STAT3 regulation of and by microRNAs in development and disease
MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs acting at the post-transcriptional level where they promote mRNA degradation and block protein translation. Recent findings suggest that complex transcriptional and post-transcriptional circuits control miRNAs. STAT3 has emerged as an important regulator of their expression and biogenesis and, in turn, STAT3 signaling pathways are controlled by distinct miRNAs. We summarize the current knowledge on STAT3 mediated processing of individual miRNAs and contrariwise, the modulation of the STAT3 pathway by miRNAs in development and in pathophysiological conditions such as immune processes, infection, cancer, cardiovascular disease and pulmonary hypertension.
The spectrum of STAT functions in mammary gland development
The signal transducer and activator of transcription (STAT) family of transcription factors have a spectrum of functions in mammary gland development. In some cases these roles parallel those of STATs in other organ systems, while in other instances the function of individual STATs in the mammary gland is specific to this tissue. In the immune system, STAT6 is associated with differentiation of T helper cells, while in the mammary gland, it has a fundamental role in the commitment of luminal epithelial cells to the alveolar lineage. STAT5A is required for the production of luminal progenitor cells from mammary stem cells and is essential for the differentiation of milk producing alveolar cells during pregnancy. By contrast, the initiation of regression following weaning heralds a dramatic and specific activation of STAT3, reflecting its pivotal role in the regulation of cell death and tissue remodeling during mammary involution. Although it has been demonstrated that STAT1 is regulated during a mammary developmental cycle, it is not yet determined whether it has a specific, non-redundant function. Thus, the mammary gland constitutes an unusual example of an adult organ in which different STATs are sequentially activated to orchestrate the processes of functional differentiation, cell death and tissue remodeling.
Infection-induced IL-10 and JAK-STAT: A review of the molecular circuitry controlling immune hyperactivity in response to pathogenic microbes
Generation of effective immune responses against pathogenic microbes depends on a fine balance between pro- and anti-inflammatory responses. Interleukin-10 (IL-10) is essential in regulating this balance and has garnered renewed interest recently as a modulator of the response to infection at the JAK-STAT signaling axis of host responses. Here, we examine how IL-10 functions as the “master regulator” of immune responses through JAK-STAT, and provide a perspective from recent insights on bacterial, protozoan, and viral infection model systems. Pattern recognition and subsequent molecular events that drive activation of IL-10-associated JAK-STAT circuitry are reviewed and the implications for microbial pathogenesis are discussed.
Ubiquitin-mediated regulation of JAK-STAT signaling in embryonic stem cells
LIF activates several intracellular signaling pathways including JAK-STAT, PI3K/AKT and MAPK pathways. LIF is an important cytokine for maintenance of pluripotency and self-renewal of mouse ES cells. The JAK-STAT signal plays a key role in maintenance of the pluripotency of ESCs. Recent evidence shows that several post-translational modifications regulate activation or inhibition of intracellular signal transductions. The JAK-STAT signal is also modulated by several modifications including phosphorylation, acetylation and ubiquitination. In this review, we discuss regulation of the LIF-mediated-JAK-STAT signaling pathway that contributes to self-renewal of pluripotent ESCs.
Functions of the Drosophila JAK-STAT pathway: Lessons from stem cells
JAK-STAT signaling has been proposed to act in numerous stem cells in a variety of organisms. Here we provide an overview of its roles in three well characterized stem cell populations in Drosophila, in the intestine, lymph gland and testis. In flies, there is a single JAK and a single STAT, which has made the genetic dissection of pathway function considerably easier and facilitated the analysis of communication between stem cells, their niches and offspring. Studies in flies have revealed roles for this pathway as diverse as regulating bona fide intrinsic self-renewal, integrating response to environmental cues that control quiescence and promoting mitogenic responses to stress.
The JAK-STAT pathway and hematopoietic stem cells from the JAK2 V617F perspective
Janus kinases (JAKs) are non-receptor tyrosine kinases essential for activation of signaling mediated by cytokine receptors that lack catalytic activity, including receptors for erythropoietin, thrombopoietin, most interleukins and interferon. Upon hormone binding, JAKs phosphorylate tyrosine residues in the receptor cytoplasmic domains and in JAKs themselves leading to recruitment and activation of downstream signaling proteins such as signal transducer and activator of transcription (STAT). The JAK-STAT pathway is important for functional hematopoiesis and several activating mutations in JAK proteins have recently been described as underlying cause of blood disorders. One of the best studied examples is the JAK2 V617F mutant which is found in 95% of polycythemia vera patients and 50% of patients suffering from essential thrombocythemia and primary myelofibrosis. Much effort has been made to understand how the JAK2 V617F affects hematopoietic stem cell (HSC) renewal and lineage differentiation, since convincing evidence has been provided to support the notion that the mutation is acquired at the HSC level. We discuss several in vivo models that support contrary conclusions with respect to the advantage given to HSCs by JAK2 V617F. Moreover, we provide the current knowledge about STAT5 activation and its link to HSC expansion as well as amplification of the erythroid compartment. Evidence for both JAK2 V617F mutated HSCs exhibiting skewed differentiation potential and for amplification occurring after erythroid commitment has been provided, and we will discuss whether this evidence is relevant for the disease.
JAK2-STAT3 signaling: A novel function and a novel mechanism
The function of JAK-STAT signaling in the central nervous system has been widely studied in the context of neural cell development and differentiation and in neuronal and glial responses to CNS injury. A study published recently in Neuron by Nicolas et al. now demonstrates that the JAK2-STAT3 pathway also plays an important role in the regulation of synaptic transmission. By using a combination of biochemical, pharmacological and genetic approaches they show that induction of long-term depression (LTD), an activity-dependent rapid and long-lasting decrease in synaptic strength, via NMDA receptors depends on STAT3 activation by JAK2 that can be localized specifically to postsynaptic structures. Most interestingly, they find that induction of LTD requires STAT3 phosphorylation and dimerization but is independent of nuclear translocation and transcriptional activity of STAT3. Although it remains to be clarified how NMDA receptor-mediated postsynaptic processes lead to JAK2-STAT3 activation and how this in turn translates into persistent changes in synaptic strength, these results provide evidence for a novel mechanism of signal transduction.
PKM2, STAT3 and HIF-1α: The Warburg’s vicious circle
The M2 isoform of pyruvate kinase, highly expressed in tumor cells, is known to engage a feed forward loop with the glycolysis master transcription factor HIF-1α. Gao and co-authors recently showed that dimeric PKM2 localizes to the nucleus in highly proliferating cancer cells, where it regulates in vivo growth by acting as a protein kinase and directly activating STAT3. STAT3 is therefore a novel player of the PKM2/HIF-1α feedback loop, since HIF-induced PKM2 activates STAT3 that in turn induces HIF-1α expression. These findings have profound implications for understanding the complex connections between gene regulation, metabolism, survival and proliferation in cancer.
Signal transducer and activator of transcription-1 (STAT1) plays a role in the transduction of stress and cytokine responses, DNA damage, and activation of B and T cell immune responses. The ability of STAT1 to act as a pro- or anti-apoptotic signaling molecule depends upon the cellular environment and stimulus. Post-translational modifications provide the main method of control over the function of STAT1, however, recent data in the breast has shown that loss of STAT1 from both the tumor and the surrounding mammary epithelium greatly influence the development and response to treatment of breast cancers. Here, we discuss the recent findings of Chan et al. in Breast Cancer Research who described a new role for STAT1 in the development of estrogen receptor (ER)-positive and progesterone receptor (PR)-positive luminal breast cancers.
TNF-induced necroptosis is caused by the activation of RIPK1 and the subsequent production of reactive oxygen species in the mitochondria, although the intermittent molecules of the signaling pathway responsible for this ROS-mediated type of programmed necrosis have not yet been identified. A recent article by Shulga and Pastorino in the Journal of Cell Science identifies RIPK1 as the mediator of STAT3 Ser727 phosphorylation, which leads to the translocation of the latter into the mitochondria via its interaction with GRIM-19, a member of the mitochondrial complex I. Here we discuss how the findings of the Shulga and Pastorino study shed light onto the involvement of STAT3 in necroptosis.
Acetylation and sumoylation control STAT5 activation antagonistically
STAT5 proteins are activated by tyrosine phosphorylation, but recently further post-translation modifications such as serine/threonine phosphorylation, acetylation at lysine residues or sumoylation in close vicinity of the critical tyrosine residue have been reported. Here, we discuss new findings on impaired STAT5 signaling in lymphocytes isolated from a SUMO-specific protease knockout mouse (SENP1−/−), which results in sumoylated STAT5 and abolishes tyrosine phosphorylation. Van Nguyen and colleagues examined acetylation and sumoylation of STAT5 and found that both modifications act antagonistically to control tyrosine phosphorylation of STAT5.
What does it take to make a heart? Even in the fruit fly, in which matters of the heart don’t extend to either pop music or pulp fiction, making a heart requires big decisions and processes of surprising complexity.
Determinants of the extent and duration of STAT3 signaling
Multiple molecular mechanisms have been identified that are responsible for the deregulation of the quantitative aspects of JAK-STAT signaling. These mechanisms enhance the extent and the duration of, e.g., STAT3 activation and have profound consequences on the phenotypes of the affected cells. The fine tuning of STAT3 signaling is required to maintain its physiological functions and its deregulation is associated with diverse pathological states. Deregulation can be exerted by the gain of function of components mediating the activation of STAT3 or the loss of function of molecules involved in the deactivation steps of STAT3. Gain of function mutations can involve tyrosine kinases that phosphorylate STAT3, mutations in cytokine and growth factor receptors causing their ligand independent activation, mutations in STAT3 that enhance and prolong its tyrosine phosphorylation and the autocrine or paracrine production and secretion of cytokines, most notably IL-6. Diminished deactivation of phosphorylated STAT3 can be due to the reduced expression of tyrosine phosphatases, inactivating mutations in these enzymes, silencing or functional inactivation of SOCS molecules, post-transcriptional inhibition of PIAS3 expression or deletion mutations in the lymphocyte adaptor protein, LNK. STAT3 variants that exhibit autonomous transactivation potential have been detected in 40% of patients with T-cell large granular lymphocytic leukemia in clonally expanded CD8+ T cells. These patients also were preferentially affected by neutropenia and rheumatoid disorders and the results suggest that activating STAT3 mutations in T lymphocytes could be a cause of autoimmune diseases.
Is suppression of cyst growth in PKD enough to preserve renal function?: STAT6 inhibition is a novel promising target
The autosomal dominant form of polycystic kidney disease (ADPKD) is one of the most frequent monogenic disorders and the most frequent among inherited kidney disorders. In fact it has a prevalence in the population of about 1/1,000 individuals, therefore it does not even satisfy the definition for rare diseases. It is mainly characterized by the formation of multiple cysts filled with fluid that over time develop in number and size leading to the distraction of the structure and function of the kidneys and eventually leading to chronic kidney disease/end stage kidney disease (CKD/ESKD), usually between the 4th and 7th decade of life. There are two known forms of the autosomal dominant type of polycystic kidney disease, type 1 and type 2, caused by mutations in the PKD1 and PKD2 genes, located on chromosomes 16 and 4 respectively. The polycystin 1 protein, encoded by PKD1 and mutated in ~85% of patients, is a huge protein of 4,302 amino acids with multiple transmembrane domains, 200 residues intracytoplasmic part and a huge extracellular part with multiple Ig-like PKD repeats, which probably acts as a receptor to an unknown ligand. Polycystin 1 has been shown to interact with and participate in multiple signal transduction pathways, including the G-protein coupled receptor, cAMP pathway, Wnt, mTOR, MAPK/ERK, AP1 and JAK-STAT pathway, while its intracytoplasmic C-terminal domain has been shown to be cleaved and translocated to the nucleus where it plays a role in gene transcription, in concert with P100 and STAT6.1