Protein kinase C (PKC) is a family of serine- and threonine-specific
protein kinases that can be activated by the
second messenger diacylglycerol. 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 factors
NF-kappaB and
AP-1, and may link the
T cell receptor (TCR) 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 (an
antigen presenting cell) 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 (central supramolecular activation cluster containing TCR) and pSMAC (peripheral supramolecular activation cluster containing
LFA-1 and
ICAM-1). 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 (STE20/SPS1-related, proline alanine-rich kinase) that activates the transcription factor
AP-1 (activating protein-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 factor NF-κB (nuclear factor-κB). Furthermore, PKC-θ plays a role in the activation of transcription factor NF-AT (nuclear factor of activated T cells). Thus, PKC-θ promotes inflammation in effector T cells. The kinase PKC-θ is crucial for function of
Th2 and
Th17. 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 (mediating autoimmune diseases) or by Th2 (causing allergies) 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 (
NF-κB,
NF-AT) 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 (catalytic sites among PKCs are very similar).
Allosteric inhibitors have to be more specific to concrete isoforms of PKC. s. == Interactions ==