JAK-STAT

Being a well-characterized pathway, JAK-STAT signaling serves as a valuable paradigm for studying the architecture of gene regulatory networks. The discovery of untranslated or non-coding RNAs, namely microRNAs and long non-coding RNAs, provides an opportunity to elucidate their roles in such networks. In principle, these regulatory RNAs can act as downstream effectors of the JAK-STAT pathway and/or affect signaling by regulating the expression of JAK-STAT components. Examples of interactions between signaling pathways and non-coding RNAs have already emerged in basic cell biology and human diseases such as cancer, and can potentially guide the identification of novel biomarkers or drug targets for medicine...

Dengue virus (DENV) is an important human pathogen whose byzantine relationship with the immune response is poorly understood. DENV causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome, diseases for which palliative care is the only treatment. DENV immunopathogenesis studies are complicated by the lack of an immunocompetent small-animal model, and this has hindered anti-DENV drug and vaccine development. This review describes strategies that DENV uses to evade the type I interferon response and focuses on how data gained from the study of DENV NS5-mediated STAT2 degradation may be used to create immunocompetent DENV mouse models and design anti-DENV therapeutics...

Cytokine signaling is mediated by the combinatorial usage of seven STAT proteins that form homo- or heterodimers involved in the regulation of specific transcriptional programs. Among STATs, STAT2 is classically known to dimerize with STAT1 and together with IRF9 forms the ISGF3 transcription factor complex that has long been considered a hallmark of activation by type I and type III interferons. However, accumulating evidence reveal distinct facets of STAT2 and IRF9 activity mediated by the segregation in alternative STAT1-independent complexes/pathways that are thought to trigger different transcriptional programs...

JAK-STAT signaling pathway plays an important role in the cells' development and homeostasis. Over the past decades, the studies have identified the role of the JAK-STAT pathway in cell proliferation and apoptosis. Here, we want to discuss that whether and how the JAK-STAT pathway affects the lipid metabolism of adipose tissue. A host of cytokines and hormones can regulate lipid metabolism through activating the JAK-STAT signaling pathway. Activated STATs can regulate lipid metabolism directly by influencing the expression of enzymes...

Signal transducer and activator of transcription 5 (STAT5) regulates normal lympho-myeloid development through activation downstream of early-acting cytokines, their receptors, and Janus kinases (JAKs). Despite a general understanding of the role of STAT5 in hematopoietic stem cell (HSC) proliferation, survival, and self-renewal, the transcriptional targets and mechanisms of gene regulation that control multi-lineage engraftment following transplantation for the most part remain to be understood. In this review, we focus on the role of STAT5 in HSC transplantation and recent developments toward identifying the relevant downstream target genes and their role as part of a pleiotropic STAT5 mediated signaling response...

Dendritic cells (DC) play a key role in immunity by recognizing and presenting antigens. Cytokines and cytokine-activated transcription factors are fundamental in the regulation of the DC differentiation and their functions. While the role of STAT3 in DC development is well established, the function of STAT5 in DC has yet to be fully elucidated. A recent study published in Nature Immunology by Bell et al., using the DC-specific deletion of Stat5, demonstrated the importance of STAT5 in the induction of a Th2 response in DC...

Regulatory T (Treg) lymphocytes are important mediators of the allogeneic immune response, although the mechanisms by which they are controlled are not fully understood. Studies conducted in mice, including a recent article in Immunity by Laurence et al., have shown that STAT3 is an important factor involved in the instability of natural Treg (nTreg) lymphocytes and the generation of induced Treg (iTreg) lymphocytes. The authors used T lymphocytes obtained from Foxp3-GFP reporter mice, which allowed them to track the in vivo fate of the nTreg and iTreg lymphocyte populations in the inflammatory milieu of acute GvHD...

During inflammation, several mediators directly or indirectly induce pain including pro-inflammatory cytokines and there is evidence that the JAK-STAT pathway is involved in the formation of pronociceptive cytokines. The same pathway, however, is also of importance for anti-inflammatory cytokines such as IL-4 to counteract the inflammatory reaction and-as it seems based on the current literature-nociceptive symptoms. Current therapeutic approaches targeting molecules of the JAK-STAT signaling cascade are auspicious but as this review demonstrates, more experimental and clinical studies are required to decipher the specific contribution of this pathway in the modulation of pain...

In normal tissues or tumors, cells have extensive opportunities for adhesion to their neighbors. This state is mimicked by dense cell cultures. In this review, we integrate some recent findings on a key signal transducer, STAT3 (signal transducer and activator of transcription-3), whose activity is dramatically increased following cadherin-mediated cell to cell adhesion. Cadherin engagement, favored in dense cell cultures, causes a dramatic increase in total Rac/Cdc42 protein levels through inhibition of proteasomal degradation, which is followed by activation of IL-6 and STAT3...

Understanding the mechanisms that regulate dynamic localization of a protein within a cell can provide critical insight to its functional molecular interactions. Signal transducers and activators of transcription (STATs) play essential roles in development, proliferation, and immune defense. However the consequences of STAT hyperactivity can predispose to diseases including autoimmunity and cancer. To function as transcription factors STATs must gain access to the nucleus, and knowledge of the mechanisms that regulate STAT nuclear trafficking can provide a means to control STAT action...

The signal transducer and activator of transcription (STAT) proteins are latent transcription factors that have been shown to be involved in cell proliferation, development, apoptosis, and autophagy. STAT proteins undergo activation by phosphorylation at tyrosine 701 and serine 727 where they translocate to the nucleus to regulate gene expression. STAT1 has been shown to be involved in promoting apoptotic cell death in response to cardiac ischemia/reperfusion and has recently been shown by our laboratory to be involved in negatively regulating autophagy...

Reprogramming somatic cells to pluripotency, especially by the induced pluripotent stem cell (iPSC) technology, has become widely used today to generate various types of stem cells for research and for regenerative medicine. However the mechanism(s) of reprogramming still need detailed elucidation, including the roles played by the leukemia inhibitory factor (LIF) signaling pathway. LIF is central in maintaining the ground state pluripotency of mouse embryonic stem cells (ESCs) and iPSCs by activating the Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway...

Osteoblast differentiation is a critical step in the maintenance of bone homeostasis. Osteoblast differentiation is generally maintained by growth hormone (GH) and various other endocrine and autocrine/paracrine factors. JAK2-STAT5B pathway is a central axis in the mechanism of GH signaling. Similarly, the autocrine/paracrine signaling factor IGF-1 also mediates its effects through this pathway. Analysis on JAK2-STAT5B pathway showed its importance in the IGF-1/IGF-1R mediated regulation of gene expression and osteoblast differentiation...

STAT protein species are well-known as transcription factors that regulate nuclear gene expression. Recent novel lines of research suggest new non-genomic functions of STAT5A/B and STAT6. It was discovered in human pulmonary arterial endothelial cells that STAT5A, including STAT5A-GFP, constitutively associated with the Golgi apparatus, and both STAT5A and B with the endoplasmic reticulum. Acute siRNA-mediated knockdown of STAT5A/B led to the rapid development of a dramatic cystic change in the endoplasmic reticulum (ER) characterized by deposition of the ER structural protein reticulon-4 (RTN4; also called Nogo-B) and the ER-resident GTPase atlastin-3 (ATL3) along cyst membranes and cyst-zone boundaries, accompanied by Golgi fragmentation...

A recent article published by Britschgi et al. in Cancer Cell, "JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer," describes a positive feedback loop of JAK2/STAT5 activation that drives resistance to PI3K/mTOR inhibition in breast cancer. The authors found that genetic or pharmacological inhibition of JAK2 circumvents resistance to PI3K/mTOR inhibition and go on to show the efficacy of combined PI3K/mTOR and JAK2 inhibition on reducing cancer cell number, tumor growth, and metastasis as well as increasing in vivo survival...

JAK-STAT signaling occurs in virtually every tissue of the body, and so does glucose metabolism. In this review, we summarize the regulation of glucose metabolism in the myocardium and ponder whether JAK-STAT signaling participates in this regulation. Despite a paucity of data directly pertaining to cardiac myocytes, we conclude that JAK-STAT signaling may contribute to the development of insulin resistance in the myocardium in response to various hormones and cytokines.

Signaling by cytokines such as the interferons (IFNs) involves Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) transcription factors. The beauty of the classical model of JAK-STAT signaling is its simplicity in that JAK-activated STATs in the nucleus are responsible for specific gene activation. The fact that many ligands, growth factors, and hormones use the same STAT transcription factors, but exert different functions at the level of the cell, tissue, and organ would suggest significant shortcomings in the classical model...

The redox regulation of Janus kinases (JAKs) is a complex subject. Due to other redox-sensitive kinases in the kinome, redox-sensitive phosphatases, and cellular antioxidant systems and reactive oxygen species (ROS) production systems, the net biological outcomes of oxidative stress on JAK-dependent signal transduction vary according to the specific biological system examined. This review begins with a discussion of the biochemical evidence for a cysteine-based redox switch in the catalytic domain of JAKs, proceeds to consider direct and indirect regulatory mechanisms involved in biological experiments, and ends with a discussion of the role(s) of redox regulation of JAKs in various diseases...

The cytokine-inducible transcription factors signal transducer and activator of transcription 5A and 5B (STAT5A and STAT5B) are important for the proper development of multicellular eukaryotes. Disturbed signaling cascades evoking uncontrolled expression of STAT5 target genes are associated with cancer and immunological failure. Here, we summarize how STAT5 acetylation is integrated into posttranslational modification networks within cells. Moreover, we focus on how inhibitors of deacetylases and tyrosine kinases can correct leukemogenic signaling nodes involving STAT5...

STAT2 is an essential transcription factor in type I IFN mediated anti-viral and anti-proliferative signaling. STAT2 function is regulated by tyrosine phosphorylation, which is the trigger for STAT-dimerization, subsequent nuclear translocation, and transcriptional activation of IFN stimulated genes. Evidence of additional STAT2 phosphorylation sites has emerged as well as novel roles for STAT2 separate from the classical ISGF3-signaling. This review aims to summarize knowledge of phosphorylation-mediated STAT2-regulation and future avenues of related STAT2 research...