Protein kinase C theta is an enzyme that in humans is encoded by the PRKCQgene. PKC-θ, a member of serine/threonine kinases, is mainly expressed in hematopoietic cells with high levels in platelets and T lymphocytes, where plays a role in signal transduction. Different subpopulations of T cells vary in their requirements of PKC-θ, therefore PKC-θ is considered as a potential target for inhibitors in the context of immunotherapy.
Function
is a family of serine- and threonine-specific protein kinases that can be activated by the second messengerdiacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent and phospholipid-dependent protein kinase. This kinase is important for T-cell activation. It is required for the activation of the transcription factorsNF-kappaB and AP-1, and may link the T cell receptor signaling complex to the activation of the transcription factors. PKC-θ also play a role in the apoptosis of lymphoid cells where it negatively influence and delay the aggregation of spectrin in an early phase of apoptosis.
The role of PKC-θ in T cells
PKC-θ has a role in the transduction of signals in T cells, the kinase influences their activation, survival and growth. PKC-θ is important in the signal pathway integrating signals from TCR and CD28 receptors. A junction between an APC and a T cell through their TCR and MHC receptors forms an immunological synapse. The active PKC-θ is localized in immunological synapse of T cells between the cSMAC and pSMAC. In regulatory T cells, PKC-θ is depleted from the region of immunological synapse, whereas in effector T cells, PKC-θ is present. As a result of co-stimulation by CD28 and TCR, PKC-θ is sumoylated by SUMO1 predominantly on the sites Lys325 and Lys506. Sumoylation is important because of forming of the immunological synapse. Subsequently, PKC-θ phosphorylates SPAK that activates the transcription factor AP-1. PKC-θ also initiates the assembly of proteins Carma-1, Bcl-10 and Malt-1 by phosphorylation of Carma-1. This complex of three proteins activates the transcription factorNF-κB. Furthermore, PKC-θ plays a role in the activation of transcription factor NF-AT. Thus, PKC-θ promotes inflammation in effector T cells. PKC-θ plays a role in the activation of ILC2 and contribute to the proliferation of Th2 cells. The kinase PKC-θ is crucial for function of Th2 and Th17. Moreover, PKC-θ can translocate itself to the nucleus and by phosphorylation of histones increases the accessibility of transcriptional-memory-responsive genes in memory T cells. PKC-θ plays a role in anti-tumor activity of NK cells. It was observed that in mice without PKC-θ, MHCI-deficient tumors are more often.
The possible application of its inhibitors
Properties of PKC-θ make PKC-θ a good target for therapy in order to reduce harmful inflammation mediated by Th17 or by Th2 without diminishing the ability of T cells to get rid of viral-infected cells. Inhibitors could be used in T-cell mediated adaptive immune responses. Inhibition of PKC-θ downregulates transcription factors and cause lower production of IL-2. It was observed that animals without PKC-θ are resistant to some autoimmune diseases. PKC-θ could be a target of inhibitors in the therapy of allergies. The problem is that inhibitors of PKC-θ targeting catalytic sites may have toxic effects because of low specificity. Allosteric inhibitors have to be more specific to concrete isoforms of PKC. s.
