Signal transduction by the atopy-associated human thymic stromal lymphopoietin (TSLP) receptor depends on Janus kinase function

2010 ◽  
Vol 391 (2/3) ◽  
Author(s):  
Andreas Wohlmann ◽  
Katrin Sebastian ◽  
Andreas Borowski ◽  
Sebastian Krause ◽  
Karlheinz Friedrich
Keyword(s):  
Tyrosine Kinases ◽  
Inflammatory Responses ◽  
Thymic Stromal Lymphopoietin ◽  
Janus Kinase ◽  
Type I ◽  
Atopic Diseases ◽  
Receptor System ◽  
Α Subunit ◽  
Signal Transducers ◽  
Receptor Chain

Abstract Thymic stromal lymphopoietin (TSLP) is an interleukin-(IL)-7-like cytokine with emerging pathological importance for the development of atopic diseases such as allergic asthma bronchiale. The TSLP receptor (TSLPR), a heterodimeric type I cytokine receptor, shares the IL-7R α-subunit with the IL-7 receptor system. The specific TSLPR α-chain shows similarities with the γc receptor chain, but has some unusual features within the receptor family in both its ligand-binding and cytoplasmic domain. The murine TSLPR signals via the signal transducers and activators of transcription STAT5 and STAT3, but is unique among cytokine receptors in that it activates STATs without the involvement of Janus (JAK) tyrosine kinases, but instead utilizes the Src type kinase Tec. Here, we show by Western blotting and reporter gene experiments in combination with the application of a specific JAK inhibitor that the human TSLP receptor, in contrast, requires the function of JAK1 and JAK2 for STAT activation. Moreover, we demonstrate that the human TSLPR mediates gene regulation not only through STAT5 and STAT3 but has also the potential to mediate transcription via STAT1. Our work should help to understand more thoroughly how TSLP triggers inflammatory responses in the course of atopic diseases.

scholarly journals TYK2 activity promotes ligand-induced IFNAR1 proteolysis

2006 ◽  
Vol 397 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Zrinka Marijanovic ◽  
Josiane Ragimbeau ◽  
K. G. Suresh Kumar ◽  
Serge Y. Fuchs ◽  
Sandra Pellegrini
Keyword(s):  
Tyrosine Kinases ◽  
Janus Kinase ◽  
Serine Phosphorylation ◽  
Interferon Α ◽  
Type I ◽  
Major Mechanism ◽  
Catalytic Activation ◽  
Janus Kinase 1 ◽  
Lysosomal Proteolysis ◽  
Catalytic Role

The type I IFNR (interferon receptor) is a heterodimer composed of two transmembrane chains, IFNAR1 (interferon-α receptor 1 subunit) and IFNAR2, which are associated with the tyrosine kinases Tyk2 and Jak1 (Janus kinase 1) respectively. Ligand-induced down-regulation of the type I IFNR is a major mechanism of negative regulation of cellular signalling and involves the internalization and lysosomal degradation of IFNAR1. IFNα promotes the phosphorylation of IFNAR1 on Ser535, followed by recruitment of the E3 ubiquitin ligase, β-TrCP2 (β-transducin repeats-containing protein 2), ubiquitination of IFNAR1 and proteolysis. The non-catalytic role of Tyk2 in sustaining the steady-state IFNAR1 level at the plasma membrane is well documented; however, little is known about the function of Tyk2 in the steps that precede and succeed serine phosphorylation and ubiquitination of IFNAR1 in response to ligand binding. In the present study, we show that catalytic activation of Tyk2 is not essential for IFNAR1 internalization, but is required for ligand-induced IFNAR1 serine phosphorylation, ubiquitination and efficient lysosomal proteolysis.

Janus kinases in cytokine signalling

1996 ◽  
Vol 351 (1336) ◽  
pp. 159-166 ◽  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Janus Kinase ◽  
Cytokine Receptor ◽  
Protein Tyrosine Kinases ◽  
Signalling Pathways ◽  
Functional Responses ◽  
Janus Kinases ◽  
Signal Transducers ◽  
Catalytic Domains

Hematopoiesis is largely regulated by the binding of cytokines to receptors of the cytokine receptor superfamily. Although lacking catalytic domains, members of the cytokine receptor superfamily mediate ligand dependent activation of tyrosine phosphorylation which is critical for all receptor functions. Recent studies have demonstrated that this is mediated through the association and activation of members of the Janus kinase (Jak) family of protein tyrosine kinases. The activated Jaks phosphorylate the receptors, creating docking sites for SH2 containing signalling proteins which are tyrosine phosphorylated following their association with the receptor complex. Among the substrates of tyrosine phosphorylation are members of the signal transducers and activators of transcription family of proteins (Stats). Various cytokines induce the tyrosine phosphorylation and activation of one or more of the six family members. The pattern of Stat activation provides a level of cytokine individuality that is not observed in the activation of other signalling pathways. Although not required for mitogenic responses, it is speculated that the Stats may mediate many of the cytokine specific functional responses of hematopoietic cells.

scholarly journals Direct Interaction of Jak1 and v-Abl Is Required for v-Abl-Induced Activation of STATs and Proliferation

1998 ◽  
Vol 18 (11) ◽  
pp. 6795-6804 ◽  
Author(s):  
Nika N. Danial ◽  
Julie A. Losman ◽  
Tianhong Lu ◽  
Natalie Yip ◽  
Kartik Krishnan ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Leukemia Virus ◽  
Direct Interaction ◽  
Janus Kinase ◽  
Signaling Proteins ◽  
Interaction Domain ◽  
Signal Transducers ◽  
Stat Proteins ◽  
Immature B Cells

ABSTRACT In Abelson murine leukemia virus (A-MuLV)-transformed cells, members of the Janus kinase (Jak) family of non-receptor tyrosine kinases and the signal transducers and activators of transcription (STAT) family of signaling proteins are constitutively activated. In these cells, the v-Abl oncoprotein and the Jak proteins physically associate. To define the molecular mechanism of constitutive Jak-STAT signaling in these cells, the functional significance of the v-Abl–Jak association was examined. Mapping the Jak1 interaction domain in v-Abl demonstrates that amino acids 858 to 1080 within the carboxyl-terminal region of v-Abl bind Jak1 through a direct interaction. A mutant of v-Abl lacking this region exhibits a significant defect in Jak1 binding in vivo, fails to activate Jak1 and STAT proteins, and does not support either the proliferation or the survival of BAF/3 cells in the absence of cytokine. Cells expressing this v-Abl mutant show extended latency and decreased frequency in generating tumors in nude mice. In addition, inducible expression of a kinase-inactive mutant of Jak1 protein inhibits the ability of v-Abl to activate STATs and to induce cytokine-independent proliferation, indicating that an active Jak1 is required for these v-Abl-induced signaling pathways in vivo. We propose that Jak1 is a mediator of v-Abl-induced STAT activation and v-Abl induced proliferation in BAF/3 cells, and may be important for efficient transformation of immature B cells by the v-abloncogene.

scholarly journals JAK inhibitors: a potential treatment for JDM in the context of the role of interferon-driven pathology

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Meredyth G. Ll Wilkinson ◽  
Claire T. Deakin ◽  
Charalampia Papadopoulou ◽  
Despina Eleftheriou ◽  
Lucy R. Wedderburn
Keyword(s):  
Janus Kinase ◽  
Type I ◽  
Jak Inhibitors ◽  
Skin Changes ◽  
Signal Transducers ◽  
Systemic Involvement ◽  
Receptor Complexes ◽  
Resistant Disease ◽  
Multiple Components

AbstractJuvenile Idiopathic Inflammatory Myopathies (IIM) are a group of rare diseases that are heterogeneous in terms of pathology that can include proximal muscle weakness, associated skin changes and systemic involvement. Despite options for treatment, many patients continue to suffer resistant disease and lasting side-effects. Advances in the understanding of the immunopathology and genetics underlying IIM may specify new therapeutic targets, particularly where conventional treatment has not achieved a clinical response. An upregulated type I interferon signature is strongly associated with disease and could be a prime target for developing more specific therapeutics. There are multiple components of the IFN pathway that could be targeted for blockade therapy.Downstream of the cytokine receptor complexes are the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, which consists of JAK1–3, TYK2, and STAT1–6. Therapeutic inhibitors have been developed to target components of this pathway. Promising results have been observed in case studies reporting the use of the JAK inhibitors, Baricitinib, Tofacitinib and Ruxolitinib in the treatment of refractory Juvenile Dermatomyositis (JDM). There is still the question of safety and efficacy for the use of JAK inhibitors in JDM that need to be addressed by clinical trials. Here we review the future for the use of JAK inhibitors as a treatment for JDM.

scholarly journals STAT1 signaling modulates HIV-1–induced inflammatory responses and leukocyte transmigration across the blood-brain barrier

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2062-2072 ◽  
Author(s):  
Anathbandhu Chaudhuri ◽  
Bo Yang ◽  
Howard E. Gendelman ◽  
Yuri Persidsky ◽  
Georgette D. Kanmogne
Keyword(s):  
Blood Brain Barrier ◽  
Inflammatory Responses ◽  
Janus Kinase ◽  
Brain Barrier ◽  
Signal Transducers ◽  
Monocyte Migration ◽  
Blood Brain ◽  
Integral Role ◽  
Enhanced Expression ◽  
Hiv 1

The relationship among neuroinflammation, blood-brain barrier (BBB) dysfunction, and progressive HIV-1 infection as they affect the onset and development of neuroAIDS is incompletely understood. One possible link is signal transducers and activators of transcription (STATs) pathways. These respond to proinflammatory and regulatory factors and could affect neuroinflammatory responses induced from infected cells and disease-affected brain tissue. Our previous works demonstrated that HIV-1 activates pro-inflammatory and interferon-alpha–inducible genes in human brain microvascular endothelial cells (HBMECs) and that these genes are linked to the Janus kinase (JAK)/STAT pathway. We now demonstrate that HIV-1 activates STAT1, induces IL-6 expression, and diminishes expression of claudin-5, ZO-1, and ZO-2 in HBMECs. The STAT1 inhibitor, fludarabine, blocked HIV-1–induced IL-6, diminished HIV-1–induced claudin-5 and ZO-1 down-regulation, and blocked HIV-1– and IL-6–induced monocyte migration across a BBB model. Enhanced expression and activation of STAT1 and decreased claudin-5 were observed in microvessels from autopsied brains of patients with HIV-1–associated dementia. These data support the notion that STAT1 plays an integral role in HIV-1–induced BBB damage and is relevant to viral neuropathogenesis. Inhibition of STAT1 activation could provide a unique therapeutic strategy to attenuate HIV-1–induced BBB compromise and as such improve clinical outcomes.

The mechanism of IL-5 signal transduction

1998 ◽  
Vol 275 (3) ◽  
pp. C623-C633 ◽  
Author(s):  
Tetsuya Adachi ◽  
Rafeul Alam
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinases ◽  
Cell Function ◽  
Tyrosine Phosphatase ◽  
Receptor System ◽  
Α Subunit ◽  
Transduction Mechanism ◽  
Gm Csf ◽  
Signal Transduction Mechanism ◽  
Eosinophil Degranulation

Cytokines are important regulators of hematopoiesis. They exert their actions by binding to specific receptors on the cell surface. Interleukin-5 (IL-5) is a critical cytokine that regulates the growth, activation, and survival of eosinophils. Because eosinophils play a seminal role in the pathogenesis of asthma and allergic diseases, an understanding of the signal transduction mechanism of IL-5 is of paramount importance. The IL-5 receptor is a heterodimer of α- and β-subunits. The α-subunit is specific, whereas the β-subunit is common to IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) receptors and is crucial for signal transduction. It has been shown that there are two major signaling pathways of IL-5 in eosinophils. IL-5 activates Lyn, Syk, and JAK2 and propagates signals through the Ras-MAPK and JAK-STAT pathways. Studies suggest that Lyn, Syk, and JAK2 tyrosine kinases and SHP-2 tyrosine phosphatase are important for eosinophil survival. In contrast to their survival-promoting activity, Lyn and JAK2 appear to have no role in eosinophil degranulation or expression of surface adhesion molecules. Raf-1 kinase, on the other hand, is critical for eosinophil degranulation and adhesion molecule expression. Btk is involved in IL-5 stimulation of B cell function. However, it does not appear to be important for eosinophil function. Thus a clear segregation of signaling molecules based on their functional importance is emerging. This review describes the signal transduction mechanism of the IL-3/GM-CSF/IL-5 receptor system and compares and contrasts IL-5 signaling between eosinophils and B cells.

scholarly journals Selective Janus kinase inhibition preserves interferon-λ–mediated antiviral responses

2021 ◽  
Vol 6 (59) ◽  
pp. eabd5318
Author(s):  
Daniel Schnepf ◽  
Stefania Crotta ◽  
Thiprampai Thamamongood ◽  
Megan Stanifer ◽  
Laura Polcik ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Influenza Virus Infection ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Type I ◽  
Antiviral Responses ◽  
Tyrosine Kinase 2 ◽  
Efficient Type ◽  
Janus Kinase Inhibition

Inflammatory diseases are frequently treated with Janus kinase (JAK) inhibitors to diminish cytokine signaling. These treatments can lead to inadvertent immune suppression and may increase the risk of viral infection. Tyrosine kinase 2 (TYK2) is a JAK family member required for efficient type I interferon (IFN-α/β) signaling. We report here that selective TYK2 inhibition preferentially blocked potentially detrimental type I IFN signaling, whereas IFN-λ–mediated responses were largely preserved. In contrast, the clinically used JAK1/2 inhibitor baricitinib was equally potent in blocking IFN-α/β– or IFN-λ–driven responses. Mechanistically, we showed that epithelial cells did not require TYK2 for IFN-λ–mediated signaling or antiviral protection. TYK2 deficiency diminished IFN-α–induced protection against lethal influenza virus infection in mice but did not impair IFN-λ–mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors used in place of broadly acting JAK1/2 inhibitors may represent a superior treatment option for type I interferonopathies to counteract inflammatory responses while preserving antiviral protection mediated by IFN-λ.

scholarly journals Janus Kinase Signaling: Oncogenic Criminal of Lymphoid Cancers

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5147
Author(s):  
Boheng Li ◽  
Qin Wan ◽  
Zhubo Li ◽  
Wee-Joo Chng
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Janus Kinase ◽  
Signal Transducers ◽  
Lymphoid Malignancies ◽  
Stat Pathway

The Janus kinase (JAK) family are known to respond to extracellular cytokine stimuli and to phosphorylate and activate signal transducers and activators of transcription (STAT), thereby modulating gene expression profiles. Recent studies have highlighted JAK abnormality in inducing over-activation of the JAK/STAT pathway, and that the cytoplasmic JAK tyrosine kinases may also have a nuclear role. A couple of anti-JAK therapeutics have been developed, which effectively harness lymphoid cancer cells. Here we discuss mutations and fusions leading to JAK deregulations, how upstream nodes drive JAK expression, how classical JAK/STAT pathways are represented in lymphoid malignancies and the noncanonical and nuclear role of JAKs. We also summarize JAK inhibition therapeutics applied alone or synergized with other drugs in treating lymphoid malignancies.

scholarly journals Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

2019 ◽  
Vol 4 (42) ◽  
pp. eaav7501 ◽  
Author(s):  
Christopher J. A. Duncan ◽  
Benjamin J. Thompson ◽  
Rui Chen ◽  
Gillian I. Rice ◽  
Florian Gothe ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Type I ◽  
Interferon Signaling ◽  
Direct Role ◽  
Signal Transducers ◽  
Whole Exome ◽  
Specific Protease

Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase–signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

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