Abstract
Protein kinase C-theta (PKCθ) is a key enzyme in T lymphocytes, where it plays an important role in signal transduction downstream of the activated T cell antigen receptor (TCR) and the CD28 costimulatory receptor. Interest in PKCθ as a potential drug target has increased following recent findings that PKCθ is essential for harmful inflammatory responses mediated by Th2 (allergies) and Th17 (autoimmunity) cells as well as for graft-versus-host disease (GvHD) and allograft rejection, but is dispensable for beneficial responses such as antiviral immunity and graft-versus-leukemia (GvL) response. TCR/CD28 engagement triggers the translocation of the cytosolic PKCθ to the plasma membrane (PM), where it localizes at the center of the immunological synapse (IS), which forms at the contact site between an antigen-specific T cell and antigen-presenting cells (APC). However, the molecular basis for this unique localization, and whether it is required for its proper function have remained unresolved issues until recently. Our recent study resolved these questions by demonstrating that the unique V3 (hinge) domain of PKCθ and, more specifically, a proline-rich motif within this domain, is essential and sufficient for its localization at the IS, where it is anchored to the cytoplasmic tail of CD28 via an indirect mechanism involving Lck protein tyrosine kinase (PTK) as an intermediate. Importantly, the association of PKCθ with CD28 is essential not only for IS localization, but also for PKCθ-mediated activation of downstream signaling pathways, including the transcription factors NF-κB and NF-AT, which are essential for productive T cell activation. Hence, interference with formation of the PKCθ-Lck-CD28 complex provides a promising basis for the design of novel, clinically useful allosteric PKCθ inhibitors. An additional recent study demonstrated that TCR triggering activates the germinal center kinase (GSK)-like kinase (GLK) and induces its association with the SLP-76 adaptor at the IS, where GLK phosphorylates the activation loop of PKCθ, converting it into an active enzyme. This recent progress, coupled with the need to study the biology of PKCθ in human T cells, is likely to facilitate the development of PKCθ-based therapeutic modalities for T cell-mediated diseases.
Highlights
Protein kinase C-theta (PKCθ) is a key regulator of signal transduction in activated T cells that is linked to multiple pathways downstream of the T cell antigen receptor (TCR; Isakov and Altman, 2002)
DAG remains bound to the cell membrane where, in addition to PKC, it activates effector molecules such as RasGRP, a guanine nucleotide exchange factor (GEF) for Ras (Lorenzo et al, 2000), while the hydrophilic IP3 diffuses through the cytosol and binds IP3-receptors, which function as ligand-gated Ca2+ channels in the endoplasmic reticulum (ER), thereby triggering the release of free Ca2+ ions into the cytoplasm (Takai et al, 1979; Khan et al, 1992; Bourguignon et al, 1994)
We demonstrated that PKCθ physically associated with the cytoplasmic tail of CD28 www.frontiersin.org following TCR/CD28 costimulation
Summary
Protein kinase C-theta (PKCθ) is a key regulator of signal transduction in activated T cells that is linked to multiple pathways downstream of the T cell antigen receptor (TCR; Isakov and Altman, 2002). Localization of PKCθ at the center of the IS is essential for activation of signaling pathways that promote T cell-dependent immune responses against distinct antigens and pathogens. The present manuscript provides background information on the molecules involved in this process and describes in more detail the studies that clarified a new mechanism by which PKCθ is being recruited to the center of the IS and is essential for the induction of PKCθ-dependent activation signals. DAG, together with inositol 1,4,5-trisphophate (IP3), are products of phospholipase C-mediated hydrolysis of the membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2; Berridge and Irvine, 1984; Nishizuka, 1984). These two second messengers transduce signals from a plethora of activated receptors: the hydrophobic www.frontiersin.org
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