JAK-STAT最新文献

{"title":"JAK-STAT signaling in stem cells and their niches in Drosophila.","authors":"Nina Bausek","doi":"10.4161/jkst.25686","DOIUrl":"https://doi.org/10.4161/jkst.25686","url":null,"abstract":"<p><p>JAK-STAT signaling is a highly conserved regulator of stem cells and their niches. Aberrant activation in hematopoietic stem cells is the underlying cause of a majority of myeloproliferative diseases. This review will focus on the roles of JAK-STAT activity in three different adult stem cell systems in Drosophila. Tightly controlled levels of JAK-STAT signaling are required for stem cell maintenance and self-renewal, as hyperactivation of the pathway is associated with stem cell overproliferation. JAK-STAT activity is further essential for anchoring the stem cells in their respective niches by regulating different adhesion molecules. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e25686"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.25686","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dancing rhinos in stilettos: The amazing saga of the genomic and nongenomic actions of STAT3 in the heart.","authors":"Fouad A Zouein,&nbsp;Mazen Kurdi,&nbsp;George W Booz","doi":"10.4161/jkst.24352","DOIUrl":"https://doi.org/10.4161/jkst.24352","url":null,"abstract":"<p><p>A substantial body of evidence has shown that signal transducer and activator of transcription 3 (STAT3) has an important role in the heart in protecting the myocardium from ischemia and oxidative stress. These actions are attributed to STAT3 functioning as a transcription factor in upregulating cardioprotective genes. Loss of STAT3 has been implicated as well in the pathogenesis of heart failure and, in that context and in addition to the loss of a cardioprotective gene program, nuclear STAT3 has been identified as a transcriptional repressor important for the normal functioning of the ubiquitin-proteasome system for protein degradation. The later finding establishes a genomic role for STAT3 in controlling cellular homeostasis in cardiac myocytes independent of stress. Surprisingly, although a well-studied area, very few downstream gene targets of STAT3 in the heart have been definitively identified. In addition, STAT3 is now known to induce gene expression by noncanonical means that are not well characterized in the heart. On the other hand, recent evidence has shown that STAT3 has important nongenomic actions in cardiac myocytes that affect microtubule stability, mitochondrial respiration, and autophagy. These extranuclear actions of STAT3 involve protein-protein interactions that are incompletely understood, as is their regulation in both the healthy and injured heart. Moreover, how the diverse genomic and nongenomic actions of STAT3 crosstalk with each other is unchartered territory. Here we present an overview of what is and is not known about both the genomic and nongenomic actions of STAT3 in the heart from a structure-function perspective that focuses on the impact of posttranslational modifications and oxidative stress in regulating the actions and interactions of STAT3. Even though we have learnt a great deal about the role played by STAT3 in the heart, much more awaits to be discovered. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e24352"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.24352","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAK2 mutants (e.g., JAK2V617F) and their importance as drug targets in myeloproliferative neoplasms.","authors":"Karoline Gäbler,&nbsp;Iris Behrmann,&nbsp;Claude Haan","doi":"10.4161/jkst.25025","DOIUrl":"10.4161/jkst.25025","url":null,"abstract":"<p><p>The Janus kinase 2 (JAK2) mutant V617F and other JAK mutants are found in patients with myeloproliferative neoplasms and leukemias. Due to their involvement in neoplasia and inflammatory disorders, Janus kinases are promising targets for kinase inhibitor therapy. Several small-molecule compounds are evaluated in clinical trials for myelofibrosis, and ruxolitinib (INCB018424, Jakafi®) was the first Janus kinase inhibitor to receive clinical approval. In this review we provide an overview of JAK2V617F signaling and its inhibition by small-molecule kinase inhibitors. In addition, myeloproliferative neoplasms are discussed regarding the role of JAK2V617F and other mutant proteins of possible relevance. We further give an overview about treatment options with special emphasis on possible combination therapies. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e25025"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.25025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROCKing the JAKs.","authors":"Frank Peelman,&nbsp;Jan Tavernier","doi":"10.4161/jkst.24074","DOIUrl":"https://doi.org/10.4161/jkst.24074","url":null,"abstract":"<p><p>The endocrine cytokine leptin is mainly secreted by white adipose tissue and plasma leptin levels positively correlate with body fat mass. Via its action on neurons in the hypothalamic arcuate nucleus (ARC), leptin regulates body weight by stimulating energy expenditure and inhibiting food intake. The main signaling pathway of the leptin receptor is the JAK2-STAT3 pathway. A recent publication of Huang et al. in Nature Neuroscience shows that leptin's hypothalamic signaling via JAK2 requires the kinase ROCK1 (Rho-associated coiled-coil-containing protein kinase 1). ROCK1 directly phosphorylates JAK2, and this phosphorylation is required for the JAK2-STAT3 pathway of the leptin receptor. Gene deletion of ROCK1 in ARC neurons targeted by leptin makes these neurons less sensitive to leptin. This is reflected by a pronounced weight gain with hyperphagia, reduced locomotor activity, and increased fat accumulation. In this article we comment on the article of Huang et al. While the mechanism of ROCK1 activation in the neurons remains uncharacterized for the moment, a literature survey suggests that the interplay between ROCK1 and a JAK kinase may be a common theme for receptors that function via a JAK2 and even for other members of the JAK kinase family. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e24074"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.24074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How should we define STAT3 as an oncogene and as a potential target for therapy?","authors":"Hélène Sellier,&nbsp;Amélie Rébillard,&nbsp;Catherine Guette,&nbsp;Benjamin Barré,&nbsp;Olivier Coqueret","doi":"10.4161/jkst.24716","DOIUrl":"https://doi.org/10.4161/jkst.24716","url":null,"abstract":"<p><p>Aberrant activation of the STAT3 transcription factor has been reported in a large group of tumors and a strong biological basis now defines this protein as an oncogenic driver. Consequently, STAT3 is considered to be a promising target in the field of cancer therapy. For its inhibition to result in a successful therapeutic approach, the definition of a target tumor population identified by specific and detectable alterations is critical. The canonical activation model of STAT3 relies on a constitutive phosphorylation on its 705 tyrosine site, resulting in its dimerization, nuclear translocation, and the consequent activation of cancer genes. Therefore, it is expected that tumors expressing this phosphorylated form are addicted to STAT3 and will be sensitive to existing drugs which are targeting this dimeric form. However, recent results have shown that STAT3 can function as an oncogene in the absence of this tyrosine phosphorylation. This indicates that different forms of the transcription factor also play an important role in tumor growth and chemotherapy resistance. This complicates the definition of STAT3 as an oncogene and as a potential prognosis and predictive biomarker. The obligation to target a defined tumor type implies that future clinical trials should use a precise definition of STAT3 activation. This will allow tumors addicted to this oncogene to be identified correctly, leading to a strong rationale for patient stratification. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e24716"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.24716","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis.","authors":"Lei Bao,&nbsp;Huayi Zhang,&nbsp;Lawrence S Chan","doi":"10.4161/jkst.24137","DOIUrl":"https://doi.org/10.4161/jkst.24137","url":null,"abstract":"<p><p>Atopic dermatitis (AD), a common chronic inflammatory skin disease, is characterized by inflammatory cell skin infiltration. The JAK-STAT pathway has been shown to play an essential role in the dysregulation of immune responses in AD, including the exaggeration of Th2 cell response, the activation of eosinophils, the maturation of B cells, and the suppression of regulatory T cells (Tregs). In addition, the JAK-STAT pathway, activated by IL-4, also plays a critical role in the pathogenesis of AD by upregulating epidermal chemokines, pro-inflammatroy cytokines, and pro-angiogenic factors as well as by downregulating antimicrobial peptides (AMPs) and factors responsible for skin barrier function. In this review, we will highlight the recent advances in our understanding of the JAK-STAT pathway in the pathogenesis of AD. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e24137"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.24137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAK-STAT and bone metabolism.","authors":"Jiliang Li","doi":"10.4161/jkst.23930","DOIUrl":"https://doi.org/10.4161/jkst.23930","url":null,"abstract":"<p><p>Emerging evidences suggest Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway plays an important role in bone development and metabolism. Effects of JAK-STAT pathway on skeletal development are summarized based on skeletal phenotype of individual JAK and STAT gene knockout mouse. Furthermore, STAT3 has more profound effects on bone homeostasis compared with the other STATs. STAT3 mutation causes a disease called Job syndrome, most patients with which have associated craniofacial and skeletal features. Selective inactivation of STAT3 in osteoblasts decreases bone formation and skeletal responsiveness to mechanical loading. Future research includes investigating JAK-STAT signaling in osteoclasts and osteocytes. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e23930"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.23930","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SOCS, inflammation, and cancer.","authors":"Kyoko Inagaki-Ohara,&nbsp;Taisuke Kondo,&nbsp;Minako Ito,&nbsp;Akihiko Yoshimura","doi":"10.4161/jkst.24053","DOIUrl":"https://doi.org/10.4161/jkst.24053","url":null,"abstract":"<p><p>Signal transduction pathways elicited by cytokines and hormones have been shown to regulate distinct stages of development. Suppressor of cytokine signaling (SOCS) proteins are negative feedback regulators of cytokine signaling mediated by the JAK-STAT signaling pathway. In particular, SOCS1 and SOCS3 are potent inhibitors of JAKs and can play pivotal roles in inflammation, as well as in the development and progression of cancers. Abnormal expression of SOCS1 and SOCS3 in cancer cells has been reported in human carcinoma associated with dysregulation of signals from cytokine receptors, Toll-like receptors (TLRs), and hormone receptors, resulting in malignancies. In this review, we focus on the role of SOCS1 and SOCS3 in cancer development. In addition, the potential of SOCS as a therapeutic target and diagnostic aid will be discussed. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e24053"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.24053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cardioprotective effects of urocortin are mediated via activation of the Src tyrosine kinase-STAT3 pathway.","authors":"Carol Chen-Scarabelli,&nbsp;Louis Saravolatz Ii,&nbsp;Roy McCaukey,&nbsp;Gabriele Scarabelli,&nbsp;Justin Di Rezze,&nbsp;Bibhu Mohanty,&nbsp;Sean Barry,&nbsp;David Latchman,&nbsp;Vassilis Georgiadis,&nbsp;James McCormick,&nbsp;Louis Saravolatz,&nbsp;Richard Knight,&nbsp;Giuseppe Faggian,&nbsp;Jagat Narula,&nbsp;Anastasis Stephanou,&nbsp;Tiziano M Scarabelli","doi":"10.4161/jkst.24812","DOIUrl":"https://doi.org/10.4161/jkst.24812","url":null,"abstract":"<p><p>Src tyrosine kinase family was recently identified as a novel upstream modulator of MAP kinase subfamily, p42/p44, whose activation is required for urocortin (Ucn)-mediated cardioprotection. Src kinase was also shown to reduce apoptosis in different cancer cell lines, enhancing phosphorylation and DNA binding affinity of signal transducer and activator of transcription (STAT)3. In order to evaluate the effects of Ucn on the activation status of different STAT family members, HL-1 cardiac cells were incubated with Ucn (10 nM) for increasing periods of time. STAT3 was rapidly phosphorylated at Tyr705, while neither phosphorylation at Ser727 nor induction of total STAT3 was observed. Pretreatment with PP2, a selective inhibitor of Src tyrosine kinase, reduced the pSTAT(-T705) phosphorylation and transcriptional activity induced by Ucn in a dose-dependent manner. Overexpression of STAT3 in HL-1 cardiac myocytes pretreated with Ucn reduced the magnitude of cell death as compared with Ucn treatment alone, while transfection of HL-1 cells with a STAT3 mutant functionally inactive, acting as a dominant negative (DN-STAT3), enhanced the extent of cell death in a dose-dependent manner. In line with this finding, in HL-1 cardiac myocytes overexpressing STAT3 treated with Ucn, addition of the Src kinase inhibitor PP2 reversed the cytoprotective effects of Ucn, proving that the cytoprotective effects of Ucn are also mediated via the Src-pSTAT(-T705) phosphorylation pathway. By immunocytochemistry, Ucn induced nuclear translocation of pST3-T705, which was inhibited by pretreatment with PP2. Together, these data strongly suggest that Ucn can mediate cardioprotection by activating the Src-pSTAT-T705 phosphorylation pathway. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e24812"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.24812","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of proliferation, cell competition, and cellular growth by the Drosophila JAK-STAT pathway.","authors":"Tamara Zoranovic,&nbsp;Lydia Grmai,&nbsp;Erika A Bach","doi":"10.4161/jkst.25408","DOIUrl":"https://doi.org/10.4161/jkst.25408","url":null,"abstract":"<p><p>The JAK-STAT pathway is a key regulator of tissue size in Drosophila melanogaster. Here we provide an overview of its roles in processes that regulate the size of Drosophila imaginal discs, epithelia of diploid cells that proliferate and acquire specific fates in the larvae and that become functional in the adult. Drosophila has a single JAK and a single STAT gene, which has facilitated genetic dissection of this pathway. Moreover, the sophisticated genetic tools available in flies for clonal growth assays have made Drosophila an ideal organism in which to dissect the multiple roles of the JAK-STAT pathway in growth control. Studies in flies have revealed JAK-STAT pathway activity as a central node for diverse signals that control proliferation and mass accumulation. In addition, recent work has establish a new role for the pathway in cell competition, a process thought to be akin to the early stages of transformation in which more robust cells kill and take the place of less robust ones. </p>","PeriodicalId":89791,"journal":{"name":"JAK-STAT","volume":"2 3","pages":"e25408"},"PeriodicalIF":0.0,"publicationDate":"2013-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4161/jkst.25408","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31761236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}