PKCθ-regulated signalling in health and disease

Abstract

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.

Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells

“…The stable activation and membrane translocation of PKCθ requires Vav and phosphatidylinositol 3-kinase (PI3K) activation, triggered by the CD28 costimulatory signal, in addition to TCR/CD3 signal (47). PKCθ, a Ca ++ -independent, phospholipid-dependent PKC isoform, is a central player in the immunological synapse, responsible for the activation of AP-1 and NF–κB downstream of the TCR (48). In this study, we observed that activation of CD8+T-cells with PMA and ionomycin, which directly and potently stimulate the activity of PKCs (47), increases the levels of Notch1 and consequently its activity.…”

Baicalin Inhibits Human Cervical Cancer Cells by Suppressing Protein Kinase C/Signal Transducer and Activator of Transcription (PKC/STAT3) Signaling Pathway

“…By regulating targeted signaling pathways, PKCs are critical for maintaining the cellular biological processes such as cell proliferation, migration, differentiation, apoptosis and autophagy [ 4 , 16 , 17 ]. Expression alteration and dysregulation of PKCs are often associated with many human diseases including diabetes, autoimmune diseases, neurodegenerative diseases, and cardiovascular diseases [ 18 ]. Altered PCK expression levels have also been indicated to be associated with a range of human malignant cancers [ 19 ].…”

Unraveling the Effects of PPARβ/δ on Insulin Resistance and Cardiovascular Disease

“…For instance, in addition to TLR-dependent mechanisms, the presence of high plasma NEFAs increases FA flux in skeletal muscle cells, exceeding their oxidation capacity, which then leads to the accumulation of FA derivatives such as diacylglycerol (DAG) and ceramide [35] that ultimately attenuate insulin signaling. DAG activates protein kinase Cθ (PKCθ) in skeletal muscle [36], which in turn activates IKK-NF-B. Both kinases phosphorylate IRS-1 on serine residues, attenuating the insulin signaling pathway.…”