documented, as FL did not act on progenitors from marrows of Stat5a−/− mice, but did stimulate/costimulate proliferation of these cells from Stat5a+/+, Stat5b−/−, and Stat5b+/+ mice. Thus, Stat5a is essential for at least certain effects of FL. Moreover, our data confirm that Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.

scholarly journals JAK-STAT in Early Hematopoiesis and Leukemia

2021 ◽  
Vol 9 ◽  
Author(s):  
Eirini Sofia Fasouli ◽  
Eleni Katsantoni
Keyword(s):  
Hematologic Malignancies ◽  
Janus Kinase ◽  
Hematopoietic Stem ◽  
Intrinsic Signals ◽  
Extracellular Signals ◽  
Bm Niche ◽  
Pathway Activation ◽  
Research Findings ◽  
Stat Pathway

Hematopoietic stem cells (HSCs) produce all the terminally differentiated blood cells and are controlled by extracellular signals from the microenvironment, the bone marrow (BM) niche, as well as intrinsic cell signals. Intrinsic signals include the tightly controlled action of signaling pathways, as the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Activation of JAK-STAT leads to phosphorylation of members of the STAT family to regulate proliferation, survival, and self-renewal of HSCs. Mutations in components of the JAK-STAT pathway are linked with defects in HSCs and hematologic malignancies. Accumulating mutations in HSCs and aging contribute to leukemia transformation. Here an overview of hematopoiesis, and the role of the JAK-STAT pathway in HSCs and in the promotion of leukemic transformation is presented. Therapeutic targeting of JAK-STAT and clinical implications of the existing research findings are also discussed.

The role of interleukin-17 in the pathogenesis of systemic sclerosis: Pro-fibrotic or anti-fibrotic?

2021 ◽  
pp. 239719832110394
Author(s):  
Silvia Bellando-Randone ◽  
Emanuel Della-Torre ◽  
Andra Balanescu
Keyword(s):  
Systemic Sclerosis ◽  
Therapeutic Target ◽  
Inflammatory Diseases ◽  
Adaptive Immune System ◽  
Disease Stage ◽  
Target Cells ◽  
Interleukin 17 ◽  
T Helper 17 ◽  
Attractive Therapeutic Target

Systemic sclerosis is characterized by widespread fibrosis of the skin and internal organs, vascular impairment, and dysregulation of innate and adaptive immune system. Growing evidence indicates that T-cell proliferation and cytokine secretion play a major role in the initiation of systemic sclerosis, but the role of T helper 17 cells and of interleukin-17 cytokines in the development and progression of the disease remains controversial. In particular, an equally distributed body of literature supports both pro-fibrotic and anti-fibrotic effects of interleukin-17, suggesting a complex and nuanced role of this cytokine in systemic sclerosis pathogenesis that may vary depending on disease stage, target cells in affected organs, and inflammatory milieu. Although interleukin-17 already represents an established therapeutic target for several immune-mediated inflammatory diseases, more robust experimental evidence is required to clarify whether it may become an attractive therapeutic target for systemic sclerosis as well.

scholarly journals Role of the Cysteinyl Leukotrienes in the Pathogenesis and Progression of Cardiovascular Diseases

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Francesca Colazzo ◽  
Paolo Gelosa ◽  
Elena Tremoli ◽  
Luigi Sironi ◽  
Laura Castiglioni
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Diseases ◽  
Inflammatory Diseases ◽  
Asthma Management ◽  
Cardiovascular Disorders ◽  
Cysteinyl Leukotrienes ◽  
Pathway Activation ◽  
Cardioprotective Effects ◽  
Progression Of Atherosclerosis

Cysteinyl leukotrienes (CysLTs) are potent lipid inflammatory mediators synthesized from arachidonic acid, through the 5-lipoxygenase (5-LO) pathway. Owing to their properties, CysLTs play a crucial role in the pathogenesis of inflammation; therefore, CysLT modifiers as synthesis inhibitors or receptor antagonists, central in asthma management, may become a potential target for the treatment of other inflammatory diseases such as the cardiovascular disorders. 5-LO pathway activation and increased expression of its mediators and receptors are found in cardiovascular diseases. Moreover, the cardioprotective effects observed by using CysLT modifiers are promising and contribute to elucidate the link between CysLTs and cardiovascular disease. The aim of this review is to summarize the state of present research about the role of the CysLTs in the pathogenesis and progression of atherosclerosis and myocardial infarction.

scholarly journals Systematic dissection of dynein regulators in mitosis

2013 ◽  
Vol 201 (2) ◽  
pp. 201-215 ◽  
Author(s):  
Jonne A. Raaijmakers ◽  
Marvin E. Tanenbaum ◽  
René H. Medema
Keyword(s):  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Cytoplasmic Dynein ◽  
Comprehensive Overview ◽  
Motor Complex ◽  
Essential Components ◽  
Complex Thought ◽  
Specific Activities ◽  
Dynactin Complex

Cytoplasmic dynein is a large minus end–directed motor complex with multiple functions during cell division. The dynein complex interacts with various adaptor proteins, including the dynactin complex, thought to be critical for most dynein functions. Specific activities have been linked to several subunits and adaptors, but the function of the majority of components has remained elusive. Here, we systematically address the function of each dynein–dynactin subunit and adaptor protein in mitosis. We identify the essential components that are required for all mitotic functions of dynein. Moreover, we find specific dynein recruitment factors, and adaptors, like Nde1/L1, required for activation, but largely dispensable for dynein localization. Most surprisingly, our data show that dynactin is not required for dynein-dependent spindle organization, but acts as a dynein recruitment factor. These results provide a comprehensive overview of the role of dynein subunits and adaptors in mitosis and reveal that dynein forms distinct complexes requiring specific recruiters and activators to promote orderly progression through mitosis.

Abstract IA41: Role of JAK-STAT pathway activation in MPN pathogenesis and therapeutic response.

2015 ◽  
Author(s):  
Sara Meyer ◽  
Maria Kleppe ◽  
Neha Bhagwat ◽  
Priya Koppikar ◽  
Minsuk Kwak ◽  
...  
Keyword(s):  
Therapeutic Response ◽  
Pathway Activation ◽  
Stat Pathway
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