JAK Kinases in Health and Disease: An Update.
Ontology highlight
ABSTRACT:
SUBMITTER: Laurence A
PROVIDER: S-EPMC3460320 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
Publications
JAK Kinases in Health and Disease: An Update.
Laurence Arian A Pesu Marko M Silvennoinen Olli O O'Shea John J
The open rheumatology journal 20120907
Janus kinases (Jaks) are critical signaling elements for a large subset of cytokines. As a consequence they play pivotal roles in the patho-physiology of many diseases including neoplastic and autoimmune diseases. Small molecule Jak inhibitors as therapeutic agents have become a reality and the palette of such inhibitors will likely expand. This review will summarize our current knowledge on these key enzymes and their associated pharmaceutical inhibitors. ...[more]
Similar Datasets
Project description:Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia, following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The aim of this review is to summarize the latest progress in our understanding of the involvement of the JAK/STAT signaling pathway in the development of leukemia. We also attempt to provide insights into the current use of JAK/STAT inhibitors in leukemia therapy and explore pertinent clinical trials in this field.
| S-EPMC10811937 | biostudies-literature
Project description:Most cell surface receptors for growth factors and cytokines dimerize in order to mediate signal transduction. For many such receptors, the Janus kinase (Jak) family of non-receptor protein tyrosine kinases are recruited in pairs and juxtaposed by dimerized receptor complexes in order to activate one another by trans-phosphorylation. An alternative mechanism for Jak trans-phosphorylation has been proposed in which the phosphorylated kinase interacts with the Src homology 2 (SH2) domain of SH2-B, a unique adaptor protein with the capacity to homo-dimerize. Building on a rule-based kinetic modeling approach that considers the concerted nature and combinatorial complexity of modular protein domain interactions, we examine these mechanisms in detail, focusing on the growth hormone (GH) receptor/Jak2/SH2-Bbeta system. The modeling results suggest that, whereas Jak2-(SH2-Bbeta)(2)-Jak2 heterotetramers are scarcely expected to affect Jak2 phosphorylation, SH2-Bbeta and dimerized receptors synergistically promote Jak2 trans-activation in the context of intracellular signaling. Analysis of the results revealed a unique mechanism whereby SH2-B and receptor dimers constitute a bipolar 'clamp' that stabilizes the active configuration of two Jak2 molecules in the same macro-complex.
| S-EPMC2667146 | biostudies-literature
Project description:The V617F mutation in the Jak2 pseudokinase domain causes myeloproliferative neoplasms, and the equivalent mutation in Jak1 (V658F) is found in T-cell leukemias. Crystal structures of wild-type and V658F-mutant human Jak1 pseudokinase reveal a conformational switch that remodels a linker segment encoded by exon 12, which is also a site of mutations in Jak2. This switch is required for V617F-mediated Jak2 activation and possibly for physiologic Jak activation.
| S-EPMC3863620 | biostudies-literature
Project description:Lymphocyte recruitment is regulated by signaling modules based on the activity of Rho and Rap small guanosine triphosphatases that control integrin activation by chemokines. We show that Janus kinase (JAK) protein tyrosine kinases control chemokine-induced LFA-1- and VLA-4-mediated adhesion as well as human T lymphocyte homing to secondary lymphoid organs. JAK2 and JAK3 isoforms, but not JAK1, mediate CXCL12-induced LFA-1 triggering to a high affinity state. Signal transduction analysis showed that chemokine-induced activation of the Rho module of LFA-1 affinity triggering is dependent on JAK activity, with VAV1 mediating Rho activation by JAKs in a Gαi-independent manner. Furthermore, activation of Rap1A by chemokines is also dependent on JAK2 and JAK3 activity. Importantly, activation of Rap1A by JAKs is mediated by RhoA and PLD1, thus establishing Rap1A as a downstream effector of the Rho module. Thus, JAK tyrosine kinases control integrin activation and dependent lymphocyte trafficking by bridging chemokine receptors to the concurrent and hierarchical activation of the Rho and Rap modules of integrin activation.
| S-EPMC3871442 | biostudies-literature
Project description:BackgroundA comprehensive update of the classification of all available kinases was carried out. This survey presents a complete global picture of this large functional class of proteins and confirms the soundness of our initial kinase classification scheme.ResultsThe new survey found the total number of kinase sequences in the protein database has increased more than three-fold (from 17,310 to 59,402), and the number of determined kinase structures increased two-fold (from 359 to 702) in the past three years. However, the framework of the original two-tier classification scheme (in families and fold groups) remains sufficient to describe all available kinases. Overall, the kinase sequences were classified into 25 families of homologous proteins, wherein 22 families (approximately 98.8% of all sequences) for which three-dimensional structures are known fall into 10 fold groups. These fold groups not only include some of the most widely spread proteins folds, such as the Rossmann-like fold, ferredoxin-like fold, TIM-barrel fold, and antiparallel beta-barrel fold, but also all major classes (all alpha, all beta, alpha+beta, alpha/beta) of protein structures. Fold predictions are made for remaining kinase families without a close homolog with solved structure. We also highlight two novel kinase structural folds, riboflavin kinase and dihydroxyacetone kinase, which have recently been characterized. Two protein families previously annotated as kinases are removed from the classification based on new experimental data.ConclusionStructural annotations of all kinase families are now revealed, including fold descriptions for all globular kinases, making this the first large functional class of proteins with a comprehensive structural annotation. Potential uses for this classification include deduction of protein function, structural fold, or enzymatic mechanism of poorly studied or newly discovered kinases based on proteins in the same family.
| S-EPMC1079889 | biostudies-literature
Project description:INTRODUCTION: The aim of this clinical update is to summarize articles and guidelines published in the last year with the potential to change current clinical practice as it relates to women's health. METHODS: We used two independent search strategies to identify articles relevant to women's health published between March 1, 2007 and February 29, 2008. First, we reviewed the Cochrane Database of Systematic Reviews and journal indices from the ACP Journal Club, Annals of Internal Medicine, Archives of Internal Medicine, British Medical Journal, Circulation, Diabetes, JAMA, JGIM, Journal of Women's Health, Lancet, NEJM, Obstetrics and Gynecology, and Women's Health Journal Watch. Second, we performed a MEDLINE search using the medical subject heading term "sex factors." The authors, who all have clinical and/or research experience in the area of women's health, reviewed all article titles, abstracts, and, when indicated, full publications. We excluded articles related to obstetrical aspects of women's health focusing on those relevant to general internists. We had two acceptance criteria, scientific rigor and potential to impact women's health. We also identified new and/or updated women's health guidelines released during the same time period. RESULTS: We identified over 250 publications with potential relevance to women's health. Forty-six articles were selected for presentation as part of the Clinical Update, and nine were selected for a more detailed discussion in this paper. Evidence-based women's health guidelines are listed in Table 1. Table 1 Important Women's Health Guidelines in 2007-2008: New or Updated Topic Issuing organization Updated recommendations and comments Mammography screening in women 40-4917 ACP Individualized risk assessment and informed decision making should be used to guide decisions about mammography screening in this age group. To aid in the risk assessment, a discussion of the risk factors, which if present in a woman in her 40s increases her risk to above that of an average 50-year-old woman, is provided in the guidelines. In addition, available risk prediction models, such as the NIH Web site calculator (http://www.cancer.gov/bcrisktool/) can also be used to estimate quantitative breast cancer risk. This model was updated in 2008 with race-specific data for calculating risk in African-American women.18 The harms and benefits of mammography should be discussed and incorporated along with a woman's preferences and breast cancer risk profile into the decision on when to begin screening. If a woman decides to forgo mammography, the decision should be readdressed every 1 to 2 years. STD screening guidelines19 USPSTF and CDC Routine screening for this infection is now recommended for ALL sexually active women age 24 and under, based on the recent high prevalence estimates for chlamydia It is not recommended for women (pregnant or nonpregnant) age 25 and older, unless they are at increased risk for infection. STD treatment guidelines20 CDC Flouroquinolones are NO longer recommended for treatment of N. gonorrhea, due to increasing resistance (as high as 15% of isolates in 2006). For uncomplicated infections, treatment of gonorrhea should be initiated with ceftriaxone 125 mg IM or cefixime 400 mg PO and co-treatment for chlamydia infection (unless ruled out with testing). Recent estimates demonstrate that almost 50% of persons with gonorrhea have concomitant chlamydia infection21. STD = sexually transmitted disease, NIH = National Institutes of Health, ACP = American College of Physicians, USPSTF = United States Prevention Services Task Force, CDC = Centers for Disease Control.
| S-EPMC2686759 | biostudies-other
Project description:Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor-κB (NF-κB) signalling pathways is associated with the development of cancer and inflammatory diseases. JAKs and IKKs are the key regulators in the STAT3 and NF-κB signalling respectively. Therefore, the two families of kinases have been the major targets for developing drugs to regulate the two signalling pathways. Here, we report a natural compound xanthatin from the traditional Chinese medicinal herb Xanthium L. as a potent inhibitor of both STAT3 and NF-κB signalling pathways. Our data demonstrated that xanthatin was a covalent inhibitor and its activities depended on its α-methylene-γ-butyrolactone group. It preferentially interacted with the Cys243 of JAK2 and the Cys412 and Cys464 of IKKβ to inactivate their activities. In doing so, xanthatin preferentially inhibited the growth of cancer cell lines that have constitutively activated STAT3 and p65. These data suggest that xanthatin may be a promising anticancer and anti-inflammation drug candidate.
| S-EPMC6533482 | biostudies-literature
Project description:To review the role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in the progression of chronic kidney diseases.The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2, and STAT3 promote diabetic nephropathy and their inhibition appears to reduce the disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. On the basis of data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases.Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases.
| S-EPMC4673981 | biostudies-literature
Project description:The concept of a Health Promoting School has been found to be effective to improve health and well-being of students as well as a help with teaching and learning in school. Effective implementation of Health Promoting School is a complex intervention involving multi-factorial and innovative activity in many domains such as curriculum, school environment and community. Many studies evaluating Health Promoting School do not include outcomes reflecting the organisational or structural change as many of those studies are quantitative in nature and the statistical assumptions are not valid reflecting the organisational structure changes. Recent global meetings of experts have reviewed the impact on student health from the perspectives of school environment, school policies on health, action competencies on healthy living and community linkage. The English Wessex Healthy School Award Scheme and the Hong Kong Healthy School Awards Scheme have developed detailed systems to analyse whether each individual school has reached the standard of a model Health Promoting School reflecting a more holistic appreciation and understanding of all the effects of school-based health promotion with positive award-related changes. However, not many schools are able to implement Health Promoting School in its entirety, so cores indicators are needed as a starting point for wider implementation. Hong Kong Healthy School Awards Scheme is still ongoing with data for analysis of indicators with significant correlation with better health and well-being. We identified the core indicators and substantiated the requirements for successful outcomes by supplementing the established award-scheme framework with a review of recent literature and documents. Framework of Health Promoting School would go beyond improvement of health literacy to enable a more efficient system for education and health on children, hence a good investment in children.
| S-EPMC7156290 | biostudies-literature
Project description:Diabetic kidney disease (DKD) is the most important microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. The Janus kinase/signal transducer and activator of the transcription (JAK/STAT) signaling pathway, which is out of balance in the context of DKD, acts through a range of metabolism-related cytokines and hormones. JAK/STAT is the primary signaling node in the progression of DKD. The latest research on JAK/STAT signaling helps determine the role of this pathway in the factors associated with DKD progression. These factors include the renin–angiotensin system (RAS), fibrosis, immunity, inflammation, aging, autophagy, and EMT. This review epitomizes the progress in understanding the complicated explanation of the etiologies of DKD and the role of the JAK/STAT pathway in the progression of DKD and discusses whether it can be a potential target for treating DKD. It further summarizes the JAK/STAT inhibitors, natural products, and other drugs that are promising for treating DKD and discusses how these inhibitors can alleviate DKD to explore possible potential drugs that will contribute to formulating effective treatment strategies for DKD in the near future.
| S-EPMC10450957 | biostudies-literature