Pp2a STAT

Host antiviral immunity suffers strong pressure from rapidly evolving viruses. Identifying host antiviral immune mechanisms has profound implications for developing antiviral strategies. Here, we uncover an essential role for the tumor suppressor Ras-association domain family (RASSF) in Drosophila antiviral response. Loss of dRassf in fat body leads to increased vulnerability to viral infection and impaired Imd pathway activation accompanied by detrimental JAK/STAT signaling overactivation. Mechanistically, dRASSF protects TAK1, a key kinase of Imd pathway, from inhibition by the STRIPAK PP2A phosphatase complex...

Influenza A viruses (IAVs) are respiratory pathogens that are able to hijack multiple cellular mechanisms to drive their replication. Consequently, several viral and cellular proteins undergo posttranslational modifications such as dynamic phosphorylation/dephosphorylation. In eukaryotic cells, dephosphorylation is mainly catalyzed by protein phosphatase 2A (PP2A). While the function of kinases in IAV infection is quite well studied, only little is known about the role of PP2A in IAV replication. Here, we show, by using knockdown and inhibition approaches of the catalytic subunit PP2Ac, that this phosphatase is important for efficient replication of several IAV subtypes...

Innate immunity is the essential way for host cells to resist viral infection through the production of IFNs and proinflammatory cytokines. IRF3 plays a critical role in innate immune response to viral infection. However, the role of IRF1 in innate immunity remains largely unknown. In this study, we found that IRF1 is upregulated through IFN/JAK/STAT signaling pathway upon viral infection. Silencing IRF1 attenuates innate immune response to viral infection. IRF1 interacts with IFR3 and augments the activation of IRF3 through blocking the interaction between IRF3 and PP2A...

Type I interferon (IFN-I) production is efficiently induced to ensure a potent innate immune response to viral infection. How this response can be enhanced, however, remains to be explored. Here, we identify a new cytoplasmic long non-coding RNA (lncRNA), lncLrrc55-AS, that drives a positive feedback loop to promote interferon regulatory factor 3 (IRF3) signaling and IFN-I production. We show that lncLrrc55-AS is virus-induced in multiple cell types via the IFN-JAK-STAT pathway. LncLrrc55-AS-deficient mice display a weakened antiviral immune response and are more susceptible to viral challenge...

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations enable constitutive active downstream signaling of PI3K/AKT, KRAS/ERK and JAK/STAT pathways, and promote tumor progression by inducing uncontrolled proliferation, evasion of apoptosis and migration of non-small cell lung cancer (NSCLC). In addition, such EGFR mutations increase the susceptibility of patients with NSCLC to tyrosine kinase inhibitor (TKI) therapy, but treated patients will invariably relapse with resistant disease...

Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...

Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...

Interferon regulatory transcription factor 1 (IRF-1) regulates downstream signals of tumor necrosis factor α (TNF-α). The activity of IRF-1 is mediated by Jak/Stat signaling pathway. In this study, we found that PPAR γ coactivator-1α (PGC-1α) is able to suppress the induction of IRF-1. Treatment with TNF-α in MC3T3 cells leads to a sustainable increase in the expression of IRF-1 and its target gene cyclooxygenase 2 (COX-2). In contrast, TNF-α treatment led to a sustainable reduction in expression of PGC-1α...

Autophagy is one of the major immune mechanisms engaged to clear intracellular infectious agents. However, several pathogens have evolved strategies to evade autophagy. Here, we demonstrated that Mycobacteria, Shigella, and Listeria but not Klebsiella, Staphylococcus, and Escherichia inhibit IFNG-induced autophagy in macrophages by evoking selective and robust activation of WNT and SHH pathways via MTOR. Utilization of gain- or loss-of-function analyses as well as mir155-null macrophages emphasized the role of MTOR-responsive epigenetic modifications in the induction of Mir155 and Mir31...

Mammalian cells have developed several mechanisms to sense viruses and initiate adequate responses such as production of interferons. Interferons activate the antiviral response through the Jak-STAT signalling pathway. To establish a chronic infection, viruses need to counteract this barrier of defence. The hepatitis C and hepatitis B viruses are known to up-regulate the expression of protein phosphatase 2A (PP2A). In this study, we show that PP2Ac associates with Jak1/Tyk2/STAT1 and reduces Jak1/Tyk2/STAT1 phosphorylation resulting in an impairment of the IFNα-induced HCV antiviral response...

Histone acetylation via CBP/p300 coordinates the expression of proinflammatory cytokines in the activation phase of inflammation, particularly through mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB), and signal transducers and activators of transcription (STAT) pathways. In contrast, histone deacetylases (HDACs) and protein phosphatases are mainly involved in the attenuation phase of inflammation. The role of reactive oxygen species (ROS) in the inflammatory cascade is much more important than expected...

Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-gamma and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-gamma in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia...

Alpha4 phosphoprotein in the mTOR pathway is a prolactin (PRL)-downregulated gene product that interacts with the catalytic subunit of serine/threonine protein phosphatase 2A (PP2Ac) in rat Nb2 lymphoma cells. Transient overexpression of alpha4 in COS-1 cells inhibited PRL-inducible interferon-regulatory-1 (IRF-1) promoter activity, but the mechanism underlying this inhibition was not known. The present study showed a stable alpha4-PP2Ac complex that was not dissociated by rapamycin in COS-1 cells. Transient overexpression of alpha4 in COS-1 cells had no effect on endogenous PP2Ac protein levels but significantly increased PP2Ac carboxymethylation and PP2A activity as compared to controls...

Interferon-alpha (IFN-alpha)-2b is known to have antiproliferative effects on hematological malignant cells, especially chronic myelogenous leukaemia (CML). However, it can induce cytogenetical remissions in a very small percentage of the patients. Also during interferon therapy, resistance can emerge in the CML clones. K562 is an in vitro model cell line transformed from a Ph positive CML patient. It can be induced to differentiate to granulocytic and/or monocytic lineages with certain molecules. IFN-alpha-2b generally exerts its effects on CML cells by Janus family kinases (Jak/Stat) pathway, mostly through tyrosine kinase system...

Accumulating evidence indicates that expression of anaplastic lymphoma kinase (ALK), typically due to t(2;5) translocation, defines a distinct type of T/null-cell lymphoma (TCL). The resulting nucleophosmin (NPM) /ALK chimeric kinase is constitutively active and oncogenic. Downstream effector molecules triggered by NPM/ALK remain, however, largely unidentified. Here we report that NPM/ALK induces continuous activation of STAT3. STAT3 displayed tyrosine phosphorylation and DNA binding in all (four of four) ALK+ TCL cell lines tested...

Signal transducers and activators of transcription (STATs) are rapidly phosphorylated on tyrosine residues in response to cytokine and growth factor stimulation of cell surface receptors. STATs hereafter are translocated to the nucleus where they act as transcription factors. Recent reports suggest that serine phosphorylation of STATs also is involved in the regulation of STAT-mediated gene transcription. Here, we studied the role of serine/threonine phosphatases in STAT3 signaling in human antigen-specific CD4(+) T cell lines and cutaneous T cell lymphoma lines, expressing a constitutively activated STAT3...

Ligand binding to the angiotensin II (Ang II) AT1 receptor on vascular smooth muscle cells (VSMCs) activates the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. We have shown previously that the JAK2 tyrosine kinase and the Src family p59 Fyn tyrosine kinase are required for Ang II-induced STAT1 tyrosine phosphorylation in VSMCs. The mitogen-activated protein kinase phosphatase, MKP-1, is required for STAT1 tyrosine dephosphorylation. In the present study, using specific enzyme inhibitors and antisense oligonucleotides, we show that Ang II-induced tyrosine phosphorylation and nuclear translocation of STAT3 in VSMCs is mediated by p60 c-Src, whereas tyrosine dephosphorylation is mediated by calcineurin...

Vanadate is an insulinomimetic agent that has potent inhibitory effect on tyrosine phosphatases. We have recently demonstrated that low concentration of vanadate stimulates phosphotyrosine-dependent signal transduction pathways leading to gene expression and DNA synthesis in mesangial cells. To further examine the mechanisms by which vanadate activates mesangial cell, we studied its effect on signal transducer and activators of transcription (STAT). Incubation of lysates from vanadate-stimulated mesangial cells with a specific high affinity sis-inducible DNA element (SIE) resulted in the formation of protein-DNA complex...

Interleukin-11 is a stromal derived cytokine important in hematopoiesis. IL-11 intracellular signaling travels through cytoplasmic kinases of the Janus family. How JAKs accomplish the multiple functions of IL-11 has not been determined and until recently only a few associated downstream proteins have been identified. We present evidence here for the IL-11 induced association of PP2A, P13K, and Yes to JAK2. Reciprocal immunoprecipitations support the mutual involvement of these signaling components in IL-11 mediated signal transduction...