Advanced‐stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor‐κB and nuclear factor of activated T cells pathways

Engagement of the B-cell antigen receptor (BCR) induces the activation of various transcription factors, including NFAT (nuclear factor of activated T-cells) and NF-κB (nuclear factor κB), which participate in long-term biological responses such as proliferation, survival and differentiation of B-lymphocytes. We addressed the biochemical basis of this process using the DT40 chicken B-cell lymphoma. We discovered that Bruton's tyrosine kinase (BTK) and phospholipase C-γ2 (PLC-γ2) are required to activate NFAT and NF-κB, and to produce the lipid second messenger diacylglycerol in response to BCR cross-linking. Therefore the functional integrity of the BTK/PLC-γ2/diacylglycerol signalling axis is crucial for BCR-directed activation of both transcription factors NFAT and NF-κB.

Download Full-text

The Essential Role of MEKK3 Signaling in Angiotensin II-induced Calcineurin/Nuclear Factor of Activated T-cells Activation

Journal of Biological Chemistry ◽

10.1074/jbc.m506493200 ◽

2005 ◽

Vol 280 (44) ◽

pp. 36737-36746 ◽

Cited By ~ 39

Author(s):

Shahrzad Abbasi ◽

Bing Su ◽

Rodney E. Kellems ◽

JianHua Yang ◽

Yang Xia

Keyword(s):

T Cells ◽

Angiotensin Ii ◽

Essential Role ◽

Nuclear Factor ◽

Activated T Cells

Download Full-text

Regulation of expression of the IL-2 and IL-5 genes and the role of proteins related to nuclear factor of activated T cells

Journal of Allergy and Clinical Immunology ◽

10.1016/s0091-6749(95)70197-4 ◽

1995 ◽

Vol 96 (6) ◽

pp. 1126-1135 ◽

Cited By ~ 12

Author(s):

L TSURUTA ◽

H LEE ◽

E MASUDA ◽

T YOKOTA ◽

N ARAI ◽

...

Keyword(s):

T Cells ◽

Nuclear Factor ◽

Regulation Of Expression ◽

Activated T Cells

Download Full-text

PKCθ-regulated signalling in health and disease

Biochemical Society Transactions ◽

10.1042/bst20140180 ◽

2014 ◽

Vol 42 (6) ◽

pp. 1484-1489 ◽

Cited By ~ 7

Author(s):

Pulak R. Nath ◽

Noah Isakov

Keyword(s):

Signal Transduction ◽

T Cells ◽

T Cell ◽

Immunological Synapse ◽

Cell Types ◽

Cell Receptor ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Activated T Cells ◽

Health And Disease

Protein kinase Cθ (PKCθ) is a key enzyme in T-lymphocytes where it plays an important role in signal transduction downstream of the activated T-cell receptor (TCR) and the CD28 co-stimulatory receptor. Antigenic stimulation of T-cells triggers PKCθ translocation to the centre of the immunological synapse (IS) at the contact site between antigen-specific T-cells and antigen-presenting cells (APCs). The IS-residing PKCθ phosphorylates and activates effector molecules that transduce signals into distinct subcellular compartments and activate the transcription factors, nuclear factor κB (NF-κB), nuclear factor of activated T-cells (NFAT) and activating protein 1 (AP-1), which are essential for the induction of T-cell-mediated responses. Besides its major biological role in T-cells, PKCθ is expressed in several additional cell types and is involved in a variety of distinct physiological and pathological phenomena. For example, PKCθ is expressed at high levels in platelets where it regulates signal transduction from distinct surface receptors, and is required for optimal platelet activation and aggregation, as well as haemostasis. In addition, PKCθ is involved in physiological processes regulating insulin resistance and susceptibility to obesity, and is expressed at high levels in gastrointestinal stromal tumours (GISTs), although the functional importance of PKCθ in these processes and cell types is not fully clear. The present article briefly reviews selected topics relevant to the biological roles of PKCθ in health and disease.

Download Full-text

Interleukin-6 Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclastogenesis by Diverting Cells into the Macrophage Lineage: Key Role of Serine727 Phosphorylation of Signal Transducer and Activator of Transcription 3

Endocrinology ◽

10.1210/en.2007-1719 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3688-3697 ◽

Cited By ~ 89

Author(s):

Laurence Duplomb ◽

Marc Baud’huin ◽

Céline Charrier ◽

Martine Berreur ◽

Valérie Trichet ◽

...

Keyword(s):

Osteoclast Differentiation ◽

Nuclear Factor Κb ◽

Mouse Bone Marrow ◽

Nuclear Factor ◽

Signal Transducer ◽

Blood Monocytes ◽

Receptor Activator ◽

Few Data ◽

Macrophage Lineage

Osteoclasts are bone-resorptive cells that differentiate from hematopoietic precursors upon receptor activator of nuclear factor κB ligand (RANKL) activation. Previous studies demonstrated that IL-6 indirectly stimulates osteoclastogenesis through the production of RANKL by osteoblasts. However, few data described the direct effect of IL-6 on osteoclasts. To investigate this effect, we used several models: murine RAW264.7 cells, mouse bone marrow, and human blood monocytes. In the three models used, the addition of IL-6 inhibited RANKL-induced osteoclastogenesis. Furthermore, IL-6 decreased the expression of osteoclast markers and up-modulated macrophage markers. To elucidate this inhibition, signal transducer and activator of transcription (STAT) 3, the main signaling molecule activated by IL-6, was analyzed. Addition of two STAT3 inhibitors completely abolished RANKL-induced osteoclastogenesis, revealing a key role of STAT3. We demonstrated that a basal level of phosphorylated-STAT3 on Serine727 associated with an absence of phosphorylation on Tyrosine705 is essential for osteoclastogenesis. Furthermore, a decrease of Serine727 phosphorylation led to an inhibition of osteoclast differentiation, whereas an increase of Tyrosine705 phosphorylation upon IL-6 stimulation led to the formation of macrophages instead of osteoclasts. In conclusion, we showed for the first time that IL-6 inhibits RANKL-induced osteoclastogenesis by diverting cells into the macrophage lineage, and demonstrated the functional role of activated-STAT3 and its form of phosphorylation in the control of osteoclastogenesis.

Download Full-text